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Prostate Cancer Progress Report: Addressing the Recommendations of the PRG Group

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Table of Contents

Transmittal Letter ..................................................................................................................................... iii

Acknowledgments...................................................................................................................................... iv

Executive Summary .................................................................................................................................... v

Chapter 1 Prostate Cancer Research: 1998–2002..............................................................................1-1

The Prostate Cancer Burden .............................................................................................................1-1

The Prostate Cancer Progress Review Group ..................................................................................1-3

Five Years of Progress .......................................................................................................................1-3

Investment in Prostate Cancer Research ..........................................................................................1-4

Research Results Obtained and Applied ..........................................................................................1-13

Evolution of the PRG Process..........................................................................................................1-16

Looking to the Future .......................................................................................................................1-17

Chapter 2 Initiatives ...............................................................................................................................2-1

NCI’s Investment and Response .......................................................................................................2-2

NCI’s Future Investments in Resource and Capacity Building ........................................................2-13

Chapter 3 Prostate Cancer Biology ......................................................................................................3-1

NCI’s Investment and Response .......................................................................................................3-2

Ongoing NCI Research: Recent Progress in Prostate Cancer Biology .............................................3-9

Continuing Needs and Evolution.......................................................................................................3-12

NCI’s Future Investment in Prostate Cancer Biology .....................................................................3-12

NCI-Supported Research Referenced in Chapter 3 ........................................................................3-14

Chapter 4 Etiology and Prevention of Prostate Cancer .....................................................................4-1

NCI’s Investment and Response .......................................................................................................4-2

Ongoing NCI Research: Recent Progress in Prostate Cancer Etiology and Prevention ...................4-9

Continuing Needs and Evolution....................................................................................................... 4-11

NCI’s Future Investment in Prostate Cancer Etiology and Prevention ...........................................4-12

NCI-Supported Research Referenced in Chapter 4 ........................................................................4-13

Chapter 5 Prostate Cancer Early Detection, Diagnosis, and Prognosis ..........................................5-1

NCI’s Investment and Response .......................................................................................................5-2

Ongoing NCI Research: Recent Progress in Prostate Cancer Early Detection,

Diagnosis, and Prognosis....................................................................................................................5-8

Continuing Needs and Evolution.......................................................................................................5-10

NCI’s Future Investment in Prostate Cancer Early Detection, Diagnosis, and Prognosis ..............5-10

NCI-Supported Research Referenced in Chapter 5 ........................................................................ 5-11
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Prostate Cancer Progress Report: Addressing the Recommendations of the PRG Group

Chapter 6 Scientific Model Systems for Prostate Cancer ...................................................................6-1

NCI’s Investment and Response .......................................................................................................6-2

Ongoing NCI Research: Recent Progress in Scientific Model Systems ............................................6-5

Continuing Needs and Evolution.........................................................................................................6-7

NCI’s Future Investment in Scientific Model Systems ......................................................................6-7

NCI-Supported Research Referenced in Chapter 6 ..........................................................................6-8

Chapter 7 Prostate Cancer Treatment ...................................................................................................7-1

NCI’s Investment and Response .......................................................................................................7-2

Ongoing NCI Research: Recent Progress in Prostate Cancer Treatment ......................................7-12

Continuing Needs and Evolution.......................................................................................................7-15

NCI’s Future Investment in Prostate Cancer Treatment .................................................................7-16

NCI-Supported Research Referenced in Chapter 7 ........................................................................7-16

Chapter 8 Prostate Cancer Control, Survivorship, and Outcomes ....................................................8-1

NCI’s Investment and Response .......................................................................................................8-2

Ongoing NCI Research: Recent Progress in Prostate Cancer Control,

Survivorship, and Outcomes...............................................................................................................8-7

Continuing Needs and Evolution.........................................................................................................8-8

NCI’s Future Investment in Prostate Cancer Control, Survivorship, and Outcomes .........................8-9

NCI-Supported Research Referenced in Chapter 8 ........................................................................8-10

Appendix A - Prostate Cancer Working Group Membership Roster ..................................................... A-1

Appendix B - NCI-Supported Research Projects Relevant to Prostate Cancer That Were Active

in 2002 ...................................................................................................................................................... B-1

Appendix C - U.S. Patents Resulting from NCI-Funded Research on Prostate Cancer: 1998–2002 .... C-1
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Prostate Cancer Progress Report: Addressing the Recommendations of the PRG Group

NATIONAL CANCER INSTITUTE

Transmittal Letter From the Working Group

It is our pleasure to submit the Prostate Cancer Progress Report to the Director of the National

Cancer Institute (NCI). It constitutes the first assessment of progress in addressing the research priorities

identified in the 1998 report of the Prostate Cancer Progress Review Group (PRG), entitled Defeating

Prostate Cancer: Crucial Directions for Research. This progress report characterizes trends in the

NCI prostate cancer research portfolio from 1998 to 2002. It presents trends in measures of progress as

broad as overall NCI funding levels and as specific as numbers of projects relevant to particular research

priorities. In addition to a retrospective view of accomplishments since 1998, the progress report looks

forward by providing a bridge to the future NCI efforts described in the NIH Prostate Cancer Research

Plan FY 2003–FY 2008.

This report is designed to assist the Institute in efforts to accelerate progress against prostate cancer

by assessing past research investments and identifying future research needs. It is a unique reference

documenting NCI-supported prostate cancer research and the resources available to the prostate cancer

research community. We believe that this report will enable readers to better understand the scope of the

Institute’s prostate cancer research portfolio and identify research and information resources. It will also

help to guide implementation of the NCI plans described in the NIH Prostate Cancer Research Plan

FY 2003–FY 2008.

Respectfully,

James Corrigan James W. Jacobson Cherie Nichols

William D. Figg, Sr. Richard Kaplan Howard Parnes

Richard B. Hayes Alison Martin Arnold L. Potosky

Andrew Hruszkewycz Suresh Mohla James V. Tricoli
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Prostate Cancer Progress Report: Addressing the Recommendations of the PRG Group

Acknowledgments

The development of this progress report by the NCI Prostate Cancer Working Group would not have

been possible without significant contributions from many other individuals. We would especially like to

recognize the work of the following individuals and organizations.

X Kevin Callahan, Margaret Ames, and other staff of the NCI Office of Science Planning and

Assessment (OSPA) made contributions in a wide variety of areas, including expertise on the

PRGs, knowledge of NCI initiatives and programs, development of measures of progress, design

of the process for mapping NCI-funded projects to PRG priorities, participation in working group

meetings, and review of draft documents.

X Other NCI staff contributed essential data. Brenda Edwards and Lynn Ries of the Surveillance

Epidemiology and End Results (SEER) program in the Division of Cancer Control and Population

Sciences (DCCPS) provided expertise and data on trends in disease statistics. Lakshmi Grama of

the Office of Cancer Information Products and Systems (CIPS) contributed expertise and data on

clinical trials. Staff of the Financial Management Branch (FMB) provided information on prostate

cancer research funding. Staff in the Division of Extramural Activities (DEA), the Center for

Cancer Research (CCR), and the Division of Cancer Epidemiology and Genetics (DCEG) provided data on extramural and intramural NCI-sponsored research projects.

X The staff of Science Applications International Corporation (SAIC) contributed significant technical expertise and dedicated effort to the management, analysis, technical writing, and production

of the report. SAIC’s efforts were led by Catherine Hall, Sabina Robinson, and Jeff Zalatoris.

Significant contributions were made by Eric Levine, Beth Mathews-Bradshaw, Karen Rulli,

Maneesha Solanki, Nancy Volkers, Julie Jessup, Jennifer Secula, and their colleagues.

X The staff of the Constella Group, particularly Paul Nedzbala and Jeffrey Morris, assisted in

assembling data on the NCI’s prostate cancer research portfolio.
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Prostate Cancer Progress Report: Addressing the Recommendations of the PRG Group

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Executive Summary

Prostate cancer is the most common cancer (aside from nonmelanoma skin cancer) and the second

leading cause of cancer-related death in men in the United States. In 2002, an estimated 189,000 men

were diagnosed with, and 30,200 died from, this disease. African American men are more likely than

other racial and ethnic populations both to develop and to die from prostate cancer. While recent trends of

stabilizing incidence and decreasing mortality rates are encouraging, prostate cancer remains a major

health burden for American men and requires continued action.

In 1997, the National Cancer Institute (NCI) convened the Prostate Cancer Progress Review Group

(PRG), a multidisciplinary committee of scientists, clinicians, and advocates, to help NCI define a national

research agenda for prostate cancer. The Prostate Cancer PRG issued a 1998 report entitled Defeating

Prostate Cancer: Crucial Directions for Research, which included priority research questions that

should be addressed to advance prevention, detection, diagnosis, and treatment of prostate cancer. An

internal NCI Prostate Cancer Working Group was recently convened to assess the research progress

made since the release of this report. Besides producing the Prostate Cancer Progress Report, this

working group contributed to the NIH Prostate Cancer Research Plan FY 2003–FY 2008.

The NCI Prostate Cancer Progress Report documents trends in the NCI prostate cancer research

portfolio from 1998 to 2002. Multiple measures of progress are presented at varying levels of specificity,

ranging from overall trends in NCI funding, projects, and resulting peer-reviewed publications, to more

specific trends in the number of projects relevant to particular research priorities identified by the PRG.

Recognizing the evolutionary nature of research, this progress report also relates priority research

questions identified by the PRG to the objectives of the more recently released NIH Prostate Cancer

Research Plan FY 2003–FY 2008.

Between 1998 and 2002, the NCI substantially expanded investments in prostate cancer research as

evidenced by:

X tripling of prostate cancer funding from $86.9 million in 1998 to $278.4 million in 2002,

X approximate doubling of the number of relevant projects,

X more than doubling relevant individual training and career development awards,

X expanding ongoing and initiating new programs to sustain and advance both basic and clinical

prostate cancer research,

X expanding the prostate Specialized Programs of Research Excellence (SPOREs) network from

3 to 11 sites, and

X expanding collaborative efforts and shared resources to improve the capacity to conduct prostate

cancer clinical trials.

Work is under way to translate the discoveries generated by this expanded investment into new

prostate cancer prevention, detection, diagnosis, and treatment interventions that will save lives. The

following two pages summarize the NCI’s investment by research category.

NCI’s ability to capitalize on advances in prostate cancer research and care will require

continued basic, translational, and clinical research support. This progress report, which documents the

NCI’s responses to the recommendations of the Prostate Cancer PRG, will help guide efficient and

effective implementation of the NCI plans described in the NIH Prostate Cancer Research Plan

FY 2003–FY 2008.
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Prostate Cancer Progress Report: Addressing the Recommendations of the PRG Group

NCI’s Prostate Cancer Research Investment

Increased from $86.9 Million in 1998 to $278.4 Million in 2002

Millions of Dollars

1998

2002

0 10 20 30 40 50 60 70 80

Cancer Control,

Survivorship, and Outcomes

Treatment

Scientific Model Systems

Early Detection,

Diagnosis, and Prognosis

Etiology and Prevention

Biology

Biology

X Funding increased from $15.2M to $41.7M.

X Number of projects increased from 160 to 302.

X New initiatives included Age-Related Prostate Growth, Role of Hormones and Growth Factors in

Prostate Cancer, and Molecular and Cellular Biology of Metastatic Tumor Cells.

Etiology and Prevention

X Funding increased from $19.5M to $78.9M.

X Number of projects increased from 112 to 203.

X Ongoing clinical trials include the SELECT trial.

X New initiatives included NCI Cohort Consortium, RAPID, and the Small Grants Program for Cancer

Epidemiology.

Early Detection, Diagnosis, and Prognosis

X Funding increased from $7.1M to $41.0M.

X Number of projects increased from 58 to 140.

X New initiatives included Clinical Proteomics Program, Director’s Challenge, Early Detection

Research Network, and Exploratory/Developmental Grants for Diagnostic Cancer Imaging.

Growth of NCI’s Investment in

Extramural Research by

Scientific Category

Scientific Model Systems

X Funding increased from $3.6M to $11.3M.

X Number of projects increased from 40 to 99.

X New initiatives included Mouse Models of Human Cancers Consortium, Cancer Therapy-Related Use

of Genetically Engineered Mice, and Competing Supplements for Organotypic Models of Cancer.

Treatment

X Funding increased from $16.9M to $57.6M.

X Number of projects increased from 143 to 277.

X Ongoing clinical trials include the PIVOT study and the Phase III Study of Docetaxel and Estramustine

versus Mitoxantrone and Prednisone (SWOG 9916).

X New initiatives included Quick-Trials for Novel Cancer Therapies, Program for Assessment of Clinical

Cancer Tests, and National Cooperative Drug Discovery Groups.

Cancer Control, Survivorship, and Outcomes

X Funding increased from $6.5M to $20.3M.

X Number of projects increased from 24 to 48.

X Ongoing clinical trials include the PLCO and PCOS studies.

X New initiatives included Special Populations Networks, Cancer Research Network, Cancer

Interventions and Surveillance Modeling Network, Health Communications in Cancer Control, and

Cancer Outcomes Measurement Working Group.
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Prostate Cancer Progress Report: Addressing the Recommendations of the PRG Group

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Examples of Progress

Resulting from NCI’s Prostate Cancer Research Investment

Number of Research Projects

1998

2002

0 50 100 150 200 250 300 350

Cancer Control,

Survivorship, and Outcomes

Treatment

Scientific Model Systems

Early Detection,

Diagnosis, and Prognosis

Etiology and Prevention

Biology

Biology

X Recent advances include identifying molecular mechanisms of cancer initiation, progression, and

metastasis; new models of the development of androgen-independent cancers; and growth factor

contributions to cancer progression.

X Future investment is needed in new technologies (e.g., proteomics and bioinformatics) and new

model systems to advance the study of molecular mechanisms of normal prostate development and

cancer progression and the role of tumor microenvironment and macroenvironment.

Etiology and Prevention

X Recent advances include finasteride as a chemopreventive agent, diet/nutrient intake and reducing

cancer risk, gene–environment associations, and identification of biological factors of cancer.

X Future investment is needed in rapidly initiating and completing prevention trials, refining etiological

components of cancer, and validating lifestyle and chemical preventive measures.

Early Detection, Diagnosis, and Prognosis

X Recent advances include biomarker identification, imaging device enhancement, and molecular

profiling analyses.

X Future investment is needed in validating and including new biomarkers in trials, further enhancement

of noninvasive devices, and better characterization of tumors for predicting clinical behavior.

Growth of NCI’s

Relevant Prostate

Cancer Research

by Scientific

Category

Scientific Model Systems

X Recent advances include use of the TRAMP mouse model and variants, xenograft mouse models,

and metastatic mouse models using gene knockouts.

X Future investment is needed in models covering the natural progression of prostate cancer and

evaluating the similarities and differences between models and human disease.

Treatment

X Recent advances in clinical care include hormone therapy as adjuvant with external beam radiation

therapy, interstitial brachytherapy for selected patients with localized disease, and zoledronic acid for

prevention and treatment of bone metastatic disease.

X Recent advances in research include new chemotherapeutics development and evaluation and

surrogate biomarkers in clinical trials.

X Future investment is needed in enhanced capacity in the clinical trials infrastructure, enhanced

translational research, and identification and validation of new targets and new interventions.

Cancer Control, Survivorship, and Outcomes

X Recent advances include identifying causes of racial disparities, understanding patient-focused

outcomes, and treatment-related complications.

X Future investment is needed in quality-of-life assessments, enhanced surveillance, evaluation of

screening and treatment intervention outcomes, biobehavioral research, and dissemination

practices.

1-1

Chapter 1 Prostate Cancer Research: 1998–2002

NATIONAL CANCER INSTITUTE

CHAPTER

1 Prostate Cancer Research:

1998–2002

We believe that this was,

indeed, an opportune time to

reassess the Institute’s

prostate cancer research

portfolio and plan a research

agenda for prostate cancer

that will guide the prostate

cancer research field into the

next decade.

– Defeating Prostate Cancer: Crucial

Directions for Research - Report of

the Prostate Cancer Progress Review

Group, August 1998.

With an estimated 189,000 new prostate cancer diagnoses and 30,200 prostate cancer deaths in

2002,1

 prostate cancer is a disease that affects many American men and their families. In April 1997, the

National Cancer Institute (NCI) convened a multidisciplinary committee of scientists, clinicians, and

advocates to review the field of prostate cancer research and make prioritized recommendations

concerning the most needed and promising directions for future NCI investment. In August 1998, the

Prostate Cancer Progress Review Group (PRG) issued its report Defeating Prostate Cancer: Crucial

Directions for Research.

In 2001, the NCI established an internal Prostate Cancer Working Group to assist in planning,

monitoring, and tracking of progress. This report includes the Prostate Cancer Working Group’s findings

regarding the NCI’s responsiveness to the PRG recommendations, over the years 1998 through 2002.

Since the Prostate Cancer PRG issued its report, the NCI has increased its investment in

research relevant to prostate cancer in terms of dollars

spent and the number of projects supported. In addition, the monitoring of basic and clinical NCI-supported

research has been improved. Numerous resources and

programs have been sustained, expanded, and/or developed.

Peer-reviewed publications resulting from NCI-sponsored

efforts show that much progress has been made in some of

the specific topic areas identified as promising by the PRG.

Further demonstration of progress can be found in prostate

cancer-related patents that have been issued and changes in

clinical practice that have been adopted.

The Prostate Cancer Burden

Prostate cancer is the most common non-skin

cancer in men and second-most common cause of cancerrelated death in U.S. men.2 As shown in Figures 1-1 and

1-2, respectively, prostate cancer diagnosis and death rates

increased between 1973 and the early 1990s.3 Incidence rates,

in particular, rose rapidly from the mid-1980s to the early 1990s,

following the introduction of prostate-specific antigen (PSA)

screening. (See also Figure 5-1, Chapter 5.)

1 NCI’s Surveillance, Epidemiology, and End Results (SEER) Cancer Statistics Review, 1975–2001.

2 See Note 1.

3 The first year in which both incidence and mortality data were collected by the NCI’s SEER program for all races, whites, and

blacks was 1973. Beginning in the early 1990s, the collected data were expanded to include additional racial/ethnic groups. The

most recent year for which analyzed SEER data are available is 2001.
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1-2

Chapter 1 Prostate Cancer Research: 1998–2002

Figure 1-1. Prostate cancer incidence in the United States.

Data derived from NCI’s SEER program.

0

50

100

150

200

350

All Races

White

Black

American Indian,

Aleutian Islander,

or Eskimo

Asian or Pacific

Islander

Hispanic

1973 1975 1977 1979 1981 1983 1985 1987 1989 1991 1993 1995 1997 1999

Diagnosis per 100,000 Men

Year

250

300

2001

0

20

40

60

100

All Races

White

Black

American Indian,

Aleutian Islander,

or Eskimo

Asian or Pacific

Islander

Hispanic

1973 1975 1977 1979 1981 1983 1985 1987 1989 1991 1993 1995 1997 1999

Deaths per 100,000 Men

Year

80

2001

Figure 1-2. Prostate cancer mortality in the United States.

Data derived from NCI’s SEER program.

Both incidence and mortality rates began to decrease in the early 1990s. In 2001,4 the overall

incidence rate was similar to the rate in 1990 and the overall mortality rate was nearly the same as that in

1973. Blacks are particularly vulnerable to prostate cancer, with diagnosis and death rates that are

considerably higher than those of other racial groups and the overall U.S. population. The 2001 prostate

cancer mortality rate for Black men was more than twice that for the overall population.

In addition to premature death, pain, and debilitation, there is a large economic toll associated with

prostate cancer. It is estimated that around $4.6 billion is spent in the United States each year on treatment of the disease.5

 There is also the burden of lost productivity and wages.

4 See Note 1.

5 In 1996 dollars, as determined by Brown, Riley, Schussler, and Etzioni and reported in the NCI’s Cancer Progress Report -

2003 Update.
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Chapter 1 Prostate Cancer Research: 1998–2002

NATIONAL CANCER INSTITUTE

The Prostate Cancer Progress Review Group

In 1997, the NCI formed two pilot PRGs to help sharpen its focus on research directed at

specific cancer sites. The Prostate Cancer PRG was the first PRG to be convened. Consisting of

22 nationally prominent members from academia, industry, nonprofit organizations, and government, with

complementary backgrounds in basic, translational, and clinical research and in prostate cancer advocacy

issues, the group met periodically from April 1997 to May 1998.

The objectives of the Prostate Cancer PRG were to review the state of the art, receive stakeholder

input, assess the existing NCI prostate cancer research portfolio, prioritize key scientific questions, and

develop recommendations for action. To ensure that the PRG’s understanding of the state of the art in

prostate cancer research was both accurate and complete, more than 100 additional scientists, clinicians,

and advocates, from throughout the world, participated in a roundtable meeting and in expert panels that

addressed the topics of clinical trial design and implementation, prognostic marker validation, radiobiology,

screening and early detection, gene technology and gene identification, gene therapy and vaccines, and

molecular epidemiology.

In August 1998, the Prostate Cancer PRG published its report, Defeating Prostate Cancer: Crucial

Directions for Research, which addressed the following eight categories of prostate cancer research:

X Biology, Progression, and Metastasis

X Etiology and Primary Prevention

X Early Detection, Diagnosis, and Prognosis

X Laboratory and Clinical Models

X Staging and Treatment of Localized Prostate Cancer

X Systemic Therapy

X Outcomes Research

X Resources Needed

For each research category, the report includes a synopsis of current status, a statement of the PRG’s

vision, a discussion of identified challenges and opportunities, and research priorities that are presented in

the form of prioritized research questions accompanied by recommended actions.6

Five Years of Progress

To implement the PRG’s vision for progress, the NCI began to increase its investment in

prostate cancer-relevant research and document the progress made in the field. The number of

investigator-initiated research projects relevant to prostate cancer increased and specific research initiatives were expanded or implemented. Subsequent to the Prostate Cancer PRG’s work, the NCI began

tracking its expanding prostate cancer research portfolio according to the Common Scientific Outline

(CSO), a research categorization scheme adopted by multiple federal and nonfederal agencies, that is

6 The Prostate Cancer PRG report identified 156 investigative questions: 48 Priority One (i.e., highest priority), 63 Priority

Two, and 45 Priority Three. Accompanying the 48 Priority One investigative questions were 119 recommended actions. The

PRG defined Priority One questions as those that addressed critical areas of research that were ready for immediate implementation and/or responded to a recent development or breakthrough. In contrast, the Priority Two questions addressed areas that

were less critical or promising, and the Priority Three questions addressed areas that were already being examined or not yet

ready for implementation. Although the PRG report included 48 Priority One questions, some had overlapping content. For

reporting purposes, the NCI has combined one of the questions with another closely related question (addressed in Chapter 6)

and has dropped a second question, which was included, in its entirety, as part of another question (addressed in Chapter 7).
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1-4

Chapter 1 Prostate Cancer Research: 1998–2002

similar, but not identical, to the one used by the Prostate Cancer PRG.7 The sections that follow provide

an overview of:

X The NCI’s investment in prostate cancer research, in terms of dollars invested, research projects

supported, clinical trials supported, initiatives undertaken, resources developed and maintained, and

programs established and expanded

X The return on NCI’s investment, in terms of research results obtained and applied

Investment in Prostate Cancer Research

Dollars Invested

NCI’s commitment to addressing the identified challenges and opportunities in prostate

cancer research is demonstrated by growing investments in relevant activities. Figure 1-3 shows

dollar estimates for NCI prostate cancer spending from fiscal year (FY) 1998 through FY 2002. Over the

5-year period, NCI’s overall prostate cancer investment increased more than threefold.

The majority of funds devoted to prostate cancer research supported extramural research.

Figure 1-4 shows the NCI’s dollar investment for prostate cancer-relevant research during FY 1998–2002,

with the extramural component, but not the intramural support and contracts component, broken down

according to the CSO categorization scheme.

7 Although the seven research categories of the CSO are similar to the eight categories of the Prostate Cancer PRG report, notable

differences include the CSO’s separate categories for etiology and prevention, a single treatment category that does not include

staging, and division of resources among the other categories. The CSO is described in full at http://researchportfolio.cancer.gov/

cso.html.

Figure 1-3. Estimate of total NCI dollars for prostate cancer-relevant research.

Values include NCI’s total intramural and extramural support for prostate cancer research as reported by the

Financial Management Branch of the NCI’s Office of Budget and Financial Management (NCI FactBook).

0

50

150

300

1998 1999 2000 2001 2002

Fiscal Year

Millions of Dollars

250

100

200
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Chapter 1 Prostate Cancer Research: 1998–2002

NATIONAL CANCER INSTITUTE

Figure 1-4. Dollar estimates for prostate cancer-relevant

research by type of research.

To derive the values, dollars associated with each funded project were first prorated by estimated prostate cancer relevance, and this portion was then

equally distributed among applicable CSO research categories. Dollars directed at resources are included in the values for the research categories.

0

50

150

300

1998 1999 2000 2001 2002

Fiscal Year

Millions of Dollars

250

100

200

Intramural Support

and Contracts

Biology

Etiology and Prevention

Early Detection, Diagnosis,

and Prognosis

Scientific Model Systems

Treatment

Cancer Control, Survivorship,

and Outcomes

Research Projects Supported

Between 1998 and 2002, there was a large increase in the number of NCI-sponsored

research projects relevant to prostate cancer. Figure 1-5 shows the number of projects with high

prostate cancer relevance8 (i.e., 25% or greater) that were funded by the NCI each year, during

FY 1998–2002. Even using these conservative estimates of prostate cancer-relevant projects, there was a

substantial increase (85%) in the number of projects. Numbers of funded prostate cancer projects within

each research category are shown in Figure 1-6. Details concerning the NCI-sponsored research projects

in each category can be found in Chapters 3 through 8 and Appendix B9

 of this report.

8 Quantitative estimates of cancer-site relevance are made by NCI staff based on the proportion of a project considered relevant

to particular disease sites. NCI uses relevance values for calculating prorated disease-specific dollar estimates (as in Figure 1-3)

and for project tracking.

9 Appendix B identifies the FY 2002 research projects that were responsive to the Priority One questions of the PRG.

0

400

600

1000

1998 1999 2000 2001 2002

200

800

Number of Projects

Fiscal Year

Figure 1-5. Number of research projects relevant to prostate cancer.

Included in the graph are solicited and unsolicited projects and individual training and career development awards, both new and continuing, with

prostate cancer relevance values of 25 percent or more. (Solicited projects are those submitted in response to NCI initiatives in targeted topic areas;

unsolicited projects are investigator-initiated submissions received by the NCI.)
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Chapter 1 Prostate Cancer Research: 1998–2002

Figure 1-6. Number of prostate cancer-relevant projects

addressing each research category.

Each project with 25 percent or greater relevance to prostate cancer was counted once for each category to which it applied.

(Category assignment was based on the results of mapping projects to the PRG’s Priority One questions and not on original CSO assignments.

Projects assigned to more than one research category are included in the data for all appropriate categories.)

10 An NCI-sponsored clinical trial in Physician Data Query (PDQ) (1) has been reviewed and approved by NCI’s CTEP Protocol

Review Committee or by an approved NCI-designated Cancer Center Protocol Review and Monitoring System and/or (2)

receives support through an NCI grant or cooperative agreement.

0

50

100

150

200

350

Biology

Etiology and 

Prevention

Early Detection, 

Diagnosis, and 

Prognosis

Scientific Model 

Systems

Treatment

Cancer Control, 

Survivorship, and 

Outcomes

1998 1999 2000 2001 2002

Number of Projects

Fiscal Year

250

300

Clinical Trials Supported

Between 1998 and 2002, the number of active NCI-sponsored clinical trials relevant to

prostate cancer increased. Figure 1-7 shows the increase in the overall number of NCI-sponsored10

clinical trials relevant to prostate cancer that were active during the calendar years 1998 to 2002. These

clinical trials represent research on treatment, prevention, genetics, diagnostics, and supportive care.

Figure 1-7. Number of NCI–sponsored prostate cancer

clinical trials active during calendar years 1998–2002.

These data indicate overall numbers of prostate cancer clinical trials. (Information in the figure is based on a search conducted by staff of the

Office of Cancer Information Products and Systems, Office of Communications [in its PDQ Clinical Trials Database] for NCI-sponsored

prostate cancer treatment trials active at some time during the timeframe 1998 to 2002. More detailed Information about specific

trials is available on NCI’s Cancer.gov website at http://www.cancer.gov/clinical_trials.)

0

100

120

1998 1999 2000 2001 2002

80

Number of Active

Clinical Trials

Calendar Year
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Chapter 1 Prostate Cancer Research: 1998–2002

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Initiatives Undertaken

Between FY 1998 and FY 2002, numerous NCI initiatives stimulated work on the research

priorities identified by the Prostate Cancer PRG. The initiatives increased the depth and breadth of

the NCI’s research on prostate cancer by:

X Encouraging submission of applications for research projects, which are wholly or partially

focused on prostate cancer, in targeted topic areas

X Developing and maintaining resources for use by prostate cancer researchers

X Establishing and expanding programs in which research and resources are combined in

collaborative pursuit of a common goal

Table 1-1 lists the NCI initiatives that impacted prostate cancer research in FY 1998 through 200211

and the chapter of this report in which more detail is provided on the initiative.

11 Initiatives selected for inclusion are those that were begun or continued during FY 1998–2002 that resulted in programs,

resources, or research projects relevant to prostate cancer. Also selected for inclusion are NCI intramural initiatives that have a

readily identifiable component that is specific to prostate cancer.

Table 1-1. NCI Initiatives Relevant to Prostate Cancer Research: 1998–2002

INITIATIVES FOCUSED ON PROSTATE CANCER

Chapter 2 - General Initiatives

Cooperative Prostate Cancer Tissue Resource (CPCTR)

http://www.prostatetissues.org (begun in FY 1999)

Diagnostic Imaging and Guided Therapy in Prostate Cancer

CA-99-015 and PAR-99-149 (begun in FY 1999)

Molecular Epidemiology of Prostate Carcinogenesis

PA-00-080 (continued in FY 1999 and FY 2000)

Prostate Cancer Intervention Versus Observation Trial (PIVOT)

http://www.va.gov/PIVOT/ (ongoing)

Prostate, Lung, Colorectal & Ovarian Cancer Screening Trial (PLCO)

http://www3.cancer.gov/prevention/plco/index.html (ongoing)

Prostate Specialized Programs of Research Excellence (SPOREs)

http://spores.nci.nih.gov/prostate/prostate.html (expanded in 1999 and 2001)

Chapter 3 - Biology

Age-Related Prostate Growth: Biologic Mechanisms

PA-02-116 (begun in FY 2002)

Biology, Development, and Progression of Malignant Prostate Disease

PA-99-081 (begun in FY 1999)

Development of Cell-Selective Tools for Studies of the Bladder, Prostate, and Genitourinary Tract

PAR-02-143 (begun in FY 2002)

Role of Hormones and Growth Factors in Prostate Cancer

RFA-DK-01-008 (begun in 2001)
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Chapter 1 Prostate Cancer Research: 1998–2002

Chapter 4 - Etiology and Prevention

Prostate Cancer Prevention Trial

http://www.cancer.gov/pcpt (ongoing)

SELECT Prostate Cancer Prevention Trial

http://www.cancer.gov/select (ongoing)

Chapter 7 - Treatment

Quick-Trials for Prostate Cancer Therapy

PA-00-047 (begun in FY 1999; replaced by expanded Quick-Trials for Novel Cancer Therapies program in

FY 2000)

Chapter 8 - Cancer Control, Survivorship, and Outcomes

Prostate Cancer Outcomes Study (PCOS)

http://healthservices.cancer.gov/pcos (ongoing)

INITIATIVES WITH PROSTATE CANCER-RELEVANT COMPONENTS

Chapter 2 - General Initiatives

Applications of Innovative Technologies for the Molecular Analysis of Cancer

PAR-01-107 and PAR-01-106 (begun in FY 1999, continued in FY 2001)

Cancer Centers Program

http://www3.cancer.gov/cancercenters (ongoing)

Cancer Genome Anatomy Project (CGAP)

http://cgap.nci.nih.gov (ongoing)

Cancer Imaging Program (CIP)

http://www3.cancer.gov/dip

Cancer Molecular Analysis Project (CMAP)

http://cmap.nci.nih.gov (ongoing)

Cancer Prognosis and Prediction

PAR-01-062 (begun in FY 2001)

Cancer Research Training, Career Development, and Education Opportunities

http://cancertraining.nci.nih.gov (ongoing)

Cancer Therapy-Related Use of Genetically Engineered Mice

PAR-02-051 (begun in FY 2002)

Clinical Trials Cooperative Group Program

http://ctep.cancer.gov/resources/coop2.html (continued in 1999)

Common Data Elements (CDE) Initiative

http://ncicb.nci.nih.gov/CDEBrowser

Community Clinical Oncology Program (CCOP)

http://www3.cancer.gov/prevention/ccop (continued in FY 2002)

Cooperative Human Tissue Network (CHTN)

http://www-chtn.ims.nci.nih.gov (ongoing)

Director’s Challenge: Toward a Molecular Classification of Cancer

http://dc.nci.nih.gov (begun in FY 1998)

Table 1-1. (cont.)
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Table 1-1. (cont.)

Exploratory Grants for Correlative Laboratory Studies and Clinical Trials

PA-98-042 (begun in FY 1998)

Flexible System to Advance Innovative Research for Cancer Drug Discovery by Small Businesses

(FLAIR)

http://dtp.nci.nih.gov/branches/gcob/gcob_web17.html (begun in FY 1998, continued in FY 2000)

Genitourinary Cancers Faculty

(http://ccr.cancer.gov/faculties/faculty.asp?facid=131)

Improving DNA, RNA, and Protein Availability in Fixed Tissue

PAR-00-079 (begun in FY 2000)

Interdisciplinary Research Teams for Molecular Target Assessment

RFA-CA-00-001 (begun in FY 2000)

In Vivo Cellular and Molecular Imaging Centers (ICMICs)

http://www3.cancer.gov/bip/ICMICs.htm (begun in FY 1999)

Minority Institution/Cancer Center Partnership (MI/CCP) Program

http://minorityopportunities.nci.nih.gov/institutions/faqs.html (begun in FY 2001, continued in FY 2002)

Minority-Based Community Clinical Oncology Program (MBCCOP)

http://www3.cancer.gov/prevention/ccop/mbccop.html (begun in FY 2002)

Molecular Profiling Initiative (MPI)

http://cgap-mf.nih.gov/ProstateExample/index.html (ongoing)

Molecular Target Drug Discovery for Cancer

PAR-01-045 and PAR-01-046 (begun in FY 2000)

NCI Center for Bioinformatics (NCICB)

http://ncicb.nci.nih.gov

Program for Assessment of Clinical Cancer Tests (PACCT)

http://www.cancerdiagnosis.nci.nih.gov/assessment

Shared Resources for Scientists outside NCI Cancer Centers

PAR-99-127 (begun in FY 1999)

Small Animal Imaging Resource Program (SAIRP)

RFA-CA-01-012 (begun in FY 1998)

Special Populations Networks (SPNs)

http://crchd.nci.nih.gov/spn/index.html (begun in FY 1999)

Specimen Resource Locator

http://pluto3.nci.nih.gov/tissue/default.htm (ongoing)

Technologies for Comprehensive, Sensitive, and Quantitative Protein Analysis in Human Tumors: Phased

Innovation

RFA-CA-01-011 (begun in FY 2001)

Chapter 3 - Biology

Molecular and Cellular Biology of Metastatic Tumor Cells

PA-01-020 (begun in FY 2001)

Chapter 4 - Etiology and Prevention

Cancer Genetics Network (CGN)

http://epi.grants.cancer.gov/CGN (ongoing)
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Chapter 1 Prostate Cancer Research: 1998–2002

Table 1-1. (cont.)

Cancer Prevention Research Small Grant Program

PAR-00-025 (continued in FY 2000)

Chemoprevention in Genetically Identified High-Risk Groups: Interactive Research and Development

Projects

RFA-CA-98-012 (begun in FY 1998)

NCI Cohort Consortium

http://cancercontrol.cancer.gov/bb/cohort_conso.html (begun in FY 2000)

Rapid Access to Preventive Intervention Development (RAPID) Program

http://www3.cancer.gov/prevention/rapid/index.html (begun in FY 2000)

Small Grants Program for Cancer Epidemiology

http://epi.grants.cancer.gov/ResPort/grants.html (begun in FY 1998, continued in FY 2001)

Chapter 5 - Early Detection, Diagnosis, and Prognosis

Clinical Proteomics Program

http://ncifdaproteomics.com/index.php (begun in FY 1999)

Development of Clinical Imaging Drugs and Enhancers (DCIDE)

http://www3.cancer.gov/bip/dcide.htm

Development of Novel Technologies for In Vivo Imaging

PAR-01-101 and PAR-01-102 (FY 2001 continuation of Development of Novel Imaging Technologies)

Early Detection Research Network (EDRN)

http://www3.cancer.gov/prevention/cbrg/edrn (begun in FY 1998)

Exploratory Studies in Cancer Detection, Prognosis, and Prediction

PA-01-010 (begun in FY 2001)

Exploratory Studies in Cancer Diagnostics

PA-98-022 (begun in FY 1998)

Exploratory/Developmental Grants for Diagnostic Cancer Imaging

PA-01-030 (begun in FY 1998)

Gene Expression Data Portal (GEDP)

http://gedp.nci.nih.gov/dc/index.jsp (ongoing)

Innovative Technologies for the Molecular Analysis of Cancer

PAR-01-105 and PAR-01-104 (begun in FY 1998, continued in FY 1999 and FY 2001)

Tissue Array Resource Program (TARP)

http://ccr.cancer.gov/tech_initiatives/tarp (ongoing)

Chapter 6 - Scientific Model Systems

Competing Supplements for Organotypic Models of Cancer

PAR-02-052 (begun in FY 2002)

Mouse Models of Human Cancers Consortium (MMHCC)

http://emice.nci.nih.gov (begun in FY 1998)

Chapter 7 - Treatment

Cancer Drug Discovery: Diversity Generation and Smart Assays

RFA-CA-98-009 (begun in FY 1998)

Cancer Trials Support Unit

http://www.ctsu.org (ongoing)
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Table 1-1. (cont.)

Clinical Cancer Therapy Research

PA-02-002 (continued in FY 1999)

Development and Application of Imaging in Therapeutic Studies

RFA-CA-98-024 (begun in FY 1998)

Expanded Participation Project (EPP)

http://spitfire.emmes.com/study/epp (ongoing)

National Cooperative Drug Discovery Groups (NCDDGs)

http://dtp.nci.nih.gov/brances/gcob/gcob_web3.html (continued in FY1999)

Quick-Trials for Novel Cancer Therapies

PA-00-047 (FY 2000 expansion of the Quick-Trials for Novel Cancer Therapies Program begun in FY 1999)

Rapid Access to Intervention Development (RAID) Program

http://dtp.nci.nih.gov/docs/raid/raid_index.html (ongoing)

Therapeutic Modulation of Angiogenesis in Disease

PAR-98-096 (begun in FY 1998)

Translational Research Initiative

http://ctep.cancer.gov/resources/trf-overview.html

Chapter 8 - Cancer Control, Survivorship, and Outcomes

Cancer Intervention and Surveillance Modeling Network (CISNET)

http://cisnet.cancer.gov/about (begun in FY 1999, continued in FY 2002)

Cancer Outcomes Measurement Working Group (COMWG)

http://outcomes.cancer.gov/methods/measures/comwg (begun in FY 2001)

Cancer Research Network (CRN)

http://cancercontrol.cancer.gov/bb/can_research.html (begun in FY 1998)

Cancer Surveillance Using Health Claims-Based Data System

http://dccps.nci.nih.gov/ARP/research/health.asp (continued in FY 1999)

Economic Studies in Cancer Prevention, Screening, and Care

http://cancercontrol.cancer.gov/ARP/research/economic.asp (begun in FY 1999, continued in FY 2002)

Exploratory Grants for Behavioral Research in Cancer Control

PA-99-163 (begun in FY 1999)

Minority and Underserved Cancer Survivors

http://cancercontrol.cancer.gov/ocs/underserved (FY 2001)

SEER–Medicare Linked Database

http://healthservices.cancer.gov/seermedicare (ongoing)

SEER Patterns of Care/Quality of Care (POC/QOC) Initiative

http://cancercontrol.cancer.gov/bb/seer_pattern.html (expanded in FY 2001)

Small Grants Program for Behavioral Research in Cancer Control

http://dccps.nci.nih.gov/smallgrants/index.html (continued in FY 1999)

Surveillance, Epidemiology, and End Results (SEER)

http://seer.cancer.gov (expanded in FY 2001)
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Chapter 1 Prostate Cancer Research: 1998–2002

Resources Developed or Maintained

NCI initiatives have led to increased availability of products, knowledge, services,

facilities, and personnel that are critical for advancing prostate cancer research. NCI-funded

resources that benefit prostate cancer research include the following:

X Repositories for accessing biological specimens and associated clinical data from patients with

prostate cancer and men at risk of developing the disease

X Databases for accessing information that derives from multiple sources

X Animal models that mimic the development and/or progression of prostate cancer

X Forums for communicating research results and stimulating discussion and collaboration among

investigators

X Training programs for improving the skills and advancing the careers of young, mid-career, and

minority investigators

X Tools for assisting investigators in locating the resources that they require

Examples of NCI initiatives that support development or maintenance of important resources include:

X Cancer Research Training, Career Development, and Education Opportunities

X Cooperative Prostate Cancer Tissue Resource (CPCTR)

X Gene Expression Data Portal (GEDP)

X Mouse Models of Human Cancers Consortium (MMHCC) (which includes a Prostate Cancer

Committee)

Most notable among the resulting resources that advance prostate cancer research are the investigators who develop through the Cancer Research Training, Career Development, and Education Opportunities. Through grants awarded to individuals or institutions, the NCI continues to enhance the cadre of

prostate cancer investigators.

Programs Established or Expanded

NCI initiatives have established or expanded consortia, collaborative groups, networks,

partnerships, and other organized entities that advance prostate cancer research. The programs

support the following:

X Rapid development of new technologies

X Conduct of large, multi-institutional clinical trials

X Access to specialized patient populations

X Access to specialized equipment and expertise

Examples of NCI initiatives leading to new or expanded programs include:

X Clinical Trials Cooperative Group Program

X Early Detection Research Network (EDRN) (which includes a Prostate and Other Urologic

Cancers Collaborative Group)

X Minority Institution/Cancer Center Partnership (MI/CCP) Program

X Prostate Specialized Programs of Research Excellence (SPOREs)

X Rapid Access to Intervention Development (RAID) Program
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Most notable among the NCI-sponsored programs that advance prostate cancer research are the

Prostate Specialized Programs of Research Excellence (SPOREs). Individually, and in combination, the

Prostate SPOREs provide a comprehensive mix of translational research projects,12 core resources, and

training opportunities. Begun as an experiment in 1992, with a special appropriation from Congress that

funded 9 SPOREs for 3 different cancer sites, there are now 49 SPOREs for 14 cancer sites, with 7

additional SPOREs being planned. The NCI’s Prostate SPORE Program has grown from 2 SPOREs in

1992 to 11 at the end of 2002; 8 new Prostate SPOREs have been funded since the Prostate Cancer PRG

first met.

Research Results Obtained and Applied

Research Results Obtained

The NCI’s increased investment in prostate cancer research has increased the rate at

which research results are being obtained. Figure 1-8 shows the estimated number of peer-reviewed

publications indicating NCI support and relevance to prostate cancer, during calendar years 1998 through

2002. The values in Figure 1-8 should be considered conservative estimates.13 Among the peer-reviewed

publications resulting from NCI-sponsored efforts (1998–2002), 367 derived from the 11 Prostate

SPOREs.

12 Translational research aims to move findings from the basic laboratory into the clinical setting.

13 Given such factors as less than complete support acknowledgments by authors, inclusion of only the corresponding author’s

affiliation in MEDLINE, possible typographic errors in reporting grant numbers, possible data entry errors, and journal

policies on support acknowledgments, the publication counts reported in Figure 1-8 are no doubt underestimates.

Figure 1-8. Estimated number of peer-reviewed publications

on prostate cancer acknowledging NCI support.

Values are the total unique publications identified from MEDLINE and ISI / Web of Science searches. (Both databases were queried using criteria such as

(1) terms related to “prostate,” (2) presence of an NCI grant number or author address, and (3) limiting to English-language publications in peerreviewed journals. Both intramural and extramural NCI projects are represented.)

Table 1-2 lists some of the important areas of ongoing NCI-sponsored research that are represented

in recent publications. The table also includes the report chapter in which progress in these areas has

been highlighted.

0

400

600

800

1998 1999 2000 2001 2002

Number of 

Publications

Calendar Year

200

1000
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Chapter 1 Prostate Cancer Research: 1998–2002

Areas of Progress Details

Biology Chapter 3

X Early Prostate Cancer

- Genetic alterations

- Glutathione-s-transferase-1 (GSTP1) gene hypermethylation

X Development of hormone-refractory tumors

- Androgen receptor (AR) amplification or mutation

- AR coactivator overexpression

- Other potential pathways

X Progression, metastasis, and the role of tumor microenvironment

- Transforming growth factor (TGF)-beta

- Hepatocyte growth factor

X Bone metastasis

- Hyaluron synthase (HAS)

- Osteomimetic properties of invasive cells

- Urokinase-type plasminogen activator (uPA)

Etiology and Prevention Chapter 4

X Androgen receptor and androgen metabolism

- CAG repeats

- PSA gene variants

- 3-beta-hydroxysteroid dehydrogenase (HSD3B)

- Steroid 5alpha-reductase (SRD5A2)

- Cytochrome p450 enzyme

- Prostate Cancer Prevention Trial (PCPT)

X Insulin-like growth factors

X Dietary factors

- Fat and branched-chain fatty acids

- PhIP (2-amino-1-methyl-6-phenylimidazol[4,5-b]pyridine)

- Micronutrients (e.g., selenium, lycopene, genistein, and vitamin E)

- Alpha-tocopherol beta-carotene cancer prevention trial (ATBC)

X Biological agents

- Viral infections (herpesvirus and human papillomavirus)

- Bacterial infections (gonorrhea and syphilis)

Table 1-2. Recent Progress in Prostate Cancer Research

It is difficult to plan for scientific discoveries. However, NCI along

with the other NIH Institutes and Centers, can provide the vision,

creative environments, and diverse resources needed to facilitate

these discoveries and ensure a smooth flow between advances in

knowledge and application.

– National Institutes of Health, Prostate Cancer Research Plan for FY 2003–2008.
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Chapter 1 Prostate Cancer Research: 1998–2002

NATIONAL CANCER INSTITUTE

Areas of Progress Details

Early Detection, Diagnosis, and Prognosis Chapter 5

X Novel biologic markers

- Alpha-methylacyl-CoA racemase (AMACR)

- Caveolin-1 (Cav-1)

- Ribonuclease L (RNAseL)

- Prostate-specific stem cell antigen (PSCA)

- Epidermal growth factor receptor (EGFR)

- Telomerase reverse transcriptase (TERT)

X Imaging technologies

- Transrectal ultrasonography (TRUS)

- Magnetic resonance imaging (MRI)

X Molecular profiling

Scientific Model Systems Chapter 6

X Transgenic animal models

- Testing of new interventions

- New strains

X Xenografted animal models

X Knockout animal models

- Nkx3.1

- PTEN

Treatment Chapter 7

X Progress in preclinical models

X Early-stage disease

- Impact of treatment on survival

- Improved prognostic indicators

X Biochemical recurrence

X Advanced disease

- Zoledronic acid

- Radiostrontium

- Combination chemotherapies

Cancer Control, Survivorship, and Outcomes Chapter 8

X Survivorship and outcomes

- Complication rates following treatment

- Quality of life and patient satisfaction determinations

X Statistical trends and surveillance of practice patterns

- Declining mortality rates

- Racial disparities

Table 1-2. (cont.)
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Chapter 1 Prostate Cancer Research: 1998–2002

Research Results Applied

Clinical practice for treating prostate cancer has been updated on the basis of results from

NCI-sponsored research. Sexual potency-sparing interstitial brachytherapy is now considered for

certain patients with localized prostate cancer, and hormonal therapy is now considered in addition to

external beam radiation for patients with locally advanced disease.14

Although not enough evidence has been accumulated to determine whether PSA screening ultimately

saves lives,15 PSA screening has been endorsed by nongovernment organizations and is now frequently

performed on men over 50 years of age. Several diagnostic products, which were approved by the U.S.

Food and Drug Administration in 1998, have improved the speed and accuracy of measuring serum PSA

levels.

U.S. patents issued each year with relevance to prostate cancer show promise for future product

development. Investigators supported by the NCI have translated their basic discoveries into advances in

technology. Between 1998 and 2002, 69 patents relevant to prostate cancer were awarded or were

pending decisions by the U.S. Patent Trademark Office (USPTO).16 A listing of these patents can be

found in Appendix C.

Evolution of the PRG Process

As the first of two pilot PRGs to be convened, the Prostate Cancer PRG helped pave the

way for subsequent PRGs. Since 1997, 11 PRGs have been held by the NCI for specific cancer sites

or groups of related cancer sites. More recently, other federal agencies have also employed the PRG

model (e.g., the Stroke PRG convened by the National Institute of Neurological Disorders and Stroke in

2001 and the Trans-HHS PRG on Cancer Health Disparities convened by the Department of Health and

Human Services in 2003).

The NCI has developed strategic plans for addressing the priorities and recommendations of some

PRGs. This report represents the NCI’s first attempt at reporting research progress in terms of responsiveness to PRG priorities.

Since late 2001, the NCI’s Cancer.gov website has included web pages that inform prospective

investigators of cancer site-relevant funding opportunities.17 To secure consideration for exception

funding, grant applicants are encouraged to list the specific PRG priorities that will be addressed by their

proposed research. Research projects funded by the NCI are now coded, tracked, and made accessible

to the public18 according to both cancer site and standardized CSO research category.

14 NCI Prostate Cancer PDQ Treatment Summary, Version for Healthcare Professionals, National Comprehensive Cancer

Network Practice Guidelines in Oncology: Prostate Cancer.

15 NCI Prostate Cancer PDQ Screening Summary, Version for Healthcare Professionals.

16 Patents and patent applications were identified by searching the USPTO databases for prostate-relevant terms and then

selecting for projects in which the government interests/rights were attributed to grants that included the NCI’s Administering

Organization Code.

17 The NCI-sponsored prostate cancer research funding opportunities can be found at the Cancer Research Initiatives website at

http://cri.cancer.gov/.

18 The NCI Cancer Research Portfolio website can be found at http://researchportfolio.cancer.gov.
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Chapter 1 Prostate Cancer Research: 1998–2002

NATIONAL CANCER INSTITUTE

Looking to the Future

A Strategic Plan

In 2002, the NCI’s Prostate Cancer Working Group helped develop the NCI portion of the National

Institutes of Health (NIH) Prostate Cancer Research Plan for FY 2003–2008. The plan includes 7 goals

and 27 objectives, along with strategies and near-term milestones for achieving the objectives. The

research categories in the FY 2003–2008 plan correspond to, but do not exactly match, those of the

Prostate Cancer PRG or CSO. Although the plan is based on the recommendations developed by the

Prostate Cancer PRG, it also takes into account advances made since completion of the PRG’s work.

This Progress Report

This report, which documents the NCI’s responsiveness to the recommendations of the Prostate

Cancer PRG over the years 1998 through 2002, will be used, by the NCI, for efficient implementation of

the FY 2003–2008 prostate cancer research plan. Because the NCI uses the CSO research categorization scheme to track dollar investments, resources, and projects, this report has been organized according

to a modified version of the CSO, as follows:

X Initiatives

X Biology

X Etiology and Prevention19

X Early Detection, Diagnosis, and Prognosis

X Scientific Model Systems

X Treatment

X Cancer Control, Survivorship, and Outcomes

In Chapter 2, details are provided on broad NCI initiatives that address multiple categories of

prostate cancer research, along with the specific programs, resources, and/or research projects that derive

from those initiatives. In Chapters 3 through 8, progress is reported for a given research category, as a

whole, and for the individual PRG Priority One investigative questions relevant to that category. Quantitative measures are included throughout to demonstrate the extent of the NCI‘s responsiveness to the PRG

research priorities. Consistent with the CSO categorization scheme, investigative questions pertaining to

resources needed are addressed in all chapters of this report.

This report addresses only part of the progress made since 1998. First, the content is limited to NCIsponsored research that is most relevant to prostate cancer. In addition to the NCI, there are other federal

and nonfederal agencies that fund research on prostate cancer. Second, human cancers are complex

diseases; each cancer site has features that are unique and features that are shared with other cancer

sites. It is possible that the solution for preventing prostate cancer or the suffering and death resulting

from prostate cancer will ultimately derive from research directed at another cancer site, or even from

research directed at a noncancerous disease. Nevertheless, to increase the likelihood that there will be

significant breakthroughs in prevention, diagnosis, and treatment, the NCI remains committed to planning,

conducting, and assessing research that is directed at prostate cancer.

19 This chapter combines the separate CSO categories of etiology and prevention.

2-1

Chapter 2 Initiatives

NATIONAL CANCER INSTITUTE

CHAPTER

2 Initiatives

Progress in prostate

cancer is severely

impeded by limitations

in research funding,

policies, and practice.

– Defeating Prostate Cancer:

Crucial Directions for Research

- Report of the Prostate Cancer

Progress Review Group,

August 1998.

As the principal federal sponsor of cancer research and

research training, the NCI coordinates, conducts, and supports

research, training, health information dissemination, and other

programs that pertain to development, diagnosis, prevention, and

treatment of cancer and the continuing care of cancer patients and

their families.

The NCI emphasizes funding of biomedical research through

investigator-initiated applications. This paradigm has enabled

investigators to ask critical questions, to remain creative in exploring research topics within their scientific expertise, to develop

innovative technologies, and to make discoveries that expand the

scientific knowledge base.

The investigator-initiated cancer research portfolio extends

broadly across research fields; however, limitations of investigatorinitiated research include underrepresented research in priority

areas and the prohibitive cost of individually maintained resources

and advanced technologies. Therefore, research is solicited and

resources developed to encourage work in priority areas, to support

multidisciplinary research collaborations, and to enable researchers to accelerate the pace of discovery. A

recurring theme throughout the 1998 Prostate Cancer PRG report was that there are highly promising

avenues of prostate cancer research in which progress is being delayed because of limitations in

resources, infrastructure, or capacity for conducting the work. Limitations were identified in areas

that included the following:

X Reliable long-term funding at levels sufficient for sustaining progress and motivation

X The number of investigators trained in critical new skills and technologies

X The number of investigators interested in conducting certain types of studies

X Validated models that mimic the natural history and progression of human prostate cancer

X Access to large numbers of well-characterized biological samples

X Access to large numbers of prostate cancer patients or men who are at various levels of risk for

developing the disease

X Capability for efficient collection, storage, and analysis of data from large clinical trials

X Standardization of assays and other methodologies

The NCI has responded to the PRG priorities pertaining to needed research areas and

resources by expanding its investment in initiatives. Initiatives are used by the NCI to address

priorities that might not otherwise be addressed through unsolicited investigator-initiated grant applications.

In the broadest sense, initiatives1

 include:

1 The NCI uses two main funding opportunity mechanisms for soliciting extramural grant proposals in targeted topic areas –

Requests for Applications (RFAs) and Program Announcements (PAs). RFAs and PAs are published in the NIH Guide for

Grants and Contracts and the NCI’s Cancer Research Initiatives website.
NATIONAL CANCER INSTITUTE

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Chapter 2 Initiatives

INITIATIVES FOCUSED ON PROSTATE CANCER

Cooperative Prostate Cancer Tissue Resource (CPCTR) (http://www.prostatetissues.org)

Objective: A virtual resource comprising tissue specimens (which remain at the collection site) and a

centralized database.

Affected Research Categories: Biology; Etiology and Prevention; Early Detection, Diagnosis, and

Prognosis; Scientific Model Systems; Treatment

Relevant Resource Resulting from This Initiative: Four institutions provide investigators with primary

prostate tissues annotated with data concerning stage of disease, recurrence, vital status, treatment received,

histologic type, presence of prostatic intraepithelial neoplasia, availability of normal tissue, Gleason grading,

characteristics, and follow-up time.

Diagnostic Imaging and Guided Therapy in Prostate Cancer (PAR-99-149) (RFA-CA-99-015)

Objective: Support the development, risk assessment, and application of improved imaging methods for the

localization, biopsy, and image-guided biopsy or therapy of prostate cancer.

Affected Research Categories: Early Detection, Diagnosis, and Prognosis; Treatment

Relevant Research Projects Resulting from This PA/RFA:

X Androgen Receptor-Mediated Detection of Prostate

X Compton Imaging Probe for the Prostate

X Diagnostic Imaging and Guided Therapy in Prostate Cancer

X Dosimetric Markers for Image-Guided Radiation Therapy

X Dynamic Prostate Brachytherapy

X The extramural funding opportunities used for establishing new projects, resources, and programs

X The resources and programs that result from the funding opportunities

X The resources and programs that the NCI establishes within its intramural programs

By expanding ongoing initiatives and introducing new initiatives targeting prioritized research topics,

the NCI creates a cadre of researchers focusing on specific questions. By continuing ongoing and

creating new initiatives that provide infrastructure and resource support, the NCI facilitates research

projects and accelerates research discoveries utilizing centralized, shared resources.

NCI’s Investment and Response

In December 1998, the NCI issued NCI Initiatives Applicable to Prostate Cancer Research, a

notice indicating that the NCI “intends to increase its support for all forms of research on prostate

cancer through the wide range of special mechanisms available.” The purpose of the notice was to

bring “relevant NCI initiatives to the attention of prostate cancer investigators, so that they may

effectively capitalize on these opportunities.”

Chapter 1 shows the growth in NCI spending on prostate cancer research (Figure 1-3) and lists the

specific initiatives that impacted prostate cancer research (Table 1-1) during the period 1998 through 2002.

For each initiative listed in Table 1-1 that affects more than one research category, Table 2-1 provides

information on the purpose of the initiative; the research categories affected by the initiative; and the

relevant program, resource, and/or research projects that resulted from the initiative. For each initiative in

Table 1-1 that applies to a single research category, more detail is provided in the corresponding chapter of

this report.

Table 2-1. NCI Initiatives Relevant to Prostate Cancer Research:

Initiatives Affecting Multiple Research Categories
2-3

Chapter 2 Initiatives

NATIONAL CANCER INSTITUTE

X Improved Magnetic Resonance Imaging (MRI)/Magnetic Spectroscopic Imaging for Biopsy Guidance of

Prostate Cancer

X Interventional MRI/Single Photon Emission Computed Tomography (SPECT)-Guided Prostate Cancer

Biopsy and Therapy

X Low-Molecular Weight Ligands for Prostate Cancer

X MR-Guided Focused Ultrasound Ablation of Prostate

X Novel Ultrasonic Imaging of Brachytherapy Seeds

X Precise MRI-Directed Sonic Ablation of Prostate Cancer

X Real-Time Robotic Image-Guided Prostate Brachytherapy

X Ultrasound Image-Guided Stereotactic Navigational System

Molecular Epidemiology of Prostate Carcinogenesis (PA-00-080)

Objective: Stimulate development and application of biological markers of prostate cancer risk and tumor

aggressiveness for utilization in chemoprevention studies. Of special interest are studies of markers to

elucidate multiethnic differences in prostate cancer susceptibility.

Affected Research Categories: Biology; Etiology and Prevention

Relevant Research Projects Resulting from This PA:

X Analysis of Ras and Rho Activation in Prostate Cancer

X Androgen Pathway Factors and Prostate Cancer

X Androgen Receptor and Prostate Cancer Risk in Chinese

X Effects of Lycopene on High-Risk Prostatic Tissue

X Genetic Epidemiology of Prostate Cancer Aggressiveness

X Genetic Polymorphisms and Prostate Cancer Risk

X IGF-I Levels, IGF-I Genotype, and Prostate Cancer

X Mapping and Cloning Prostate Cancer Predisposition Loci

X Molecular Epidemiology of Prostate Cancer

X Molecular Epidemiology of Prostate Cancer in Tobagonians

X NSAIDs and Other Medications in Prostate Cancer Etiology

X Polymorphisms in Prostate Cancer Carcinogenesis

X Prostate Cancer in Mexican Americans and African Americans

X Risk Factors for Advanced Prostate Cancer

X Signaling in Androgen Refractory Prostate Cancer

Prostate Cancer Intervention Versus Observation Trial (PIVOT) (http://www.va.gov/PIVOT/)

Objective: Randomized trial comparing radical prostatectomy versus expectant management for the

treatment of clinically localized prostate cancer.

Affected Research Categories: Early Detection, Diagnosis, and Prognosis; Treatment; Cancer Control,

Survivorship, and Outcomes

Relevant Program Relevant to This Initiative: Begun in 1994, the trial is being conducted at over 50 U.S.

sites. Enrollment is complete at 731 men who will be followed for 15 years. The Department of Veterans

Affairs maintains a PIVOT website that is directed at the public.

Table 2-1. (cont.)
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Chapter 2 Initiatives

Table 2-1. (cont.)

Prostate, Lung, Colorectal & Ovarian Cancer Screening Trial (PLCO) (http://www3.cancer.gov/

prevention/plco/index.html)

Objective: A large clinical trial aimed at determining whether cancer screening tests reduce deaths from

prostate, lung, colorectal, and ovarian cancer. The study includes questionnaire and biologic sample

collections for early marker and etiologic studies of prostate and other cancers.

Affected Research Categories: Early Detection, Diagnosis, and Prognosis; Etiology and Prevention;

Treatment; Cancer Control, Survivorship, and Outcomes

Relevant Program Resulting from This Initiative: Publications concerning the PLCO and its initial results

can be found at http://www3.cancer.gov/prevention/plco/updates.html.

Prostate Specialized Programs of Research Excellence (SPOREs) (http://spores.nci.nih.gov/

prostate/prostate.html)

Objective: Translational research on the prevention, etiology, screening, diagnosis, and treatment of a

specific organ-site cancer.

Affected Research Categories: All

Relevant Program Resulting from This Initiative: Eleven current Prostate SPOREs; see Table 2-2 for a

listing of projects and core resources associated with each. Yearly meetings are held to facilitate communication among the researchers participating in the Prostate and Genitourinary SPOREs and among the

researchers participating in SPOREs for all cancer types.

INITIATIVES WITH PROSTATE CANCER-RELEVANT COMPONENTS

Applications of Innovative Technologies for the Molecular Analysis of Cancer (PAR-01-106)

(PAR-01-107)

Objective: Evaluate the utility and pilot the application of molecular analysis technologies in studies

relevant to cancer research.

Affected Research Categories: Biology; Early Detection, Diagnosis, and Prognosis; Treatment

Relevant Research Projects Resulting from This PA:

X Analysis of Circulating Cancer Cells Early in Disease

X Development of Bacterial Artificial Chromosome Array Comparative Genomic Hybridization

X Imaging Alternative Splicing during Tumor Progression

X In Vivo Analysis of Tumor Peptide Secretion

X Isolation and Profiling of Circulating Prostate Cancer Cells in Blood

X Molecular Analysis of Cancer—Imaging Mass Spectrometry

X Phage Display and Prostate Neoplasia Progression

X Prognostic Value of Telomere DNA in Prostate Biopsy

Cancer Centers Program (http://www3.cancer.gov/cancercenters)

Objective: Support major academic and research institutions throughout the United States to sustain

broad-based, coordinated, interdisciplinary programs in cancer research.

Affected Research Categories : All

Relevant Resource Resulting from This Initiative: Approximately 60 institutions across the United States

are being supported as NCI-Designated Cancer Centers. The NCI’s Executive Committee has designated

39 of the institutions as Comprehensive Cancer Centers based on the criteria of (1) the Center’s breadth,

depth, and interactions among basic research, clinical research, and research in prevention, control, and

population/behavioral sciences and (2) the Center’s public information, education, and outreach activities.
2-5

Chapter 2 Initiatives

NATIONAL CANCER INSTITUTE

Table 2-1. (cont.)

Cancer Genome Anatomy Project (CGAP) (http://cgap.nci.nih.gov/)

Objective: Collaborative program for determining the gene expression profiles of normal, precancerous,

and cancerous cells.

Affected Research Categories: Biology; Etiology and Prevention; Early Detection, Diagnosis, and

Prognosis

Relevant Resource Resulting from This Initiative: The program was started in 1996. Through the CGAP

website, researchers can access human and mouse genomic data, informatics tools, and information on

methods and resources. The database of expressed genes, which includes data from nearly 300 diseased

and normal prostate tissue cDNA libraries, currently lists nearly 400 genes uniquely expressed in cancerous

or precancerous prostate tissue cDNA libraries.

Cancer Imaging Program (CIP) (http://www3.cancer.gov/dip)

Objective: Promote and support cancer-related basic, translational, and clinical research in imaging

sciences and technology; and integration and application of these imaging discoveries and developments

to the understanding of cancer biology and to the clinical management of cancer and cancer risk.

Affected Research Categories: Early Detection, Diagnosis, and Prognosis; Scientific Model Systems;

Treatment; Biology

Relevant Programs Resulting from This Initiative: Prostate cancer research has been supported through

RFAs for the following programs:

X Diagnostic Imaging and Guided Therapy in Prostate Cancer – Phased Innovation Award

X In Vivo Cellular and Molecular Imaging Centers (ICMICs) and the Pre-In Vivo Cellular and Molecular

Imaging Centers (Pre-ICMICs)

X Small Animal Imaging Resource Programs

Cancer Molecular Analysis Project (CMAP) (http://cmap.nci.nih.gov)

Objective: Access to molecular data relating to cancer from different frames of reference.

Affected Research Categories: Biology; Etiology and Prevention; Early Detection, Diagnosis, and Prognosis; Treatment

Relevant Resource Resulting from This Initiative: Data can be retrieved from the CMAP website via the key

concepts of context (including prostate carcinoma), target, anomaly, profile, agent, and trial.

Cancer Prognosis and Prediction (PAR-01-062)

Objective: Develop new strategies for determining prognosis or predicting response to cancer therapy.

Affected Research Categories: Early Detection, Diagnosis, and Prognosis; Treatment

Relevant Programs Resulting from This Initiative: Pending

Cancer Research Training, Career Development, and Education Opportunities

(http://cancertraining.nci.nih.gov/)

Objective: Well-trained investigators in the

basic, clinical, population, and behavioral

sciences, who are prepared to address

problems in cancer biology, causation,

prevention and control, detection and

diagnosis, and treatment and rehabilitation.

Affected Research Categories: All

Relevant Resource Resulting from This

Initiative: More than 10 types of awards exist that support predoctoral and postdoctoral training and faculty

career development. The number of individual training and career development awards with 25 percent or

more relevance to prostate cancer has more than doubled between fiscal year (FY) 1998 and FY 2002.

0

10

20

30

50

1998 1999 2000 2001

NCISupported

Projects

per

Year

2002

40
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Chapter 2 Initiatives

Table 2-1. (cont.)

Cancer Therapy-Related Use of Genetically Engineered Mice (PAR-02-051)

Objective: Use of genetically engineered mouse cancer models for cancer therapy-related goals.

Affected Research Categories: Scientific Model Systems; Treatment

Relevant Research Projects Resulting from This PA: PI-3 Kinase Therapy in Mouse Tumor Models

Clinical Trials Cooperative Group Program (http://ctep.cancer.gov/resources/coop2.html)

Objective: Support organizations that generate and conduct clinical trials and the developmental efforts that

precede them, with emphasis on randomized Phase III trials.

Affected Research Categories: Etiology and Prevention; Early Detection, Diagnosis, and Prognosis;

Treatment; Cancer Control, Survivorship, and Outcomes

Relevant Program Resulting from This Initiative: Fourteen member organizations, with nine currently

conducting trials on prostate cancer.

Relevant Resource Resulting from This Initiative: Banked tissue resources are available to investigators

through each cooperative group.

Common Data Elements (CDE) Initiative (http://ncicb.nci.nih.gov/CDEBrowser)

Objective: Standardize and simplify the collection and reporting of data in NCI-sponsored clinical trials.

Affected Research Categories: Etiology and Prevention; Treatment; Cancer Control, Survivorship, and

Outcomes

Relevant Resource Resulting from This Initiative: A set of core and prostate-specific data elements have

been developed.

Community Clinical Oncology Program (CCOP) (http://www3.cancer.gov/prevention/ccop)

Objective: Groups of hospitals and private practices that participate in NCI-sponsored clinical trials.

Affected Research Categories: Etiology and Prevention; Treatment; Cancer Control, Survivorship, and

Outcomes

Relevant Programs Resulting from This Initiative: Sixty-one CCOPs, including 11 Minority-Based CCOPs,

participate in clinical trials with 15 research bases, of which 7 coordinate prostate cancer trials with the

CCOPs.

Cooperative Human Tissue Network (CHTN) (http://www-chtn.ims.nci.nih.gov)

Objective: Collect and distribute benign, pre-cancerous, and cancerous human tissue specimens for basic

and developmental studies in cancer research.

Affected Research Categories: All

Relevant Resource Resulting from This Initiative: Six member institutions currently coordinate the collection and distribution of specimens that include tissues obtained at surgery and autopsy, serum, and DNA/

RNA. In 2002, CHTN delivered 1,285 prostate specimens to investigators.

Director’s Challenge: Toward a Molecular Classification of Cancer (http://dc.nci.nih.gov)

Objective: Use of molecular analysis technologies for tumor classification.

Affected Research Categories: Biology; Etiology and Prevention; Early Detection, Diagnosis, and Prognosis

Relevant Program Resulting from This Initiative: The Director’s Challenge program website provides

researchers with information, tools, and microarray datasets.

Relevant Research Projects Resulting from This Initiative:

X A Cancer Taxonomy Based on Gene Expression Patterns

X Gene Expression Analysis of Cancers of the Prostate and Lung

X Molecular Characterization of Early-Stage Prostate Cancer

X Molecular Classification of Prostate Cancer 

X Molecular Reclassification of Prostate Cancer
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Chapter 2 Initiatives

NATIONAL CANCER INSTITUTE

Table 2-1. (cont.)

Exploratory Grants for Correlative Laboratory Studies and Clinical Trials (PA-98-042)

Objective: Innovative clinical therapy trials or correlative laboratory studies with patient specimens.

Affected Research Categories: Etiology and Prevention; Early Detection, Diagnosis, and Prognosis;

Treatment

Relevant Research Projects Resulting from This PA:

X Identification of a Potential Cytogenetic Marker

X Molecular Staging of Lymph Nodes—Outcome of Prostate Cancer

X Monitoring Chemotherapy in Prostate Cancer by Proton Nuclear Magnetic Resonance

X Optimized Cancer Chemotherapy via Pharmacodynamic Models

X Pulse Calcitriol for Prostate Cancer Prevention

X T Cell Signal Transduction in Cancer Immunotherapy

Flexible System to Advance Innovative Research for Cancer Drug Discovery by Small

Businesses (FLAIR) (http://dtp.nci.nih.gov/branches/gcob/gcob_web17.html)

Objective: Provide support for the extensive needs of drug and vaccine discovery through proof of principle

demonstration in clinical trials.

Affected Research Categories: Etiology and Prevention; Treatment

Relevant Research Projects Resulting from This Initiative:

X Alphavirus Prime-Boost Vaccines for Prostate Cancer

X Complementary Adenoviral Vectors for Treatment of Cancer

X Cytotoxic Gonadotropin Releasing Hormone Derivatives

X Development of DNA Methyltransferase Inhibitors as Anticancer Agents

X Development of a New Antiangiogenic Tumor Blocker SBD 1

X Human Anti-Prostate-Specific Membrane Antigen (PSMA) Antibodies for Prostate Cancer Therapy

X New Target Antigens for Prostate Cancer Vaccines

X Peptide Antagonists of Urokinase Plasminogen Activator

Genitourinary Cancers Faculty (http://ccr.cancer.gov/faculties/faculty.asp?facid=131)

Objective: Develop better methods for prevention, diagnosis, and treatment of genitourinary malignancies

through intramural collaborations, interdisciplinary research, and translational (bench-to-bedside) science.

Affected Research Categories: Biology; Etiology and Prevention; Early Detection, Diagnosis, and

Prognosis; Treatment

Relevant Resource Resulting from This Intramural Program: Faculty from approximately 20 NCI branches

and laboratories participate in a monthly seminar series and annual retreat to facilitate communication and

collaborations between laboratories. The faculty members also work together to recruit new urologic and

oncology fellows and to plan new research objectives, such as initiating a new molecular imaging study and

conducting a trial on seed implantation therapy in prostate cancer.

Improving DNA, RNA, and Protein Availability in Fixed Tissue (PAR-00-079)

Objective: Develop improved methods for fixing tissues and making nucleic acids and proteins more

readily accessible from archived specimens.

Affected Research Categories: Biology; Etiology and Prevention; Early Detection, Diagnosis, and

Prognosis; Scientific Model Systems; Treatment

Relevant Research Project Resulting from This PA: Fixation of Breast and Prostate Cancer Tissue
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Chapter 2 Initiatives

Table 2-1. (cont.)

In Vivo Cellular and Molecular Imaging Centers (ICMICs) (http://www3.cancer.gov/bip/

ICMICs.htm)

Objective: Capitalize on noninvasive and, in many cases, quantitative imaging methods for studying cancer.

Affected Research Categories: Biology; Etiology and Prevention; Early Detection, Diagnosis, and Prognosis; Scientific Model Systems; Treatment

Relevant Resource Resulting from This Initiative: Seven centers exist, with additional institutions planning

to become centers via Planning Grants for Pre-In Vivo Cellular and Molecular Imaging Centers (CA-01-010

and CA-99-002). Examples of research conducted at these centers include (1) the inhibition of cellular

growth and angiogenesis factors and (2) the development of functional tracers for molecular targets to be

used for imaging primary and metastatic prostate cancer with Positron Emission Tomography (PET) and

Single Photon Emission Computed Tomography (SPECT) techniques.

Interdisciplinary Research Teams for Molecular Target Assessment (RFA-CA-00-001)

Objective: Develop methods to assess the effects of interventions directed at specific molecular targets that

produce or are associated with the cancer phenotype.

Affected Research Categories: Etiology and Prevention; Treatment

Relevant Research Project Resulting from This PA: Mechanism-Based Evaluations of ErbB Targeted

Agents

Minority Institution/Cancer Center Partnership (MI/CCP) Program (http://

minorityopportunities.nci.nih.gov/institutions/faqs.html)

Objective: Partnerships between minority-serving institutions and NCI-designated Cancer Centers to increase training and involvement of scientists at minority institutions and develop collaborative projects that

address the disproportionate incidence and mortality of cancer in minority populations.

Affected Research Categories: All

Relevant Program Resulting from This Initiative: Twenty current partnerships, including one (University of

California Comprehensive Cancer Center/San Francisco State University) that is focused on prostate and one

other cancer type.

Minority-Based Community Clinical Oncology Program (MBCCOP) (http://www3.cancer.gov/

prevention/ccop/mbccop.html)

Objective: Groups of hospitals and private practices, with extensive minority patient populations, that

participate in NCI-sponsored clinical trials.

Affected Research Categories: Etiology and Prevention; Treatment; Cancer Control, Survivorship, and

Outcomes

Relevant Program Resulting from This Initiative: Eleven funded groups with eight currently participating in

trials on prostate cancer.

Molecular Profiling Initiative (MPI) (http://cgap-mf.nih.gov/ProstateExample/index.html)

Objective: A tissue microdissection-based approach to molecular profiling.

Affected Research Categories: Early Detection, Diagnosis, and Prognosis; Treatment

Relevant Resource Resulting from This Initiative: Prostate Molecular Profiling at NCI, which includes the

following:

X 3D Prostate Molecular Model Demo

X Prostate Microreviews
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Chapter 2 Initiatives

NATIONAL CANCER INSTITUTE

Table 2-1. (cont.)

Molecular Target Drug Discovery for Cancer (PAR-01-045) (PAR-01-046)

Objective: Exploit molecular targets for drug discovery.

Affected Research Categories: Etiology and Prevention; Treatment

Relevant Research Projects Resulting from These PAs:

X Inhibition of Androgen Receptor Activation

X New Triterpenoids for Chemoprevention of Cancer

X Photodynamic Therapy for Prostate Cancer

X Shh Signaling as a Therapeutic Target in Prostate Cancer

X Structure-Based Discovery of AKT Inhibitors

X Targeting Functional Domains in Telomerase

NCI Center for Bioinformatics (NCICB) (http://ncicb.nci.nih.gov)

Objective: Provide bioinformatics support and integrate diverse research initiatives.

Affected Research Categories: All

Relevant Research Projects Resulting from This Initiative: NCICB’s Cancer Common Ontologic Reference

Environment (caCORE) research information management system backbone software is available to researchers.

Program for the Assessment of Clinical Cancer Tests (PACCT)

(http://www.cancerdiagnosis.nci.nih.gov/assessment)

Objective: To maximize the impact of cancer treatments and to ensure translation of new knowledge about

cancer into clinical practice.

Affected Research Categories: Biology; Treatment; Early Detection, Diagnosis, and Prognosis

Relevant Programs Resulting from This Initiative: A PACCT Strategy Group was convened in order to

develop criteria for assessing which markers are ready for further development.

Relevant Resources Resulting from This Initiative: Several websites help researchers gain access to

human specimens:

X NCI Specimen Resource Locator

X Shared Pathology Informatics Network

X Tissue Array Research Program

X Tissue Expediter

Shared Resources for Scientists outside NCI Cancer Centers (PAR-99-127)

Objective: Provide additional shared resource support to institutions that do not have NCI-funded cancer

centers or planning grants.

Affected Research Categories: Etiology and Prevention; Early Detection, Diagnosis, and Prognosis;

Treatment

Relevant Resource Resulting from This PA: Viral Vector Core Facility

Small Animal Imaging Resource Program (SAIRP) (CA-01-012)

Objective: Support shared imaging research resources to be used by cancer investigators and conduct

research related to small animal imaging technology.

Affected Research Categories: Biology; Etiology and Prevention; Early Detection, Diagnosis, and Prognosis; Scientific Model Systems; Treatment

Relevant Programs Resulting from This Initiative: Ten participating institutions provide imaging resources for

investigators in their region of the United States. Examples of research conducted at these centers include (1) the

inhibition of cellular growth and angiogenesis factors and (2) the development of functional tracers for molecular

targets to be used for imaging primary and metastatic prostate cancer with PET and SPECT techniques.
NATIONAL CANCER INSTITUTE

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Chapter 2 Initiatives

Baylor College of Medicine (funded since September 1992)

Projects:

X Biological Therapy for Prostate Cancer

X Endocrinology and the Role of Stroma Genes in Prostate Cancer

X Gene Therapy for Prostate Cancer

X Markers of Progression and Metastasis

X Physical and Functional Analysis of Prostate Cancer Genes

X Prostate-Specific Gene Expression in Transgenic Animals

X The Role of CDK Inhibitors in Prostate Cancer

Cores: Administrative Core, SPORE Pathology Core, Medical Informatics Core, Transgenic Core, and

Microarray Core Facility

Table 2-1. (cont.)

Table 2-2 provides more information on the research projects, core resources, training, and other

opportunities that are provided by the 11 current Prostate SPOREs.

Table 2-2. Prostate SPOREs

Special Populations Networks (SPNs) (http://crchd.nci.nih.gov/spn/index.html)

Objective: Establish an infrastructure to promote cancer awareness within minority and medically

underserved communities and launch more research and cancer control activities aimed at specific population subgroups.

Affected Research Categories: Etiology and Prevention; Treatment; Cancer Control, Survivorship, and

Outcomes

Relevant Programs Resulting from This Initiative:

X Arkansas Special Populations Access Network 

X Cancer Awareness and Training Collaboration Coordinated by the Latino Research and Policy Center

X Cancer Awareness Network for Immigrant Minority Populations

X Increasing Access to Clinical and Educational Studies

X National Black Leadership—Cancer Control, Research, and Training Network 

Specimen Resource Locator (http://pluto3.nci.nih.gov/tissue/default.htm)

Objective: A database to help researchers locate human specimens for cancer research.

Affected Research Categories: Biology; Etiology and Prevention; Early Detection, Diagnosis, and Prognosis; Scientific Model Systems; Treatment

Relevant Resource Resulting from This Initiative: The Specimen Resource Locator website provides

investigators with information and automated tools for identifying tissue procurement systems, including those

with samples from normal and diseased prostate.

Technologies for Comprehensive, Sensitive, and Quantitative Protein Analysis in Human

Tumors: Phased Innovation (RFA-CA-01-011)

Objective: Develop innovative technologies for the sensitive quantitation of the comprehensive spectrum of

proteins present in human tissues.

Affected Research Categories: Biology; Etiology and Prevention; Early Detection, Diagnosis, and

Prognosis

Relevant Research Project Resulting from This RFA: Novel Quantitative, Comprehensive Proteomic

Technology
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Chapter 2 Initiatives

NATIONAL CANCER INSTITUTE

Dana-Farber Cancer Institute (funded since September 1992)

Projects:

X The Androgen Receptor in Hormone Refractory Disease

X Genetic and Serologic Determinants of Prostate Cancer Risk and Progression

X Genomic Expression Analysis of Tumors after Radical Prostatectomy

X PPAR as a Target of Therapy for Prostate Cancer

X Single Nucleotide Repeat Polymorphism Analysis of Recurrent Prostate Cancer after Radiation Therapy

Cores: Administration, Evaluation, and Planning Core; Biostatistics Core; Tissue and Pathology Core; and

Genomics Core

Additional: Career Development Project and Developmental Projects Program

The Johns Hopkins School of Medicine (funded since September 1992)

Projects:

X Androgen Receptor Gene Structure and Function in Human Prostate Cancer

X Cellular and Molecular Basis of Prostate Metastasis to Bone

X Down Regulation of Metastasis Suppressor Genes as Diagnostic Methods for Predicting the Biologic

Behavior of Histologically Detectable Prostate Cancer

X Gene Therapy for Human Prostate Cancer

X Human Prostate Cancer Nuclei: Abnormalities in Structure and the Development of New Molecular Markers

X Longitudinal Studies of Men with and without Prostate Cancer

X Mechanisms of Sensitivity and Drug Resistance in Prostate Cancer

X Molecular Genetics of Human Prostate Cancer

X Rational Prostate Cancer Prevention Studies

X Search for Hereditary Prostate Cancer Genes Using Linkage Analysis and Positional Cloning

X Transgenic Models of Prostate Cancer and Autoimmunity

Additional:

X Administrative Supplement: SPORE for Developing a Tissue Microarray

X Career Development Project: Determinants of Radiosensitivity in Prostate Cancer Cells

X Career Development Project: New Methods to Determine Tissue Architecture and Chromatin Structure

Mayo Clinic Rochester (funded since August 2001)

Projects:

X Biologic and Clinical Studies of the Overrepresented 8q24 Region Associated with Prostate Cancer

Progression

X Gene Therapy of Prostate Cancer Using Radioiodine

X Genetic Susceptibility in Prostate Cancer

X Human Kallikreins as Novel Markers of Prostate Cancer

X An Immune-Based Therapeutic Approach for Prostate Cancer

X Use of Fusogenic Membrane Glycoproteins for Gene Therapy of Prostate Cancer

Cores: Administrative Core, Tissue Procurement Core, Gene Discovery/Bioinformatics Core, Clinical

Follow-up Core, and Biostatistics Core

Table 2-2. (cont.)
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Chapter 2 Initiatives

Table 2-2. (cont.)

Maximize the effectiveness and efficiency of prostate cancer scientists

by providing them with essential resources and infrastructure for

conducting their research.

– National Institutes of Health, Prostate Cancer Research Plan for FY 2003–2008.

MD Anderson Cancer Center (funded since June 2001)

Projects:

X The Biology of Human Prostate Cancer Metastasis

X Epidemiologic, Molecular, and Clinical Markers of Prostate Cancer Progression

X Exploring the Molecular Diversity of Blood Vessels for Diagnostic and Therapeutic Targeting in Prostate Cancer

X Targeting Prostate Cancer Bone Metastasis

X Therapeutic Modulation of Apoptosis in Prostate Cancer Patients

Cores: Administrative Core, Biostatistics Core, and Tissue Resource and Pathology Core

Memorial Sloan-Kettering Institute for Cancer Research (funded since September 2001)

Projects:

X The Development of DNA Vaccines against Prostate Cancer with PSMA as a Target

X Mechanism-Based Therapy for Prostate Cancer

X Molecular Analysis of Carcinogenesis in the Mouse and Human Prostate

X Natural History of Prostate Cancer, Prognostic Models, and Decision Making

Cores: Pathology Core, Informatics Core, Animal Models Core, Animal Imaging Core, DNA Array Core, and

Administrative Core

Northwestern University (funded since June 2001)

Projects:

X Clinical Trial on Lycopene

X Clusterin as a Negative Prognostic Indicator in Prostate Cancer

X Generation of, and Angiostatin Levels in, Prostate Cancer

X Molecular Mechanisms of Neuropathic Erectile Dysfunction

X QOL Item Banking and Adaptive Testing in Prostate Cancer

X Suppressive Role of Androgen-Response Gene Calreticulin in Prostate Cancer

University of California, Los Angeles (funded since September 2002)

Projects:

X Interactions between Insulin-Like Growth Factor Binding Proteins and Nuclear Receptors in Prostate

Cancer

X Prostate Stem Cell Antigen in the Biology and Therapy of Prostate Cancer

X The Role of the Her-Kinase Axis in Emergence of Androgen Independence in Human Prostate Cancer

X The Role of Quantity and Composition of Dietary Fat in the Prevention of Prostate Cancer

X Targeted Therapy of PTEN Null Prostate Cancer

Cores: Administrative Core, Pathology Core, Imaging Core, Animal Models Core, and Biostatistics Core
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Chapter 2 Initiatives

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Table 2-2. (cont.)

NCI’s Future Investments in Resource and

Capacity Building

The NIH Prostate Cancer Research Plan for FY 2003–2008 describes the NCI’s planned objectives

for each category of prostate cancer research and for resource and capacity building. The FY 2003–2008

objectives for the different categories of prostate cancer research are addressed in Chapters 3–8 of this

report. The six FY 2003–2008 objectives for resource and capacity building and their alignment to the

PRG priorities for needed resources noted at the beginning of the chapter are summarized in Figure 2-1.

Building upon the framework developed by the PRG, the FY 2003–2008 objectives emphasize integration

of NCI resources, as well as new opportunities and needs.

University of California, San Francisco (funded since September 2000)

Projects:

X Anti-CTLA4 Antibody Immunologic Therapy for Prostate Cancer

X Antibody Gene Diversity Libraries and Phage Display to Generate Recombinant Human Antibodies for

Prostate Cancer Therapy

X Genomics of Prostate Cancer

X Identification of Prostate Tumor Susceptibility Genes Using Mouse Models for Prostate Cancer

X Mechanisms of Hormone Resistance in Prostate Cancer

X Viral Therapy for Prostate Cancer

Cores: Administrative Core, Tissue Core, Informatics Core, Advocacy Core, Clinical Research Core, and

Animal Technology Core

Additional: Developmental Research Program

University of Michigan (funded since September 1995)

Projects:

X Epidemiology of Prostate Cancer in African Americans

X Hereditary Prostate Cancer in African American Families

X Inhibition of Human Prostate Cancer Metastasis

X Rb as a Regulator of Prostate Tumorigenesis

X Vaccinia PSA for Androgen-Modulated, Post-Surgical Recurrence of Prostate Cancer

Cores: Administrative Core, Tissue and Animal Models Core, and Biostatistics Core

University of Washington/Fred Hutchinson Cancer Research Center (funded since September

2002)

Projects:

X Characterization of Anti-Apoptotic Genes Induced during Androgen-Independent Progression and

Chemotherapy

X Genomic and Gene Expression Profiling of Disseminated Prostate Cancer

X Molecular Predictors of Prostate Cancer Progression and Mortality

X Transcriptome and Proteome Stratification of Prostate Adenocarcinoma Phenotypes

Cores: Leadership and Administration Core, Specimen and Tissue Core, Biostatistics Core, Informatics

and Gene Expression Core, and Clinical Core

Additional: Developmental Research Program and Career Development Program
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Chapter 2 Initiatives

PRG Priorities

Education and Training of Prostate Cancer

Investigators

Continue to improve the infrastructure needed

to promote interdisciplinary research and

collaborations and develop the expertise 

needed to move discoveries to application.

FY 2003–2008 Objectives

Informatics Network of Databases and 

Specimen Repositories

 Repositories

 Databases

 Patient Consent

Preclinical Models

New Technologies

Clinical Trials

Build a stable cadre of basic, clinical, biobehavioral, and population scientists who

can work together effectively in a multidisciplinary environment.

Build an integrated suite of research resources

that enable the scientific community to 

enhance discovery and readily translate 

findings into clinical applications.

Strengthen the infrastructure needed for the

increasing number of clinical trials that are

pivotal to validating prognostic markers and

developing new preventive agents and novel

therapeutics.

Laboratory and Preclinical Models: Use 

validated models to identify and test 

preventive, detection, and therapeutic agents.

(See Figure 6-2, Chapter 6.)

Treatment: Strengthen clinical trial infrastructure including design and patient recruitment

to increase the number of rigorous clinical

trials that are pivotal to developing and testing

novel therapeutics. (See Figure 7-2, 

Chapter 7.)

Figure 2-1. NIH’s FY 2003–2008 prostate cancer resource and

infrastructure objectives build upon PRG priorities.

The NIH Prostate Cancer Research Plan for FY 2003–2008 also describes near-term initiatives for

facilitating and stimulating prostate cancer research.

X Under consideration as new initiatives are a Comprehensive Protein Fingerprinting Program, a

Comprehensive Molecular Technology Program, and a second-round Prostate Cancer Outcomes

Study.

X Prostate SPOREs, CGAP, CanCORS,2 SPNs, and Translating Research into Improved Outcomes

(TRIO) were highlighted for potential expansion.

3

Better integration is planned among the various consortia and networks that participate in prostate

cancer research.4

2 CanCORS currently focuses on lung and colorectal cancers.

3 TRIO is focused on breast and cervical cancers.

4 Toward the goal of better integration, in February 2003, the NCI’s P30/P50 Ad Hoc Working Group issued the report

Advancing Translational Cancer Research: A Vision of the Cancer Center and SPORE Programs of the Future.
3-1

Chapter 3 Prostate Cancer Biology

NATIONAL CANCER INSTITUTE

CHAPTER

3

Prostate Cancer Biology:

NCI’s Investment and

Recent Progress

To provide a foundation for its applied research on prostate cancer prevention, detection, diagnosis,

and treatment, the NCI supports basic research on the biological changes that occur during the development and progression of prostate cancer. Normal, pre-malignant, and malignant prostate tissues, including

regional and distant metastases, are characterized for structural and functional differences at tissue,

cellular, and molecular levels, with the goal of determining the entire sequence of events in all pathways

that lead to or impact progression of prostate malignancy.

In their 1998 report, the Prostate Cancer PRG described the need for continued research

on prostate cancer biology, progression, and metastasis. Studies leading to a better understanding

of normal prostate development, early prostate cancer, the transition to hormone refractory disease, tumor

microenvironment, and bone metastasis are needed to pave the way for improved prevention, detection,

and treatment. Specifically, there is a need to identify and characterize the genes and molecular markers

that are differentially expressed, the signal transduction pathways that are activated, and the tumor–

stromal interactions that take place during the different stages of prostate cancer development and

progression.

Through dynamic deliberation, the PRG identified 10 Priority One research questions that offered the

best opportunities for advancing our understanding of prostate cancer biology. The NCI has responded

to these Priority One questions and their accompanying recommendations. Significant progress

has been made in characterizing the differential expression of specific transcription factors, fatty acid

metabolizing enzymes, tumor suppressors, and oncogenes in normal and cancerous prostate tissues. These

differences can be leveraged for detection and diagnosis and

for targeted destruction of cancerous cells.

New models have been proposed to explain the transition from androgen-dependent to androgen-independent

disease—a change that heralds continued progression and

poor clinical outcome. Further insight into prostate cancer

progression has been gained from identifying and characterizing the specific growth factors and surface proteins of

stromal cells, which are, in turn, being applied to investigate

metastatic disease, including the invasive mechanism of

lymphangiogenesis and the adoption of osteo-mimetic

properties by metastatic cells.

The progress made in prostate cancer biology research

in recent years has fueled progress in the areas of prevention, detection, diagnosis, and treatment. For a more

comprehensive understanding of this progress, readers are

urged to see Chapters 4, 5, and 7 of this report.

Understanding prostate

cancer biology, progression,

and metastasis is

fundamental to improving our

abilities to successfully

prevent, diagnose, and treat

human prostate cancer.

– Defeating Prostate Cancer: Crucial

Directions for Research - Report of

the Prostate Cancer Progress Review

Group, August 1998.
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Chapter 3 Prostate Cancer Biology

NCI’s Investment and Response

From fiscal year (FY) 1998 to FY 2002, NCI’s extramural investment in research on prostate cancer

biology has grown from $15.2 million (M) to $41.7M (Figure 3-1). This increase corresponds to increases

in the number of projects that are responsive to PRG priorities in biology. Table 3-1 summarizes NCI’s

responsiveness to the 10 Prostate Cancer PRG Priority One research questions for biology.

Figure 3-1. NCI’s estimated investment in prostate cancer biology, progression,

and metastasis extramural research: 1998–2002 (in millions of dollars).

0

10

30

50

1998 1999 2000 2001 2002

Fiscal Year

Millions of Dollars40

20

NCI Efforts:

X In FY 2002, active areas of investigation included structural interactions of intracellular receptors and

specific ligands, regulation of androgen receptor-mediated transcription of DNA by associated factors,

identification of novel proteins that associate with the androgen–androgen receptor complex, and

glucocorticoid effects on tumor cells mediated through receptor binding.

X Seven projects addressed the PRG recommendation to expedite structural and pharmacological studies of

important nuclear receptors and steroid-metabolizing enzymes.

X NCI initiatives addressing this priority included Age-Related Prostate Growth: Biologic Mechanisms;

Prostate Specialized Programs of Research Excellence (SPOREs); Biology, Development, and Progression

of Malignant Prostate Disease; and Role of Hormones and Growth Factors in Prostate Cancer.

PRG Priority: What are the potential

roles of nuclear receptors, their interactive

proteins, and ligand-metabolizing enzymes

on prostate growth, tissue interactions,

and development?

0

10

20

30

50

1998 1999 2000 2001

NCISupported

Projects

per

Year

2002

40

Table 3-1. NCI Efforts Responsive to PRG Priorities in

Prostate Cancer Biologya

a A given project may map to more than one PRG Priority One question and therefore be represented in more than one figure. Projects active in

2002 are listed by Principal Investigator’s name for each PRG Priority One question in Appendix B (Tables B-1–B-11).
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NCI Efforts:

X In FY 2002, active areas of investigation included IGF-I axis in prostate development and carcinogenesis,

biochemical analysis and expression analysis of Nkx3.1 in mouse models, EPLIN protein expression and

function in embryogenesis and tissue homeostasis, signal transduction processes in normal and

dysregulated growth and differentiation, and gonadotrophin-releasing hormone and its receptor in normal

and cancerous prostate tissues.

X NCI initiatives addressing this priority included Age-Related Prostate Growth: Biologic Mechanisms;

Biology, Development, and Progression of Malignant Prostate Disease; Development of Cell-Selective

Tools for Studies of the Bladder, Prostate, and Genitourinary Tract; and Role of Hormones and Growth

Factors in Prostate Cancer.

PRG Priority: What are the biochemical and molecular events that

govern the continuation of prostate

development from early embryogenesis to the onset of adulthood, through

maturation, aging, and death?

0

3

6

9

15

1998 1999 2000 2001

NCISupported

Projects

per

Year

2002

12

NCI Efforts:

X In FY 2002, active areas of investigation included opposing effects of kinases and phosphatases in

cellular invasion, proteases that facilitate tumor growth and metastasis, protease inhibitors that prevent

tumor metastasis, identification of specific metastasis-related genes from chromosomal mapping, DNA

damage from estrogens and metabolism of estrogens, evaluation of Bcl-2 mutations in mouse models,

metastatic potential of the methylated E-cadherin gene, and CXC chemokine dysregulated expressioninduced angiogenesis.

X Five projects addressed the PRG recommendation to develop additional models to study cancer

metastasis, particularly with respect to skeletal pathophysiology and its associated biochemical

characteristics.

X NCI initiatives addressing this priority included Prostate SPOREs; Cancer Molecular Analysis Project

(CMAP); Director’s Challenge toward a Molecular Classification of Cancer; Biology, Development, and

Progression of Malignant Prostate Disease; and Molecular and Cellular Biology of Metastatic Tumor Cells.

PRG Priority: What are the molecular

determinants that govern cancer invasion,

migration, and metastasis?

0

20

60

80

120

1998 1999 2000 2001

NCISupported

Projects

per

Year

2002

40

100

Table 3-1. (cont.)
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Chapter 3 Prostate Cancer Biology

NCI Efforts:

X In FY 2002, active areas of investigation included free-radical scavengers and DNA damage,

retinoblastoma-mediated induction of cell death, isopeptidase effects on apoptosis and cell-cycle arrest,

BRCA2 and Rad51 mechanisms of DNA repair, TR3/nur77 mediation of cytochrome C release leading to

apoptosis, and comparisons of chromosomal instability and DNA repair capacity.

X NCI initiatives addressing this priority included Improving DNA, RNA, and Protein Availability in Fixed Tissue.

NCI Efforts:

X In FY 2002, active areas of investigation included connexin43-mediated gap junction communication,

genes expressed in the presence of stromal cells that influence metastasis, age and other effects on tumor

microenvironment, mechanisms of smooth muscle interactions with prostate epithelium, and signaling

mechanisms that regulate differentiation and secretion of neuroendocrine cells.

X Two projects addressed the PRG recommendation to improve transgenic and other animal systems by

introducing factors to the prostate gland in the hope of recapitulating the natural history of prostate

development and its neoplastic transformation.

X NCI initiatives addressing this priority included Prostate SPOREs; Biology, Development, and

Progression of Malignant Prostate Disease; and Role of Hormones and Growth Factors in Prostate

Cancer.

PRG Priority: What are the regulatory effector molecules that control

reciprocal interactions between

epithelial and stromal cells, among

clonal cancer epithelial cells, and

between cancer cells and most

immune-reactive cells? 0

10

20

30

1998 1999 2000 2001

NCISupported

Projects

per

Year

2002

15

5

25

NCI Efforts:

X In FY 2002, active areas of investigation included growth factors and receptors identified during tumor

induction in epithelial and stromal cells, cell adhesion molecule interacting proteins, epithelial and

endothelial cell proliferation regulated by integrin beta1C, and properties of carcinoma-associated

fibroblasts that promote tumor progression.

X NCI initiatives addressing this priority included Age-Related Prostate Growth: Biologic Mechanisms;

Development of Cell-Selective Tools for Studies of the Bladder, Prostate, and Genitourinary Tract; Prostate

SPOREs; and Biology, Development, and Progression of Malignant Prostate Disease.

PRG Priority: What are the specific cell–

cell interactions between and among

developing epithelial cells, stromal cells,

endothelial cells, neuroepithelial cells, and

inflammatory cells?

0

10

20

25

1998 1999 2000 2001

NCISupported

Projects

per

Year

2002

15

5

Table 3-1. (cont.)

PRG Priority: Are there features of

DNA damage, DNA repair, or cellcycle progression that are novel in

prostate cancer cells?

0

10

20

25

1998 1999 2000 2001

NCISupported

Projects

per

Year

2002

15

5
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NCI Efforts:

X In FY 2002, active areas of investigation included regulation of parathyroid hormone-related peptide and

derived peptides, plasminogen activator inhibitor-I role in angiogenesis, expression and mechanisms of

polycomb group proteins (e.g., EZH2) in metastasis, and molecular classification of tumor progression and

response to therapy.

X NCI initiatives addressing this priority included Prostate SPOREs; CMAP; CGAP; Director’s Challenge:

Toward a Molecular Classification of Cancer; Biology, Development, and Progression of Malignant

Prostate Disease; and Molecular and Cellular Biology of Metastatic Tumor Cells.

PRG Priority: Are there hereditary

markers, angiogenesis switches, and/

or biochemical and molecular determinants that predict progression?

0

10

30

40

60

1998 1999 2000 2001

NCISupported

Projects

per

Year

2002

20

50

NCI Efforts:

X In FY 2002, active areas of investigation included tumor vasculogenesis, DNA methylation analyses,

identification of proliferation-based changes in gene expression by microarray analysis, proteomic-based

discovery of stage-specific protein expression, distinct roles of different fibroblast growth factor receptors,

and characterization of putative tumor suppressor genes.

X Twenty-six projects addressed the PRG recommendation to validate genetic and epigenetic molecular

markers by correlating them with clinical specimens.

X Twelve projects addressed the PRG recommendation to establish powerful methods that will allow “fasttrack” discoveries.

X NCI initiatives addressing this priority included Cooperative Prostate Cancer Tissue Resource (CPCTR);

Prostate SPOREs; Cancer Genome Anatomy Project (CGAP); CMAP; Director’s Challenge: Toward a

Molecular Classification of Cancer; Applications of Innovative Technologies for the Molecular Analysis of

Cancer; and Biology, Development, and Progression of Malignant Prostate Disease.

PRG Priority: What are the genetic and

epigenetic determinants that affect

progression of prostate cancer from the

localized to disseminated state? What

molecular markers are associated with

such progression?

0

20

40

60

100

1998 1999 2000 2001

NCISupported

Projects

per

Year

2002

80

Table 3-1. (cont.)
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NCI Efforts:

X In FY 2002, active areas of investigation included bcl-2 protein regulation by Ras, p53, and C/EBP

proteins; tumor suppressor functions of proteins, including B-myc and Fez1; interactions and biological

effects of kinases and phosphatases; inactivation of glutathione S-transferase P1 by CpG island

methylation; signaling pathways in TNF-alpha-mediated apoptosis; and regulation of cell survival,

apoptosis, and sensitivity to drugs and radiation by mitochondrial-associated factors.

X Five projects addressed the PRG recommendation to support the collaborative pursuit of discovering

novel genes expressed during prostate cancer development and its progression to androgen

independence.

X NCI initiatives addressing this priority included Prostate SPOREs; Studies on Breast, Prostate, Ovarian,

and Cervical Cancer; CGAP; Applications of Innovative Technologies for the Molecular Analysis of Cancer;

CMAP; Director’s Challenge: Toward a Molecular Classification of Cancer; and Biology, Development, and

Progression of Malignant Prostate Disease.

PRG Priority: What are the critical

housekeeping and regulatory genes

that may be associated with human

prostate cancer development and

progression?

0

30

60

90

150

1998 1999 2000 2001

NCISupported

Projects

per

Year

2002

120

NCI Efforts:

X In FY 2002, active areas of investigation included intracellular calcium modulation associated with

apoptosis, structural characterization of Akt kinase, NF-kB transcription factor correlation with cellular

oxidative stress, and bioavailability and biotransformation of isoflavonoids.

NCI Efforts:

X In FY 2002, active areas of investigation included genetic map construction of chromosome region 8p21;

functional roles of BRCA2, p21, and p53 as susceptibility genes; distribution and linkage of androgen and

estrogen metabolizing enzyme polymorphisms; and linkage analysis of previously identified and novel

genetic loci.

X NCI initiatives addressing this priority included Prostate SPOREs and Molecular Epidemiology of Prostate

Carcinogenesis.

PRG Priority: How do we define

genetic susceptibility of individuals to

prostate cancer, and how is such

susceptibility associated with other

forms of malignancies or diseases?

0

5

10

15

20

1998 1999 2000 2001

NCISupported

Projects

per

Year

2002

Table 3-1. (cont.)

Additional prostate cancer biology

projects that did not address the PRG

priority questions in this table.

0

2

4

6

10

1998 1999 2000 2001

NCISupported

Projects

per

Year

2002

8
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Much of the NCI’s responsiveness to PRG recommendations has been through initiatives soliciting

new projects on prostate cancer biology. The initiatives relevant to research on prostate cancer biology

between 1998 and 2002 include the following list of general initiatives that are described in Table 2-11

(Chapter 2) and the category-specific initiatives that are listed and described in Table 3-2:2

X Applications of Innovative Technologies for the Molecular Analysis of Cancer

X Cancer Centers Program

X Cancer Genome Anatomy Project (CGAP)

X Cancer Imaging Program

X Cancer Molecular Analysis Project (CMAP)

X Cancer Research Training, Career Development, and Education Opportunities

X Cooperative Human Tissue Network (CHTN)

X Cooperative Prostate Cancer Tissue Resource (CPCTR)

X Director’s Challenge: Toward a Molecular Classification of Cancer

X Improving DNA, RNA, and Protein Availability in Fixed Tissue

X In Vivo Cellular and Molecular Imaging Centers (ICMICs)

X Minority Institution/Cancer Center Partnership (MI/CCP) Program

X Molecular Epidemiology of Prostate Carcinogenesis

X NCI Center for Bioinformatics

X Program for the Assessment of Clinical Cancer Tests (PACCT)

X Prostate Specialized Programs of Research Excellence (SPOREs)

X Small Animal Imaging Resource Program (SAIRP)

X Specimen Resource Locator

X Technologies for Comprehensive, Sensitive, and Quantitative Protein Analysis in Human Tumors:

Phased Innovation

1 Initiatives that impact multiple categories of prostate cancer research.

2 Initiatives unique to the biology research category.
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Chapter 3 Prostate Cancer Biology

INITIATIVES FOCUSED ON PROSTATE CANCER

Age-Related Prostate Growth: Biologic Mechanisms (PA-02-116)

Objective: Explore biologic mechanisms of initiation and progression of age-related development and

pathophysiologic processes.

Relevant Research Programs Resulting from This Program Announcement (PA): Pending

Biology, Development, and Progression of Malignant Prostate Disease (PA-99-081)

Objective: Study the biology underlying the development and progression of malignant prostatic disease.

Relevant Research Projects Resulting from This PA:

X Androgen-Independent Prostate Cancer: Mechanisms and Treatment

X Angiopoietins in Prostate Biology and Disease

X Apoptosis Regulation by Lipid Signals in Prostate Cancer

X Beta Catenin in Prostate Cancer

X Cyclin D1 Function in Prostate Cancer

X Death Receptors in Prostate Cancer Biology and Apoptosis

X Ebp1 Control of Prostate Cancer Cell Growth

X Endothelial Growth Factor in Prostate Cancer Metastasis

X EphA2 Agonists as Novel Inhibitors of Tumor Progression

X Fibroblast Growth Factor Receptor Signaling in Prostate Development and Cancer

X Functional Analysis of the PTEN Tumor Suppressor Protein

X Gene Expression in Diet-Induced Prostate Cancer

X Growth Control of Prostate Cancer Cells by Plant Phenols

X GSTP1 Gene Repression in Prostate Cancer

X Host/Tumor Interactions in Immunotherapy of Prostate Cancer

X Integrin Signaling Pathways in Prostate Cancer

X Mechanism of Apoptosis by Par4

X Mechanisms of Metastasis in Experimental Prostate Cancer

X Modes of Prostate Cancer Progression—Role of p53 Pathway

X Molecular Dissection of 13q14 in Prostate Cancer

X Molecular Regulation of Androgen Receptor Activation

X Neutral Endopeptidase Inactivation in Advanced Prostate Cancer

X Progression/Oncogene Induced Prostate Cancer

X Prostate Cancer, Bone Metastasis, and Metalloproteinases

X Prostate Cancer Metastatic Colonization—Role of MKK4

X Prostate Carcinogensis and PKC Signaling

X Prostatic Vasculogenic Mimicry: A New Metastatic Pathway

X Repressors in Prostate Cancer

X Role of a New Ets Factor, PDEF, in Prostate Cancer

X Serine Proteases in Prostate Cancer Metastasis

X Testing of Novel Apoptotic Agents in Prostate Cancer

X TGF-Beta/Smads and Androgen Signaling in Prostate Cancer

X TNF-Alpha-Mediated Apoptosis in Prostate Cancer

X Tumor Suppressor Gene at 13q21 in Prostate Cancer

Table 3-2. NCI Initiatives Relevant to Prostate Cancer Research:

Biology
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Table 3-2. (cont.)

Development of Cell-Selective Tools for Studies of the Bladder, Prostate, and Genitourinary

Tract (PAR-02-143)

Objective: Develop new, cell-selective research tools and methods that apply to studies of the bladder,

prostate, and other organs of the genitourinary tract.

Relevant Research Projects Resulting from This PA: Pending

Role of Hormones and Growth Factors in Prostate Cancer (RFA-DK-01-008)

Objective: Explore the underlying mechanisms of action of hormones and growth factors in regulating

prostate development, growth, and tumorigenesis.

Relevant Research Projects Resulting from This Request for Applications (RFA):

X Calcitonin in Prostate Growth and Neoplasia

X Eph Kinase Signaling in Prostate Cancer

INITIATIVES WITH PROSTATE CANCER-RELEVANT COMPONENTS

Molecular and Cellular Biology of Metastatic Tumor Cells (PA-01-020)

Objective: Study the molecular and cellular biology of metastatic tumor cells through collaborations that

facilitate scientific interchange between investigators with experience in the biology of metastasis and in more

basic scientific disciplines such as molecular or cellular biology, or biochemistry.

Relevant Research Project Resulting from This PA: Prostate Cancer Metastasis to Bone

Ongoing NCI Research: Recent Progress in

Prostate Cancer Biology

Early Prostate Cancer

Prostate cancer development proceeds through a series of defined states, including preinvasive

disease or prostatic intraepithelial neoplasia, androgen-dependent cancer, and eventually androgenindependent metastasis. Studies using rodent models and human tumor samples have contributed

significantly toward a better understanding of early prostate carcinogenesis.

Molecular genetic studies of prostate cancer have identified mutations, deletions, or loss of expression of tumor suppressor genes (e.g., Nkx3.1, p53, and PTEN) as well as overexpression or amplification

of oncogenes (e.g., c-MYC, HER2, and BCL-2) in subsets of tumors (Abate-Shen and Shen, 2000; Moul

et al., 2002). Due to the heterogeneity of prostate cancer itself and the focal nature of oncogene/tumor

suppressor gene alterations, the role of these genes in prostate cancer onset and the diagnostic and/or

prognostic value of such gene alterationsremain uncertain. Molecular genetic alterations that are present

in a homogeneous manner and with high frequency in prostate cancer are being discovered through

unbiased genome scanning or global gene expression profiling approaches. Some of the more common

prostate cancer-associated genetic alterations now include loss of glutathione S-transferase-pi expression,

overexpression of HEPSIN and alpha-methylacyl-CoAracemase, and consistent loss or gain of specific

chromosomal hot spots.

Analysis of genome alterations in prostate cancer cells has revealed that somatic inactivation of

GSTP1, which encodes the carcinogen-detoxifying enzyme glutathione S-transferase-pi, may serve as an

initiating genome lesion for prostatic carcinogenesis (Nelson et al., 2001). The loss of GSTP1 leaves cells

vulnerable to damage, increasing the chances of further genetic mutation that could lead to malignant

transformation. The inactivation of this gene occurs by a mechanism of gene silencing termed
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hypermethylation (Lin X et al., 2001) and is detected in up to 90 percent of prostate cancers (Lee et al.,

1994). There is an association between hypermethylation and loss of GSTP1 protein expression in men

with prostate cancer (Song et al., 2002), and NCI-supported work has shown that it may be possible to

screen for GSTP1 levels in urine (Gonzolgo et al., 2003).

Development of Hormone-Refractory Tumors

Standard therapy for prostate cancer relies on blocking or removing hormones called androgens,

which are necessary for normal prostate growth. While most tumors initially respond to this therapy, the

tumor may become resistant (refractory), resulting in disease progression. Recent research has shown

that, perhaps counterintuitively, the androgen receptor (AR) has a functional role in androgen-refractory

prostate cancer (Zegarra-Moro et al., 2002). Data from several laboratories have resulted in the

elucidation of multiple mechanisms behind the transformation of a tumor from androgen dependence to

androgen independence (Grossmann et al., 2001).

X Amplification of the AR gene may increase the sensitivity of tumor cells to the remaining

androgens in the body (Grossmann et al., 2001; Zegarra-Moro et al., 2002). The AR gene is

rarely amplified in primary prostate but is amplified in up to 30 percent of androgen-refractory

prostate tumors. AR gene amplification also has been associated with p53 mutations.

X Mutations in the AR gene may make the AR more sensitive to androgens or allow it to bind to

other steroids, adrenal androgens, or even anti-androgens (Grossmann et al., 2001; Zegarra-Moro

et al., 2002).

X Overexpression of AR coactivators, or reduced expression of AR corepressors, could lead to

activation of the AR by other hormones or even by anti-androgens. AR coactivators may also

stimulate the transcription of AR in the presence of low levels of androgens or other steroids and

activate pathways downstream of the AR (Grossmann et al., 2001; Zegarra-Moro et al., 2002).

X Tumor cells may bypass the AR pathway altogether in their transformation to androgen independence. Possible mechanisms include neuroendocrine cell differentiation, activation of PI3 kinase

and related pathways, and loss of PTEN function (Grossmann et al., 2001).

Progression, Metastasis, and the Role of Tumor Microenvironment

A growing body of evidence indicates that the microenvironment in which tumors develop profoundly

affects the many steps of tumor progression. Results from experimental tumor models emphasize the

contribution of stromal components within this microenvironment in shaping several aspects of tumor

formation, including growth efficiency, growth rate, ability to metastasize, and extent of invasiveness. For

example, NCI-supported investigators have demonstrated that prostate tumor growth in vivo could be

accelerated by co-culture with cancer-associated fibroblasts, but not by benign tissue-associated fibroblasts (Olumi et al., 1998). These effects are mediated in part by paracrine signaling mechanisms

between tumor cells and neighboring stromal fibroblasts, leading to the generation of a reactive stromal

environment that, in turn, promotes tumorigenesis. This reciprocal interaction has been described as

causing a “vicious cycle” between stromal and tumor cell components within the prostate and may

contribute to prostate cancer progression.

One mechanism by which this “vicious cycle” is activated is through the secretion of cytokines,

growth factors, and/or extracellular matrix components by the tumor. These factors may alter the

morphology and gene expression of surrounding stroma such that it reciprocally induces the growth and

gene expression of tumor epithelium. For example, recent NCI-supported research has shown that a

soluble protein termed transforming growth factor-beta (TGF-beta) stimulates the switch of prostate

stromal fibroblasts located near the tumor to a reactive state, in which they display a myofibroblast phenotype and express tenascin (Tuxhorn et al., 2002). TGF-beta was also shown to regulate the stroma’s

ability to initiate and promote angiogenesis and tumor growth. In one experiment, prostate tumors were
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generated in the presence of reactive stroma and a TGF-beta inhibitor. The resulting tumors had fewer

blood vessels than control tumors and were nearly half the size of control tumors (Tuxhorn et al., 2001).

Thus, it is evident that TGF-beta plays an important role in prostate cancer progression.

A second paracrine signaling loop that is active in prostate cancer progression involves the soluble

protein hepatocyte growth factor (HGF) and its cognate ligand c-Met. NCI-funded researchers recently

reported that the addition of prostate-derived stromal cells to prostate tumor cells significantly enhanced

the growth of the tumor cells in nude mice (Nakashiro et al., 2000). In vitro studies revealed that HGF

was the molecule responsible for this effect and that HGF secreted by the stromal cells directly stimulates

the growth of prostate carcinoma cells by binding to c-Met receptors expressed on the surface of those

cells (Nakashiro et al., 2000). Furthermore, these researchers determined that expression of c-Met on the

tumor cells increases with stage of prostate cancer progression (Nakashiro et al., 2003).

In addition to paracrine-mediated mechanisms of tumor progression, autocrine signaling and genetic

instability may also contribute to the “vicious cycle” of prostate cancer progression. NCI-supported

research has shown that soluble factors such as Nox1 and vascular endothelial growth factor are secreted

by the tumor cells themselves and can promote further tumor growth (Arbiser et al., 2002). Chromosomal

loss or gain in prostate tumor cells can be exacerbated by the interaction of tumor cells with stromal

components (Rhee et al., 2001; Tlsty, 2001). The extent to which each of these mechanisms contributes

to prostate tumor progression and metastasis is a continuing area of research.

Bone Metastasis

A major contribution to our understanding of the process of bone metastasis has been the demonstration that the bone microenvironment critically influences the behavior of cancer cells that metastasize to

bone by altering the phenotype of the metastatic tumor cells. Furthermore, some of the molecular mechanisms responsible for the bi-directional interaction between bone and tumor cells in vivo have been

recently identified. A few examples are briefly described.

Hyaluronan synthase (HAS, the enzyme used to produce hyaluronan) is necessary for bone metastasis. Increased expression of hyaluronan synthase by prostate tumor cells triggers adhesion of the tumor

cells to bone marrow endothelial cells, allowing the tumor cells to spread to bone (Simpson et al., 2001;

Simpson et al., 2002a). When HAS synthesis was inhibited in prostate cancer cells injected into mice, the

resulting tumors were smaller and had up to an 80 percent reduction in vascularization compared with

controls (Simpson et al., 2002b). Conversely, when tumor cells were transfected with the gene for HAS3

(one of three forms of the enzyme), they grew at a faster rate in cell culture and formed larger tumors

than control cells when injected into mice (Liu et al., 2001).

As prostate cancer cells become more aggressive, they exhibit osteo-mimetic properties such as the

inappropriate expression of osteoblast-specific genes and proteins, which can stimulate the formation of

osteoblastic lesions in the bone. For example, the osteotropic prostate cancer cell line C4-2B, but not its

non-skeletal metastatic parent cell line LNCaP, induces bone mineralization through the release of factors

such as osteocalcin, alkaline phosphatase, and osteonectin (Lin DL et al., 2001). The production of these

proteins by prostate carcinoma cells illustrates potential mechanisms by which metastatic skeletal lesions

are formed that characterize advanced prostate cancer (Keller et al., 2001).

The role of proteases in prostate cancer metastasis is another active area of interest. Urokinasetype plasminogen activator (uPA) is a protease that is normally expressed in the bone and stimulates the

natural turnover of bone cells. This enzyme is also expressed by metastatic prostate cancer cells that

spread to the bone. Increased expression of uPA by tumor cells in the bone contributes to the proteolytic

remodeling of the bone matrix, resulting in increased survival for tumor cells in the bone microenvironment

(Goltzman, 1997). Maspin is a potent inhibitor of uPA that is expressed by normal prostate cells but not

highly invasive prostate cancer cells. Recent work has shown that tumor cells engineered to express

maspin cannot form invasive tumors in the bone. Such maspin-containing cells can neither degrade bone
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nor induce blood vessel formation and remain enmeshed in calcified extracellular matrix (Cher et al.,

2003). Thus, maspin presents an exciting therapeutic potential to treat and prevent bone metastasis in

prostate cancer.

Continuing Needs and Evolution

Recent research on the biology of prostate cancer has

opened many doors. The advent of microarray technology

will facilitate the analysis of hundreds of tumors and thousands of genes and is already helping illuminate the complex

web of biological changes that leads to prostate cancer. For

example, microarray analysis of metastatic prostate cancer

tissue versus localized prostate cancer tissue showed greater

upregulation of neural cell adhesion molecule (N-CAM) in

the nerves of metastatic tissue, implicating N-CAM in neural

invasion and metastasis (Li et al., 2003a). Recently, published microarray studies have implicated altered expression

of NAG-1, ASCT2, ZnT4, 5-alpha-reductase-2, protein

kinase C-mu, and many others in prostate cancer initiation

and/or progression (Iczkowski and Pantazis, 2003; Li et al.,

2003b; Henshall et al., 2003; Luo et al., 2003; Jaggi et al.,

2003).

For biological knowledge to translate into clinical practices that can reduce the burden of prostate

cancer, research must continue to examine and understand the biology of the normal prostate, especially as

it relates to the earliest stages of malignant transformation. Studies on cell–cell and cell–matrix communication will further the understanding of carcinogenesis and lead to treatments targeting both the tumor and

its microenvironment. The discovery of tumor markers, as well as markers of progression and of response

to treatment, will allow for earlier diagnosis and targeted treatment of a disease that continues to be the

most commonly diagnosed cancer and the second-leading cause of cancer death in U.S. men.

NCI’s Future Investment in Prostate Cancer Biology

The NIH Prostate Cancer Research Plan for FY 2003–2008 describes the NCI’s planned objectives

for research on the biology, progression, and metastasis of prostate cancer. The objectives are based on

the priorities identified by the PRG and the advances that have taken place since completion of the PRG’s

work. The five FY 2003–2008 objectives and their alignment to the ten PRG priorities are shown in

Figure 3-2.

We are beginning to define

the intracellular mechanisms

responsible for malignant

transformation and cancer

progression, as well as the

interactions between the

cancer cell and its

environment that influence

organ invasion, metastases,

hormone-independent

growth, and resistance to cell

death.

– National Institutes of Health,

Prostate Cancer Research Plan for

FY 2003–2008.
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Figure 3-2. NIH’s FY 2003–2008 prostate cancer biology research

objectives build upon the 1998 PRG priorities.

PRG Priorities

What are the potential roles of nuclear 

receptors, their interactive proteins, and ligand

metabolizing enzymes on prostate growth,

tissue interactions, and development?

Identify the molecular pathways that cause

prostate cancer and its progression and

metastasis.

FY 2003–2008 Objectives

What are the molecular determinants that 

govern cancer invasion, migration, and 

metastasis?

What are the biochemical and molecular 

events that govern the continuation of prostate

development from early embryogenesis to the

onset of adulthood, through maturation, aging,

and death?

What are the specific cell–cell interactions

between and among developing epithelial cells,

stromal cells, endothelial cells, neuroepithelial 

cells, and inflammatory cells?

What are the regulatory effector molecules 

that control reciprocal interactions between

epithelial and stromal cells, among clonal 

cancer epithelial cells, and between cancer

cells and most immune-reactive cells? 

Are there features of DNA damage, DNA 

repair, or cell-cycle progression that are novel

in prostate cancer cells?

What are the genetic and epigenetic determinants that affect progression of prostate

cancer from the localized to disseminated

state? What molecular markers are 

associated with such progression?

Are there hereditary markers, angiogenesis

switches, and/or biochemical and molecular

determinants that predict progression?

What are the critical housekeeping and

regulatory genes that may be associated with

human prostate cancer development and

progression?

How do we define genetic susceptibility of

individuals to prostate cancer, and how is such

susceptibility associated with other forms of

malignancies or diseases?

Understand the role of tumor microenvironment in the development of prostate cancer.

Understand the molecular mechanisms 

behind androgen-independent prostate cancer

(AIPC).

Understand the role of the tumor macroenvironment in the development of prostate 

cancer.

Understand the relationship between the 

clinical course and biological features of

prostate cancer to further understand the

molecular and cellular underpinnings of the

disease and improve prevention, detection,

and treatment.
NATIONAL CANCER INSTITUTE

3-14

Chapter 3 Prostate Cancer Biology

NCI-Supported Research Referenced in Chapter 3

Abate-Shen C, Shen MM. Molecular genetics of prostate cancer. Genes Dev. 2000 Oct 1;14(19):2410–34.

Arbiser JL, Petros J, Klafter R, Govindajaran B, McLaughlin ER, Brown LF, Cohen C, Moses M, Kilroy S,

Arnold RS, Lambeth JD. Reactive oxygen generated by Nox1 triggers the angiogenic switch. Proc Natl Acad Sci

USA. 2002 Jan 22;99(2):715–20.

Cher ML, Biliran HR Jr, Bhagat S, Meng Y, Che M, Lockett J, Abrams J, Fridman R, Zachareas M, Sheng S. Maspin

expression inhibits osteolysis, tumor growth, and angiogenesis in a model of prostate cancer bone metastasis. Proc

Natl Acad Sci USA. 2003 Jun 24;100(13):7847–52.

Goltzman D. Mechanisms of the development of osteoblastic metastases. Cancer. 1997 Oct 15;80(8 Suppl):1581–7.

Gonzalgo ML, Pavlovich CP, Lee SM, Nelson WG. Prostate cancer detection by GSTP1 methylation analysis of

postbiopsy urine specimens. Clin Cancer Res. 2003 Jul;9(7):2673.

Grossmann ME, Huang H, Tindall DJ. Androgen receptor signaling in androgen-refractory prostate cancer. JNCI.

2001;93(22):1687.

Henshall SM, Afar DE, Rasiah KK, Horvath LG, Gish K, Caras I, Ramakrishnan V, Wong M, Jeffry U, Kench JG, Quinn

DI, Turner JJ, Delprado W, Lee CS, Golovsky D, Brenner PC, O’Neill GF, Kooner R, Stricker PD, Grygiel JJ, Mack DH,

Sutherland RL. Expression of the zinc transporter ZnT4 is decreased in the progression from early prostate disease to

invasive prostate cancer. Oncogene. 2003 Sep 4;22(38):6005–12.

Iczkowski KA, Pantazis CG. Overexpression of NSAID-activated gene product in prostate cancer. Int J Surg Pathol.

2003 Jul;11(3):159–66.

Jaggi M, Rao PS, Smith DJ, Hemstreet GP, Balaji KC. Protein kinase C mu is down-regulated in androgenindependent prostate cancer. Biochem Biophys Res Commun. 2003 Jul 25;307(2):254–60.

Keller ET, Zhang J, Cooper CR, Smith PC, McCauley LK, Pienta KJ, Taichman RS. Prostate carcinoma skeletal

metastases: Cross-talk between tumor and bone. Cancer Metastasis Rev. 2001;20(3-4):333–49.

Lee WH, Morton RA, Epstein JI, Brooks JD, Campbell PA, Bova GS, Hsieh WS, Isaacs WB, Nelson WG. Cytidine

methylation of regulatory sequences near the pi-class glutathione S-transferase gene accompanies human prostatic

carcinogenesis. Proc Natl Acad Sci USA. 1994 Nov 22;91(24):11733–7.

Li R, Wheeler T, Dai H, Ayala G. Neural cell adhesion molecule is upregulated in nerves with prostate cancer invasion.

Hum Pathol. 2003a May;34(5):457–61.

Li R, Younes M, Frolov A, Wheeler TM, Scardino P, Ohori M, Ayala G. Expression of neutral amino acid transporter

ASCT2 in human prostate. Anticancer Res. 2003b Jul–Aug;23(4):3413–8.

Lin DL, Tarnowski CP, Zhang J, Dai J, Rohn E, Patel AH, Morris MD, Keller ET. Bone metastatic LNCaP-derivative

C4-2B prostate cancer cell line mineralizes in vitro. Prostate. 2001 May 15;47(3):212–21.

Lin X, Tascilar M, Lee WH, Vles WJ, Lee BH, Veeraswamy R, Asgari K, Freije D, van Rees B, Gage WR, Bova GS,

Isaacs WB, Brooks JD, DeWeese TL, De Marzo AM, Nelson WG. GSTP1 CpG island hypermethylation is responsible

for the absence of GSTP1 expression in human prostate cancer cells. Am J Pathol. 2001 Nov;159(5):1815–26.

Liu N, Gao F, Han Z, Xu X, Underhill CB, Zhang L. Hyaluronan synthase 3 overexpression promotes the growth of

TSU prostate cancer cells. Cancer Res. 2001 Jul 1;61(13):5207–14.

Luo J, Dunn TA, Ewing CM, Walsh PC, Isaacs WB. Decreased gene expression of steroid 5 alpha-reductase 2 in

human prostate cancer: Implications for finasteride therapy of prostate carcinoma. Prostate. 2003 Oct 1;57(2):134–9.

Moul JW, Merseburger AS, Srivastava S. Molecular markers in prostate cancer: The role in preoperative staging. Clin

Prostate Cancer. 2002;1:42–50.

Nakashiro K, Hayashi Y, Oyasu R. Immunohistochemical expression of hepatocyte growth factor and c-Met/HGF

receptor in benign and malignant human prostate tissue. Oncol Rep. 2003 Sep–Oct;10(5):1149–53.

Nakashiro K, Okamoto M, Hayashi Y, Oyasu R. Hepatocyte growth factor secreted by prostate-derived stromal cells

stimulates growth of androgen-independent human prostatic carcinoma cells. Am J Pathol. 2000 Sep;157(3):795–803.

Nelson WG, DeMarzo AM, DeWeese TL. The molecular pathogenesis of prostate cancer: Implications for prostate

cancer prevention. Urology. 2001:57(4):39.
3-15

Chapter 3 Prostate Cancer Biology

NATIONAL CANCER INSTITUTE

Olumi AF, Dazin P, Tlsty TD. A novel coculture technique demonstrates that normal human prostatic fibroblasts

contribute to tumor formation of LNCaP cells by retarding cell death. Cancer Res. 1998 Oct 15;58(20):4525–30.

Rhee HW, Zhau HE, Pathak S, Multani AS, Pennanen S, Visakorpi T, Chung LW. Permanent phenotypic and genotypic changes of prostate cancer cells cultured in a three-dimensional rotating-wall vessel. In Vitro Cell Dev Biol

Anim. 2001 Mar;37(3):127–40.

Simpson MA, Reiland J, Burger SR, Furcht LT, Spicer AP, Oegema TR Jr, McCarthy JB. Hyaluronan synthase elevation in metastatic prostate carcinoma cells correlates with hyaluronan surface retention, a prerequisite for rapid

adhesion to bone marrow endothelial cells. J Biol Chem. 2001 May 25;276(21):17949–57.

Simpson MA, Wilson CM, Furcht LT, Spicer AP, Oegema TR Jr, McCarthy JB. Manipulation of hyaluronan synthase

expression in prostate adenocarcinoma cells alters pericellular matrix retention and adhesion to bone marrow endothelial cells. J Biol Chem. 2002a Mar 22;277(12):10050–7.

Simpson MA, Wilson CM, McCarthy JB. Inhibition of prostate tumor cell hyaluronan synthesis impairs subcutaneous growth and vascularization in immunocompromised mice. Am J Pathol. 2002b Sep;161(3):849–57.

Song JZ, Stirzaker C, Harrison J, Melki JR, Clark SJ. Hypermethylation trigger of the glutathione-S-transferase gene

(GSTP1) in prostate cancer cells. Oncogene. 2002 Feb 7;21(7):1048–61.

Tlsty TD. Stromal cells can contribute oncogenic signals. Semin Cancer Biol. 2001 Apr;11(2):97–104.

Tuxhorn JA, Ayala GE, Rowley DR. Reactive stroma in prostate cancer progression. J Urol. 2001 Dec;166(6):2472–83.

Tuxhorn JA, Ayala GE, Smith MJ, Smith VC, Dang TD, Rowley DR. Reactive stroma in human prostate cancer: Induction

of myofibroblast phenotype and extracellular matrix remodeling. Clin Cancer Res. 2002 Sep;8(9):2912–23.

Zegarra-Moro OL, Schmidt LJ, Huang H, Tindall DJ. Disruption of androgen receptor function inhibits proliferation of

androgen-refractory prostate cancer cells. Cancer Res. 2002;62(4):1008.

4-1

Chapter 4 Etiology and Prevention of Prostate Cancer

NATIONAL CANCER INSTITUTE

CHAPTER

4

Etiology and Prevention of Prostate

Cancer: NCI’s Investment and

Recent Progress

An important goal in prostate cancer

prevention is to identify men at high risk

of developing life-shortening forms of the

disease, and to understand how lifestyle

characteristics and exogenous exposures

influence this risk. This understanding will

allow the development of effective

prevention strategies.

– Defeating Prostate

Cancer: Crucial

Directions for

Research - Report of

the Prostate Cancer

Progress Review

Group, August 1998.

By pursuing research on the direct causes and modulators of prostate cancer, the NCI has opened

the door to the possibility of prostate cancer prevention. Genetic, dietary, lifestyle, and environmental

factors are being examined for their impact on prostate cancer risk. In addition, the biologic pathways

leading to the onset of prostate cancer or the progression of an otherwise indolent prostate cancer are

being characterized. These endeavors have led to behavioral and drug-based strategies for reducing risk

and blocking the cellular and molecular events that are required for tumor formation.

In their 1998 report, the Prostate

Cancer PRG described the continuing

challenge of determining prostate

cancer risk factors and enabling the

development of preventive agents. The

report indicated that, while prevention is an

appealing approach to controlling prostate

cancer, classic epidemiologic studies have

revealed few indisputable risk factors to

pinpoint exact causes. Studies have documented the risk factors of age, family history,

race/ethnicity, and nationality, but this

documentation has not identified the biological, environmental, and lifestyle causes of

prostate cancer or the interactions of these

factors. The lack of established risk factors

limits preventive efforts and highlights the

need to better understand the biology of both

normal and malignant prostate cells and

tissues. In addition, a better understanding

of how genetic predisposition and exogenous factors interact to determine prostate cancer susceptibility is

needed to design effective prevention strategies. Beyond identifying prevention strategies, this approach

will facilitate the development of methods to aggressively control progression of the disease and reduce

mortality.

NCI has been responsive to the eight PRG Priority One questions related to prostate

cancer etiology and prevention. The questions and accompanying recommendations in the 1998 report

addressed the priorities for identifying genetic, dietary, environmental, and other risk factors to develop a

sound knowledge base. Corresponding with this line of research, NCI-sponsored investigators have been

working to determine which of these risk factors are due to racial differences; whether there are genetic

and/or environmental interactions that modify risk; and the identity of promising preventive agents and

activities. Biological studies of carcinogenesis and clinical studies on higher risk cohorts have accelerated

the discovery of important biological mechanisms of prostate cancer and the identification of how different

etiologic variables interact and contribute to the onset and progression of disease.
NATIONAL CANCER INSTITUTE

4-2

Chapter 4 Etiology and Prevention of Prostate Cancer

NCI’s Investment and Response

From fiscal year (FY) 1998 to FY 2002, the NCI investment for extramural prostate cancer etiology

and prevention research grew from $19.5 million (M) to $78.9M (Figure 4-1).

0

10

20

40

50

80

1998 1999 2000 2001 2002

Fiscal Year

Millions of Dollars

70

30

60

Figure 4-1. NCI’s extramural investment in prostate cancer etiology

and prevention research: 1998–2002 (in millions of dollars).

NCI’s response to the eight Prostate Cancer PRG Priority One research questions for etiology and

prevention is summarized in Table 4-1.

NCI Efforts:

X In FY 2002, active areas of investigation included linkage analysis of previously identified and novel

genetic loci, association of genetic polymorphisms (e.g., androgen receptor and insulin-like growth factor

[IGF] pathway genes, and drug metabolizing genes) and prostate cancer risk and carcinogenesis, genetic

studies in Chinese and Israeli men, prostate epithelial cell transformation, genetic analysis of hereditary

prostate cancer, genetics of prostate susceptibility, and BRCA1 as a prostate tumor suppressor gene.

X The feasibility of accruing prostate cancer patient–sibling pairs is being assessed for the clinical trial

Genetic Mapping of Interactive Susceptibility Loci in Patients and Siblings with Breast, Colon, Lung, or

Prostate Cancer (E-1Y97).

X Eighteen projects addressed the PRG recommendation that families with multiple cases of prostate

cancer be studied to identify hereditary factors.

X The PRG recommended genetic factors be studied:

- Fourteen projects addressed the recommendation that factors involved in testosterone synthesis,

function, and degradation be examined.

- Forty-one projects addressed the association of genetic polymorphisms and prostate cancer.

- Three projects addressed the development of transgenic or gene knockout mice to validate the role of

genes associated with prostate cancer.

PRG Priority: What genes are important

in the etiology of prostate cancer? What

fraction of familial prostate cancer is

monogenic with Mendelian inheritance of

susceptibility alleles? What is the function

of such genes?

0

10

20

30

80

1998 1999 2000 2001

NCISupported

Projects

per

Year

2002

40

50

60

70

Table 4-1. NCI Efforts Responsive to PRG Priorities in

Prostate Cancer Etiology and Preventiona

a A given project may map to more than one PRG Priority One question and therefore be represented in more than one figure. Projects active

in 2002 are listed by Principal Investigator’s name for each PRG Priority One question in Appendix B (Tables B-12–B-20).
4-3

Chapter 4 Etiology and Prevention of Prostate Cancer

NATIONAL CANCER INSTITUTE

NCI Efforts:

X In FY 2002, active areas of investigation included biostatistics and epidemiology, metals and

carcinogenesis, role of viruses (e.g., herpesviruses), effects of medications (e.g., NSAIDs), and

occupational exposures.

X NCI initiatives addressing this priority included the Small Grants Program for Cancer Epidemiology.

NCI Efforts:

X In FY 2002, active areas of investigation included genes expressed in diet-induced cancer, molecular

epidemiology of dietary prevention, diet and multiethnic populations and cancer, carcinogenicity of

heterocyclic amines, and prevention and cancer control through various dietary components/supplements

(e.g., lycopene, selenium, flaxseed, beta-carotene, and alpha-tocopherol).

X The Selenium and Vitamin E Cancer Prevention Trial (SELECT) is projected to complete the accrual of

32,400 men by summer 2004 to determine if dietary selenium and/or vitamin E are beneficial in reducing

prostate cancer risk.

X Examples of additional clinical trials addressing this priority include the following:

- Phase I Study of Lycopene for the Chemoprevention of Prostate Cancer (NCI-P00-0143)

- Phase II Randomized Study of Dietary Soy in Patients with Elevated PSA Levels (NCI-P02-0207)

- Phase II Randomized Study of the Effects of a Low-Fat, High-Fiber Diet on Serum Factors in Patients

with Prostate Cancer (NCI-G01-1973)

X The PRG recommended that the role of nutrients be examined in large-scale investigations. Twenty-four

projects addressed the recommendation to initiate long-term nutritional science and epidemiologic studies

and to attach dietary measurement studies to ongoing clinical trials.

X The PRG recommended specific studies of the biochemistry of nutrients:

- Nine projects addressed the role of nutrients in androgen production and prostate physiology.

- Fifteen projects addressed the genetic factors regulating metabolism and transport of specific nutrients.

X NCI initiatives addressing this priority included Molecular Epidemiology of Prostate Carcinogenesis,

Prostate SPOREs, Cancer Prevention Research Small Grant Program, and Small Grants Program for

Cancer Epidemiology.

X In 2000, NCI sponsored a workshop on Emerging Opportunities in Cancer Epidemiology; and in 2001,

NCI and the Office of Rare Diseases sponsored a workshop on Genetic Susceptibility to Prostate Cancer.

X NCI initiatives addressing this priority included Prostate Specialized Programs of Research Excellence

(SPOREs), Molecular Epidemiology of Prostate Carcinogenesis, Cancer Genetics Network (CGN), and

Small Grants Program for Cancer Epidemiology.

PRG Priority: Which dietary nutrients

affect risk of prostate cancer (e.g., fat,

phytoestrogens, and micronutrients)?

What are the mechanisms by which these

nutrients alter risk?

0

10

30

40

60

1998 1999 2000 2001

NCISupported

Projects

per

Year

2002

20

50

Table 4-1. (cont.)

PRG Priority: What other exogenous risk

factors are involved in prostate cancer

(e.g., viral, exercise, vasectomy, and

sexual factors)?

0

10

20

40

1998 1999 2000 2001

NCISupported

Projects

per

Year

2002

15

5

30

25

35
NATIONAL CANCER INSTITUTE

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Chapter 4 Etiology and Prevention of Prostate Cancer

NCI Efforts:

X In FY 2002, active areas of investigation included physical changes of prostate correlated to molecular

changes, PSA level and PSA glycosylation correlated to patient clinical status, endogenous sex hormone

levels, polymorphisms of susceptibility genes including metabolism and transport genes, stage-specific

gene expression libraries, and reactive oxygen damage to DNA.

X Examples of clinical trials addressing this priority include the following:

- Phase II Randomized Prevention Study of Fat- and/or Flaxseed-Modified Diets in Patients with Newly Diagnosed

Prostate Cancer (NCI-P02-0235)

- Phase II Randomized Study of Dietary Soy in Patients with Elevated PSA Levels (NCI-P02-0207)

- Phase II Randomized Study of the Effects of a Low-Fat, High-Fiber Diet on Serum Factors in Patients with

Prostate Cancer (NCI-G01-1973)

- Phase II Randomized Study of Doxercalciferol in Patients with Localized Prostate Cancer (NCI-N01-CN-95130)

- Phase II Randomized Study of Toremifene Followed by Radical Prostatectomy in Patients with Stage I or II

Adenocarcinoma of the Prostate (NCI-P01-0181)

- Phase II Clinical Trial of Soy Isoflavones prior to Radical Prostatectomy

- Phase II Chemoprevention Trial of Selenium and Prostate Cancer (Watchful Waiting with Selenium Trial)

- Phase III Trial of Selenium for Prostate Cancer Prevention (Negative Biopsy Trial)

- Phase III Randomized Study of Selenium as Chemoprevention of Prostate Cancer in Patients with High-Grade

Prostatic Intraepithelial Neoplasia (NCI-P02-0203)

- Randomized Study of Flutamide for Prostate Cancer Prevention in Patients with High-Grade Prostatic

Intraepithelial Neoplasia ( NCI-P00-0156)

- Randomized Study of Isoflavones in Reducing Risk Factors in Patients with Stage I or II Prostate Cancer (NCI-4031)

X Twelve projects addressed the PRG recommendation that prospective cohort studies be used to evaluate

risk of recurrence, metastasis, and/or death.

X NCI initiatives addressing this priority included Molecular Epidemiology of Prostate Carcinogenesis, Prostate

SPOREs, the Clinical Trials Cooperative Group Program, Exploratory Grants for Correlative Laboratory Studies

and Clinical Trials, and the Minority-Based Community Clinical Oncology Program (MBCCOP).

NCI Efforts:

X In FY 2002, active areas of investigation included susceptibility genes in African and Hispanic Americans,

genetic polymorphisms in different populations, epidemiology outside the United States (e.g., Shanghai and

Africa), and epidemiology in rural areas of the United States.

X Thirty-six projects addressed the PRG recommendation to establish cohorts of African American, Hispanic

American, and Asian American men to study genetic and lifestyle factors in different populations.

X NCI initiatives addressing this priority included Molecular Epidemiology of Prostate Carcinogenesis, the

NCI Cohort Consortium, and the Small Grants Program for Cancer Epidemiology.

PRG Priority: Which genetic and exogenous risk factors account for differences

in incidence and mortality among African

American, Caucasian, Hispanic, and Asian

American populations?

0

10

20

40

1998 1999 2000 2001

NCISupported

Projects

per

Year

2002

15

5

30

25

35

Table 4-1. (cont.)

PRG Priority: Are there genetic or

exogenous factors associated with

prostate cancer progression, as opposed

to its incidence?

0

10

20

40

1998 1999 2000 2001

NCISupported

Projects

per

Year

2002

15

5

30

25

35
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Chapter 4 Etiology and Prevention of Prostate Cancer

NATIONAL CANCER INSTITUTE

NCI Efforts:

X In FY 2002, active areas of investigation included biological mechanisms of chemoprotection by

cottonseed oil, retinoids, isoflavones, and sanguinarine; proliferative inflammatory atrophy as a target for

preventive therapy; bioavailability of tea polyphenols; and plant engineering for new dietary sources of

selenium.

X In addition to the dietary intervention clinical trials, listed for a priority described earlier, the following trials

address this priority: Prostate Cancer Prevention Trial (NCI-P93-0049) and Phase IIB Randomized

Chemoprevention Study of Eflornithine (DFMO) in Patients at High Genetic Risk for Prostate Cancer

(NCI-P00-0164).

X Sixteen projects addressed the PRG recommendation to investigate mechanisms of potential

chemopreventive interventions.

X The PRG recommended that the design of chemoprevention trials be examined to make the process

more efficient:

- Eleven projects addressed the development of endpoint or surrogate endpoint markers for

chemoprevention trials.

- Three projects addressed efficient and appropriate design of new prevention trials.

X In August 1999, the NCI sponsored the workshop Strategies for New Clinical Trials for Prostate Cancer

Chemoprevention. The Proceedings of the workshop were published in the April 2001 Supplement to

Urology.

b

X NCI initiatives addressing this priority included Molecular Epidemiology of Prostate Carcinogenesis,

Prostate SPOREs, the Clinical Trials Cooperative Group Program, MBCCOP, Molecular Target Drug

Discovery for Cancer, the Cancer Prevention Research Small Grant Program, Chemoprevention in

Genetically Identified High-Risk Groups: Interactive Research and Development Projects, and Rapid

Access to Preventive Intervention Development (RAPID) Program.

NCI Efforts:

X In FY 2002, active areas of investigation included pharmacogenetics of metabolizing enzymes; correlation

of selenium, beta-carotene, and IGF-1 gene variants to clinical disease; international studies of cancer

epidemiology; and risks attributed to herbicide exposure.

X Thirteen projects addressed the PRG recommendation to support studies that evaluate gene–environment

interactions.

X NCI initiatives addressing this priority included Prostate SPOREs, the NCI Cohort Consortium, and the

Small Grants Program for Cancer Epidemiology.

PRG Priority: Are there interactions

between genetic predisposition and

exogenous exposures?

0

10

20

25

1998 1999 2000 2001

NCISupported

Projects

per

Year

2002

15

5

Table 4-1. (cont.)

PRG Priority: What interventions can

alter the underlying etiology of prostate

cancer? What are the most promising

potential preventive agents and activities?

0

10

20

40

1998 1999 2000 2001

NCISupported

Projects

per

Year

2002

15

5

30

25

35

b Urology 57 Issue 4 (Supplement 1).
NATIONAL CANCER INSTITUTE

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Chapter 4 Etiology and Prevention of Prostate Cancer

NCI Efforts:

X In FY 2002, active areas of investigation included general demographic analysis and developing

isoflavone-fortified foods.

NCI Efforts:

X In FY 2002, active areas of investigation included mechanisms of dietary protection in lac transgenic mice

and rats, hormone treatments and caloric restriction in mice with or without specific tumor suppressors,

dihydroxyvitamin D mechanisms of prevention in mice with human prostate tumor xenografts, preventive

effects of plant phenols on mice, and selecting chemopreventive agents using the transgenic

adenocarcinoma mouse prostate model.

X NCI initiatives addressing this priority included Prostate SPOREs.

PRG Priority: What is the potential of

new animal models for testing of potential

chemopreventive agents?

0

3

6

9

15

1998 1999 2000 2001

NCISupported

Projects

per

Year

2002

12

Table 4-1. (cont.)

Additional etiology and prevention

projects that did not address the PRG

priority questions in this table.

0

2

4

6

10

1998 1999 2000 2001

NCISupported

Projects

per

Year

2002

8

A portion of the NCI’s responsiveness to PRG priorities and recommended actions consisted of

clinical trials. In addition to the compounds in clinical trials listed in Table 4-1, the following compounds

have been recently examined for effectiveness at reducing the risk of prostate cancer development or

progression: Exisulind, Celecoxib, Acapodene (GTx-006), Casodex, vitamin C, and multivitamins.

The initiatives relevant to research on prostate cancer etiology and prevention between FY 1998 and

2002 include the following list of general initiatives that are described in Table 2-11

 (Chapter 2) andthe

category-specific initiatives that are listed and described in Table 4-2:2

X Cancer Centers Program

X Cancer Genome Anatomy Project (CGAP)

X Cancer Molecular Analysis Project (CMAP)

X Cancer Research Training, Career Development, and Education Opportunities

X Clinical Trials Cooperative Group Program

X Common Data Elements (CDE) Initiative 

1 Initiatives that impact multiple categories of prostate cancer research.

2 Initiatives unique to the research category of Etiology and Prevention.
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Chapter 4 Etiology and Prevention of Prostate Cancer

NATIONAL CANCER INSTITUTE

X Community Clinical Oncology Program (CCOP)

X Cooperative Human Tissue Network (CHTN)

X Cooperative Prostate Cancer Tissue Resource (CPTCR)

X Director’s Challenge: Toward a Molecular Classification of Cancer

X Exploratory Grants for Correlative Laboratory Studies and Clinical Trials

X Flexible System to Advance Innovative Research for Cancer Drug Discovery by Small

Businesses

X Improving DNA, RNA, and Protein Availability in Fixed Tissue

X Interdisciplinary Research Teams for Molecular Target Assessment

X In Vivo Cellular and Molecular Imaging Centers (ICMICs)

X Minority Institution/Cancer Center Partnership (MI/CCP) Program

X Minority-Based Community Clinical Oncology Program (MBCCOP)

X Molecular Epidemiology of Prostate Carcinogenesis

X Molecular Target Drug Discovery for Cancer

X NCI Center for Bioinformatics

X Program for the Assessment of Clinical Cancer Tests (PACCT) 

X Prostate, Lung, Colorectal & Ovarian Cancer Screening Trial (PLCO)

X Prostate Specialized Programs of Research Excellence (SPOREs)

X Shared Resources for Scientists outside NCI Cancer Centers

X Small Animal Imaging Resource Program (SAIRP)

X Special Populations Networks (SPNs)

X Specimen Resource Locator

X Technologies for Comprehensive, Sensitive, and Quantitative Protein Analysis in

Human Tumors: Phased Innovation

Table 4-2. NCI Initiatives Relevant to Prostate Cancer Research:

Etiology and Prevention

INITIATIVES FOCUSED ON PROSTATE CANCER

Prostate Cancer Prevention Trial (PCPT) (http://www.cancer.gov/pcpt)

Objective: Randomized trial to evaluate whether the drug finasteride (Proscar) could prevent prostate

cancer in men ages 55 and over.

Relevant Program Resulting from This Initiative: Enrollment in PCPT began in 1993, and nearly 19,000 men

participated in the trial. PCPT was concluded early due to the finding that finasteride reduced the incidence of

prostate cancer by 25 percent; however, men taking finasteride were more likely to have higher grade tumors.

SELECT Prostate Cancer Prevention Trial (http://www.cancer.gov/select)

Objective: Prospective trial in 32,400 healthy men to determine whether selenium and vitamin E are

effective at preventing prostate cancer.

Relevant Program Resulting from This Initiative: Recruitment for the Selenium and Vitamin E Cancer

Prevention Trial began in August 2001 and is expected to be completed in summer 2004. The SELECT

homepage provides additional information for SELECT investigators and participants.
NATIONAL CANCER INSTITUTE

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Chapter 4 Etiology and Prevention of Prostate Cancer

Table 4-2. (cont.)

INITIATIVES WITH PROSTATE CANCER-RELEVANT COMPONENTS

Cancer Genetics Network (CGN) (http://epi.grants.cancer.gov/CGN/)

Objective: A national network of centers specializing in the study of inherited predisposition to cancer.

Relevant Resources Resulting from This Initiative: There are currently nine participating centers. Among

the ongoing CGN studies, one is specific to prostate cancer: Recruitment of Families with Prostate Cancer.

Cancer Prevention Research Small Grant Program (PAR-00-025)

Objective: Developmental research in chemoprevention agent development, biomarkers, early detection,

and nutrition science.

Relevant Research Projects Resulting from This Program Announcement:

X Bioavailability of Tea Polyphenols in Prostate Cancer

X Cancer-Relevant Proteins in the Human Prostate Proteome

X Chemoprevention of Prostate Cancer by Sanguinarine

X Chemopreventive Action of Human Selenium Binding Protein

X Chemopreventive Effects of Dietary Cottonseed Oil 

X Dietary Isoflavone-Regulated Genes in Prostate Cancer

X Dietary Soy Effects on Markers of Prostate Cancer

X DNA Methylation in Early Detection of Prostate Cancer

X Efficacy of Prostate-Specific Antigen (PSA) Screening and Prostate Cancer Mortality

X Inhibition of Prostate Carcinogenesis by Apigenin

X Prostate Cancer Chemoprevention by Apigenin

X Prostate Cancer Chemoprevention by COX 2 Inhibition

X Tea Targeting Proteasome—A Role in Cancer Prevention

Chemoprevention in Genetically Identified High-Risk Groups: Interactive Research and

Development Projects (RFA-CA-98-012)

Objective: Integrated, multidisciplinary research programs that define and evaluate chemopreventive

strategies in asymptomatic subjects at high risk for cancer.

Relevant Research Project Resulting from This Request for Applications (RFA): Chemoprevention of

Familial Prostate Cancer

NCI Cohort Consortium (http://cancercontrol.cancer.gov/bb/cohort_conso.html)

Objective: Support multicohort investigations of cancer etiology. Large-scale epidemiologic investigations

are needed to verify preliminary epidemiologic findings from smaller studies and to elucidate genetic and

environmental interrelationships in cancer causation.

Relevant Resource Resulting from This Initiative: The NCI Cohort Consortium supports investigators leading

23 U.S. and international cohort studies of cancer etiology, with exposure data and biologic specimens for

700,000 study participants. Initial investigations on prostate cancer etiology, including more than 5,000 prostate

cancer cases, are focusing on the genetics of hormonal and growth factor determinants of this disease.

Rapid Access to Preventive Intervention Development (RAPID) Program (http://

www3.cancer.gov/prevention/rapid/index.html)

Objective: Movement of novel molecules and concepts from the laboratory to the clinic for clinical trials of

efficacy.

Relevant Research Project Resulting from This Initiative: Preclinical Development of Four Flavonoids from

Broussonetia Papyrifera
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Chapter 4 Etiology and Prevention of Prostate Cancer

NATIONAL CANCER INSTITUTE

Small Grants Program for Cancer Epidemiology (http://epi.grants.cancer.gov/ResPort/grants.html)

Objective: Build relationships between large research institutions and community-based programs and

address cancer burden in minority communities.

Relevant Research Projects Resulting from This Initiative:

X Androgen Pathway and Genetic Risk of Prostate Cancer

X Androgens Regulate IGF Pathway and Prostate Diseases

X Beta 2 Adrenergic Receptors and Prostate Cancer Risk

X Calcidiol Therapy for Prostate Cancer

X Development and Evaluation of a Soyfood Questionnaire

X Epidemiology of Cancer Mortality in Chicago Heart Association Detection Project

X Epidemiology of Prostate Cancer—Ornithine Decarboxylase and Androgen Receptor (AR) Genotypes

X Feasibility of New Prostate Cancer Molecular Genetic Technology

X Genetics of Prostate Cancer in an African American Population

X Markov Chain Monte Carlo for Very Large Pedigrees

X Meta Analysis of Risk Factors for Prostate Cancer

X Modifiable Risk Factors for Prostate Cancer

X Molecular Biomarkers for Prostate Cancer Susceptibility

X Oncogenic Human Papillomaviruses and Prostate Cancer Risk

X Postmortem PSA: Role in Epidemiology of Prostate Cancer

X Prostate Cancer Morbidity and Metal Working Fluids

X Tissue Vitamin E Levels and Prostate Cancer Risk

X Variation of the HSD17B3 Gene and Prostate Cancer

Table 4-2. (cont.)

Ongoing NCI Research: Recent Progress in Prostate

Cancer Etiology and Prevention

Risks for prostate cancer are approximately doubled among men who have a family history of this

disease compared to men with no family history. Genome-wide analysis of large multiple-case prostate

cancer families has identified several chromosomal regions potentially linked to this disease; however, the

prostate cancer inheritance pattern is genetically complex (Easton et al., 2003), with several candidate

genes identified in high-risk families, including RNAseL (Carpten et al., 2002), ELAC2 (Tavtigian et al.,

2001), and MSR1 (Xu et al., 2002a).

Androgen Receptor and Androgen Metabolism

While testosterone and its more potent metabolite dihydrotestosterone (DHT) are necessary for

normal prostate development, these hormones have also been linked to prostate cancer. Additionally,

androgen deprivation leads to physiological changes in the prostate, which result in clinical responses in

prostate cancer patients. Investigators are examining androgen-associated cellular and genetic factors in

the etiology of prostate cancer.

Prostate cancer susceptibility is being investigated at the genetic level by examining the AR gene and

genes regulated by AR. Within the AR gene, there is a region in which the codon CAG is repeated

multiple times, and the number of repeats can vary in different men. In multiple studies, men having AR

genes with fewer CAG repeats were associated with a higher risk for prostate cancer, regardless of their

racial/ethnic background. The presence of fewer repeats was found significantly more often in the higher
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Chapter 4 Etiology and Prevention of Prostate Cancer

risk African American population than in lower risk Asian populations (Irvine et al., 1995; Bennett et al.,

2002). The functional relevance of this repeat polymorphism has been examined by studying the interaction of the AR variants with variants of the PSA gene, which is regulated by AR. A comparison of the AR

and PSA genotypes indicated that men with the higher risk types of both genes had 5 times the risk for all

prostate cancer and 10 times the risk for advanced prostate cancer (Xue et al., 2000).

Researchers have investigated the possibility that genes encoding androgen metabolizing enzymes

may be prostate cancer susceptibility genes. At least two enzymes of the 3-beta-hydroxysteroid dehydrogenase (HSD3B) family are involved in androgen biosynthesis and are expressed in prostate tissue.

Variations in these genes were found significantly more often in men with prostate cancer than in men

without cancer, and this effect was more pronounced in men with a hereditary form of cancer (Chang et

al., 2002). Steroid 5-alpha reductase (SRD5A2) is the enzyme responsible for the metabolic conversion of

testosterone to DHT. A genetic variant of SRD5A2 was associated with sevenfold and fourfold increases

in the risk of clinically significant prostate cancer in African American and Hispanic men, respectively

(Makridakis et al., 1999; Jaffe et al., 2000). A case-control study analyzed genetic variants of the cytochrome p450 enzyme CYP17, which is involved in testosterone biosynthesis. One variant of CYP17 was

associated with prostate cancer risk in white men with a family history of the disease (Stanford et al.,

2002).

The NCI’s Prostate Cancer Prevention Trial (PCPT), a randomized, double-blind, placebo-controlled

trial, investigated the prevention potential of 7 years of finasteride treatment. This drug acts to decrease the

amount of DHT by blocking 5-alpha reductase. Almost 19,000 healthy men ages 55 and older participated in

the nationwide study. The PCPT was concluded early when findings revealed that finasteride results in a 25

percent reduction in the incidence of prostate cancer; however, it was also found that men taking finasteride

had higher grade tumors than their placebo counterparts (Thompson et al., 2003) (NCI-P93-0049).

Insulin-Like Growth Factors

IGF factors are important for regulation of prostate cell proliferation, differentiation, apoptosis, and

tumorigenesis. Epidemiologic investigations suggest that IGF-1 and its major binding protein, IGFBP-3, are

related to prostate cancer risk (Li et al., 2003). The underlying genetics of the IGF pathway and its

interrelationship with dietary and other factors in prostate cancer development are under current

investigation.

Dietary Factors

While numerous epidemiologic studies have associated a lower energy diet, especially a diet low in

animal fats, with a slightly reduced risk for prostate cancer, mechanisms of carcinogenesis due to high-fat

diets have been explored recently. Prostate cancer risk has been associated with total energy intake, and

the risk for regional/distant prostate cancer has been associated with dietary fat and calcium (Kristal et al.,

2002). Red meat and dairy products are major sources of branched-chain fatty acids that are metabolized

by the enzyme alpha-methylacyl-CoA-racemase (AMACR). Genetic variants of AMACR have been

identified, some of which significantly associate with prostate cancer

risk (Zheng et al., 2002). Studies investigating the preparation of

foods have generally associated meats prepared by grilling or frying

with a greater risk than other means of cooking. A byproduct of

grilling meat is the heterocyclic amine, PhIP (2-amino-1-methyl-6-

phenylimidazol[4,5-b]pyridine); PhIP is a putative carcinogen of the

rat prostate (Archer et al., 2000). N-acetyltransferases (NAT)-1

and -2 are the enzymes principally responsible for the metabolic

inactivation of PhIP. Genetic variants of NAT1 and NAT2 have been

associated with a significantly increased risk for prostate cancer

(Hein et al., 2002).
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Chapter 4 Etiology and Prevention of Prostate Cancer

NATIONAL CANCER INSTITUTE

A diet high in meats and dairy products typically will be lower in vegetables and fruits that are

associated with lower risk for prostate cancer. Specific micronutrients (e.g., selenium, lycopene, genistein,

and vitamin E) have been associated with a reduced risk for prostate cancer. Lycopene, a carotenoid

antioxidant found in tomatoes and other red fruits, has been consistently associated with reduced risk for

cancer (Gann et al., 1999). Mechanistically, dietary antioxidants have been hypothesized to detoxify

reactive oxygen species (ROS), which are DNA-damaging molecules. However, enzymes exist that can

repair DNA damaged by ROS. Certain DNA repair enzymes are being investigated as potential prostate

cancer susceptibility genes, including BRCA, ERCC, and hOGG, and genetic variants of the hOGG1 gene

have been associated with hereditary prostate cancer (Xu et al., 2002b).

Prevention Trials

Recent results from NCI-sponsored research have increased the understanding of risk factors and

prevention methods. Findings from the Alpha-Tocopherol Beta-Carotene Cancer Prevention Study,

conducted by the NCI in collaboration with the National Public Health Institute of Finland, indicate that

daily use of a modest-dose of alpha-tocopherol (a form of Vitamin E) can lead to a striking reduction in

prostate cancer incidence (Heinonen et al., 1998). Based on this knowledge, a similar study revealed that

long-term alpha-tocopherol supplementation decreased serum androgen concentrations thought to contribute to the incidence and mortality of prostate cancer (Hartman et al., 2001).

Sexually Transmitted Diseases

Prostate tissues can be infected by pathogens, including viral and bacterial agents of sexually

transmitted diseases. Although oncogenic strains of human herpesvirus and human papillomavirus have

been identified in prostatic tissues, multiple studies have not established their association with prostate

cancer. Past incidence of gonorrhea has been associated with prostate cancer, and the risk appears to

increase with increasing occurrences of gonorrhea and syphilis (Rosenblatt et al., 2001; Hayes et al.,

2000). Pathologic underpinnings linking infectious agents and prostate inflammatory pathways are under

investigation (DeMarzo et al., 2003).

Continuing Needs and Evolution

The use of genes and specific genotype patterns associated with increased risk for prostate cancer

to develop prevention, screening, and prognostic applications is currently limited by the scope of the

genetic studies. For some of the genes that appear associated with the risk of prostate cancer development or progression, the small scale of the studies has led to contradictory results among different

research groups. Large-scale, multi-institutional studies are being conducted to validate the association

and causation of putative susceptibility genes with prostate cancer risk, incorporating advanced genomic

analyses by haplotyping and genomic scans, to address the

complexities of genetic and environmental interrelationships.

Genetic etiology studies are collecting and analyzing data on

other lifestyle and environmental factors to ascertain any specific

linkages between certain genes and the environment. The

development of nationwide and international cohorts requires a

standardized mechanism for collecting, analyzing, and reporting

data and enhanced resources to support these studies.

Prostate cancer prevention studies have followed significant

advances in dietary and androgen metabolism research. Predominantly, specific micronutrients from dietary sources are being

investigated for their potential to reduce the progression of cancer

from localized to disseminated disease. As indicated earlier,

We have made significant

strides in detecting,

diagnosing, and treating

prostate cancer, but a

fuller understanding of the

genetic, biochemical, and

environmental risk factors

that contribute to its

development and

progression is key to

effective prevention.

– National Institutes of Health,

Prostate Cancer Research Plan

for FY 2003-2008.
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Chapter 4 Etiology and Prevention of Prostate Cancer

selenium, soy isoflavones, and other micronutrients are being examined prospectively in clinical trials to

validate results. Within the last 4 years, nearly 10 such prevention studies were initiated. Additionally, as the

biological etiology of prostate cancer is continually refined, new targets for preventive interventions will need

to be rapidly validated, and interventions will need to be prospectively examined in clinical trials.

NCI’s Future Investment in Prostate Cancer

Etiology and Prevention

The NIH Prostate Cancer Research Plan for FY 2003–2008 describes the NCI’s planned objectives

for research on prostate cancer etiology and prevention. The plans are based on the priorities that were

identified by the PRG and the advances that have taken place since completion of the PRG’s work. The

three FY 2003–2008 objectives and their alignment to the eight PRG priorities are summarized in

Figure 4-2. In addition, there is one PRG priority in etiology and prevention that also aligns with an FY

2003–2008 objective in the category of laboratory and preclinical models.

Figure 4-2. NIH’s FY 2003–2008 prostate cancer etiology and prevention

objectives build upon the 1998 PRG priorities.

PRG Priorities

What genes are important in the etiology of

prostate cancer? What fraction of familial

prostate cancer is monogenic with Mendelian

inheritance of susceptibility alleles? What is

the function of such genes?

Identify the roles of biochemical and environmental risk ractors, susceptibility genes, and

their interactions in prostate cancer causation

and progression.

Identify genetic, environmental, and lifestyle

factors responsible for incidence and mortality

variations among groups defined by race,

ethnicity, and geography.

Identify and evaluate promising preventive

agents and strategies that target cancer 

causes.

Laboratory and Preclinical Models: Use 

validated models to identify and test preventive, detection, and therapeutic agents. (See

Figure 6-2, Chapter 6.)

Which dietary nutrients affect risk of prostate

cancer (e.g., fat, phytoestrogens, and

micronutrients)? What are the mechanisms

by which these nutrients alter risk?

What other exogenous risk factors are 

involved in prostate cancer (e.g., viral,

exercise, vasectomy, and sexual factors)?

Which genetic and exogenous risk factors

account for differences in incidence and 

mortality among African American, Caucasian,

Hispanic, and Asian American populations?

Are there genetic or exogenous factors

associated with prostate cancer progression,

as opposed to its incidence?

FY 2003–2008 Objectives

Are there interactions between genetic predisposition and exogenous exposures?

What interventions can alter the underlying

etiology of prostate cancer? What are the

most promising potential preventive agents

and activities?

What is the potential of new animal models

for testing of potential chemopreventive 

agents?
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Chapter 4 Etiology and Prevention of Prostate Cancer

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NCI-Supported Research Referenced in Chapter 4

Archer CL, Morse P, Jones RF, Shirai T, Haas GP, Wang CY. Carcinogenicity of the N-hydroxy derivative of

2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine, 2-amino-3, 8-dimethyl-imidazo[4,5-f]quinoxaline and

3, 2'-dimethyl-4-aminobiphenyl in the rat. Cancer Lett. 2000 Jul 3;155(1):55–60.

Bennett CL, Price DK, Kim S, Liu D, Jovanovic BD, Nathan D, Johnson ME, Montgomery JS, Cude K,

Brockbank JC, Sartor O, Figg WD. Racial variation in CAG repeat lengths within the androgen receptor gene among

prostate cancer patients of lower socioeconomic status. J Clin Oncol. 2002 Sep 1;20(17):3599–604.

Carpten J, Nupponen N, Isaacs S, Sood R, Robbins C, Xu J, Faruque M, Moses T, Ewing C, Gillanders E, Hu P,

Bujnovszky P, Makalowska I, Baffoe-Bonnie A, Faith D, Smith J, Stephan D, Wiley K, Brownstein M, Gildea D, Kelly

B, Jenkins R, Hostetter G, Matikainen M, Schleutker J, Klinger K, Connors T, Xiang Y, Wang Z, De Marzo A,

Papadopoulos N, Kallioniemi OP, Burk R, Meyers D, Gronberg H, Meltzer P, Silverman R, Bailey-Wilson J,

Walsh P, Isaacs W, Trent J. Germline mutations in the ribonuclease L gene in families showing linkage with HPC1. Nat

Genet. 2002 Feb;30(2):181–4.

Chang BL, Zheng SL, Hawkins GA, Isaacs SD, Wiley KE, Turner A, Carpten JD, Bleecker ER, Walsh PC, Trent JM,

Meyers DA, Isaacs WB, Xu J. Joint effect of HSD3B1 and HSD3B2 genes is associated with hereditary and sporadic

prostate cancer susceptibility. Cancer Res. 2002 Mar 15;62(6):1784–9.

DeMarzo AM, Nelson WG, Isaacs WB, Epstein JI. Pathological and molecular aspects of prostate cancer. Lancet.

2003 Mar 15;361(9361):955–64.

Easton DF, Schaid DJ, Whittemore AS, Isaacs WJ; International Consortium for Prostate Cancer Genetics. Where are

the prostate cancer genes?—A summary of eight genome wide searches. Prostate. 2003 Dec 1;57(4):261–9.

Gann PH, Ma J, Giovannucci E, Willett W, Sacks FM, Hennekens CH, Stampfer MJ. Lower prostate cancer risk in men

with elevated plasma lycopene levels: Results of a prospective analysis. Cancer Res. 1999 Mar 15;59(6):1225–30.

Hartman TJ, Dorgan JF, Woodson K, Virtamo J, Tangrea JA, Heinonen OP, Taylor PR, Barrett MJ, Albanes D. Effects

of long-term alpha-tocopherol supplementation on serum hormones in older men. Prostate. 2001 Jan 1;46(1):33–8.

Hayes RB, Pottern LM, Strickler H, Rabkin C, Pope V, Swanson GM, Greenberg RS, Schoenberg JB, Liff J, Schwartz

AG, Hoover RN, Fraumeni JF Jr. Sexual behaviour, STDs, and risks for prostate cancer. Br J Cancer. 2000

Feb;82(3):718–25.

Hein DW, Leff MA, Ishibe N, Sinha R, Frazier HA, Doll MA, Xiao GH, Weinrich MC, Caporaso NE. Association of

prostate cancer with rapid N-acetyltransferase 1 (NAT1*10) in combination with slow N-acetyltransferase 2 acetylator

genotypes in a pilot case-control study. Environ Mol Mutagen. 2002;40(3):161–7.

Heinonen OP, Albanes D, Virtamo J, Taylor PR, Huttunen JK, Hartman AM, Haapakoski J, Malila N, Rautalahti M,

Ripatti S, Maenpaa H, Teerenhovi L, Koss L, Virolainen M, Edwards BK. Prostate cancer and supplementation with

alpha-tocopherol and beta-carotene: Incidence and mortality in a controlled trial. J Natl Cancer Inst. 1998 Mar

18;90(6):440–6.

Irvine RA, Yu MC, Ross RK, Coetzee GA. The CAG and GGC microsatellites of the androgen receptor gene are in

linkage disequilibrium in men with prostate cancer. Cancer Res. 1995 May 1;55(9):1937–40.

Jaffe JM, Malkowicz SB, Walker AH, MacBride S, Peschel R, Tomaszewski J, Van Arsdalen K, Wein AJ,

Rebbeck TR. Association of SRD5A2 genotype and pathological characteristics of prostate tumors. Cancer Res. 2000

Mar 15;60(6):1626–30.

Kristal AR, Cohen JH, Qu P, Stanford JL. Associations of energy, fat, calcium, and vitamin D with prostate cancer risk.

Cancer Epidemiol Biomarkers Prev. 2002 Aug;11(8):719–25.

Li L, Yu H, Schumacher F, Casey G, Witte JS. Relation of serum insulin-like growth factor-I (IGF-I) and IGF binding

protein-3 to risk of prostate cancer (United States). Cancer Causes Control. 2003 Oct;14(8):721–6.

Makridakis NM, Ross RK, Pike MC, Crocitto LE, Kolonel LN, Pearce CL, Henderson BE, Reichardt JK. Association of

mis-sense substitution in SRD5A2 gene with prostate cancer in African-American and Hispanic men in Los Angeles,

USA. Lancet. 1999 Sep 18;354(9183):975–8.
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Chapter 4 Etiology and Prevention of Prostate Cancer

Rosenblatt KA, Wicklund KG, Stanford JL. Sexual factors and the risk of prostate cancer. Am J Epidemiol. 2001 Jun

15;153(12):1152–8.

Stanford JL, Noonan EA, Iwasaki L, Kolb S, Chadwick RB, Feng Z, Ostrander EA. A polymorphism in the CYP17 gene

and risk of prostate cancer. Cancer Epidemiol Biomarkers Prev. 2002 Mar;11(3):243–7.

Tavtigian SV, Simard J, Teng DH, Abtin V, Baumgard M, Beck A, Camp NJ, Carillo AR, Chen Y, Dayananth P,

Desrochers M, Dumont M, Farnham JM, Frank D, Frye C, Ghaffari S, Gupte JS, Hu R, Iliev D, Janecki T, Kort EN, Laity

KE, Leavitt A, Leblanc G, McArthur-Morrison J, Pederson A, Penn B, Peterson KT, Reid JE, Richards S, Schroeder M,

Smith R, Snyder SC, Swedlund B, Swensen J, Thomas A, Tranchant M, Woodland AM, Labrie F, Skolnick MH,

Neuhausen S, Rommens J, Cannon-Albright LA. A candidate prostate cancer susceptibility gene at chromosome 17p.

Nat Genet. 2001 Feb;27(2):172–80.

Thompson IM, Goodman PJ, Tangen CM, Lucia MS, Miller GJ, Ford LG, Lieber MM, Cespedes RD, Atkins JN,

Lippman SM, Carlin SM, Ryan A, Szczepanek CM, Crowley JJ, Coltman CA Jr. The influence of finasteride on the

development of prostate cancer. N Engl J Med. 2003 Jul 17;349(3):215–24.

Xu J, Zheng SL, Komiya A, Mychaleckyj JC, Isaacs SD, Hu JJ, Sterling D, Lange EM, Hawkins GA, Turner A,

Ewing CM, Faith DA, Johnson JR, Suzuki H, Bujnovszky P, Wiley KE, DeMarzo AM, Bova GS, Chang B, Hall MC,

McCullough DL, Partin AW, Kassabian VS, Carpten JD, Bailey-Wilson JE, Trent JM, Ohar J, Bleecker ER,

Walsh PC, Isaacs WB, Meyers DA. Germline mutations and sequence variants of the macrophage scavenger receptor

1 gene are associated with prostate cancer risk. Nat Genet. 2002a Oct;32(2):321–5.

Xu J, Zheng SL, Turner A, Isaacs SD, Wiley KE, Hawkins GA, Chang BL, Bleecker ER, Walsh PC, Meyers DA,

Isaacs WB. Associations between hOGG1 sequence variants and prostate cancer susceptibility. Cancer Res. 2002b

Apr 15;62(8):2253–7.

Xue W, Irvine RA, Yu MC, Ross RK, Coetzee GA, Ingles SA. Susceptibility to prostate cancer: Interaction between

genotypes at the androgen receptor and prostate-specific antigen loci. Cancer Res. 2000 Feb 15;60(4):839–41.

Zheng SL, Chang BL, Faith DA, Johnson JR, Isaacs SD, Hawkins GA, Turner A, Wiley KE, Bleecker ER, Walsh PC,

Meyers DA, Isaacs WB, Xu J. Sequence variants of alpha-methylacyl-CoA racemase are associated with prostate

cancer risk. Cancer Res. 2002 Nov 15;62(22):6485–8.
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Chapter 5 Prostate Cancer Early Detection, Diagnosis, and Prognosis

NATIONAL CANCER INSTITUTE

CHAPTER

5

Prostate Cancer Early Detection,

Diagnosis, and Prognosis: NCI’s

Investment and Recent Progress

Management of cancer begins with the early detection of disease. For men in whom cancer has

been detected, the disease can be most successfully controlled when diagnostic and prognostic measures

accurately predict the course of disease progression and the most suitable treatment interventions.

Research in early detection, diagnosis, and prognosis is aimed at enhancing diagnostic specificity and

selectivity with noninvasive techniques.

From the late 1980s through the early 1990s, the incidence rates for prostate cancer increased

(Figure 1-1 [Chapter 1] and Figure 5-1). This increase corresponded with the widespread adoption of

prostate specific antigen (PSA) testing, which received Food and Drug Administration approval in 1986.

In the 1990s, there was a decrease in the rate (Figure 5-1) and absolute number of new prostate cancer

diagnoses in which cancer was found to have already spread to sites distant from the prostate.

0

50

100

150

200

250

Overall

Unstaged

Localized/

regional

Distant

1975 1977 1979 1981 1983 1985 1987 1989 1991 1993 1995 1997 1999

Rate per 100,000

Year of Diagnosis

Figure 5-1. U.S. prostate cancer incidence rates by stage.

Data derived from NCI’s Surveillance, Epidemiology, and End Results (SEER) Program.

Rates are per 100,000 men and age-adjusted to the 2000 U.S. standard.

In their 1998 report, the Prostate Cancer PRG described pivotal needs in early detection,

diagnosis, and prognosis research for better management of localized disease. The report

emphasized the importance of both early

detection of prostate cancer and predicting the clinical course of tumors for

individual patients. While early detection,

particularly through the use of PSA

screening, has led to an increase in the

number of early-stage prostate cancer

diagnoses, not all clinically significant

tumors detected by PSA screening are

life threatening. Since many of the

definitive therapies for prostate cancer

can have a significant impact on quality

of life, patients face difficult decisions

The primary problem

remains our inability

to distinguish

between “indolent”

and “aggressive”

carcinomas.

– Defeating Prostate

Cancer: Crucial Directions

for Research - Report of

the Prostate Cancer

Progress Review Group,

August 1998.
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Chapter 5 Prostate Cancer Early Detection, Diagnosis, and Prognosis

when choosing among different types of therapies. Therefore, the identification of additional diagnostic

and prognostic markers that can distinguish indolent (i.e., slow-growing) from aggressive prostate carcinomas was, and still is, considered of critical importance.

The Prostate Cancer PRG identified several areas that offered the best opportunities to advance

prostate cancer research for early detection, diagnosis, and prognosis. Specifically, the natural history of

prostate cancer was considered a major knowledge gap; more information was needed on all the biological

steps from the onset of prostate cancer through advanced, metastatic disease. Better definitions of steps

in the natural history of prostate cancer will enable researchers and clinicians to differentiate indolent from

aggressive carcinomas. Fortunately, in the late 1990s new prostate cancer models and molecular technologies were developed that could be harnessed to accelerate future research. The PRG recommended

emphasizing the development, validation, and application of biologic determinants that can provide reliable

prognostic information and serve as surrogate markers for assessing the response to treatment. Areas of

particular interest that were identified included molecular assays to replace tissue-based assays, computer

and mathematical-modeling techniques, improved body-imaging techniques, and computer-assisted image

analysis.

The NCI has responded to the five PRG Priority One questions and recommendations.

Multiple initiatives support research to develop molecular profiles of cancer and novel imaging techniques.

Significant progress has been made, particularly in the area of identifying new markers. New biologic

markers will improve our ability to screen for and detect prostate cancer in its early stage and predict

which therapy, if any, is optimal for individual patients.

NCI’s Investment and Response

From fiscal year (FY) 1998 to FY 2002, NCI’s investment in early detection, diagnosis, and prognosis

prostate cancer extramural research has grown from $7.1 million (M) to $41.0M (Figure 5-2). Much of

this investment was made in the form of increases in the number of projects that respond to PRG Priority

One questions. Table 5-1 summarizes NCI’s responsiveness to the five Prostate Cancer PRG Priority

One research questions for prostate cancer early detection, diagnosis, and prognosis.

0

10

20

30

40

50

1998 1999 2000 2001 2002

Fiscal Year

Millions of Dollars

Figure 5-2. NCI’s investment in prostate cancer early detection, diagnosis,

and prognosis extramural research: 1998–2002 (in millions of dollars).
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Chapter 5 Prostate Cancer Early Detection, Diagnosis, and Prognosis

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NCI Efforts:

X In FY 2002, active areas of investigation included validating novel biologic markers, validating

intermediate markers for intervention studies, developing statistical methods, and developing a cancer

taxonomy based on gene expression.

X NCI initiatives that supported the PRG recommendation that a consortium be developed to evaluate and

validate prognostic markers included the Early Detection Research Network’s Prostate and Other

Urologic Cancers Collaborative Group and the 11 Prostate SPOREs.

X Additional NCI initiatives addressing this priority included Director’s Challenge: Toward a Molecular

Classification of Cancer and the Clinical Proteomics Program.

PRG Priority: How should prognostic

markers be validated?

0

10

35

1998 1999 2000 2001

NCISupported

Projects

per

Year

2002

15

5

25

20

30

NCI Efforts:

X In FY 2002, active areas of investigation included novel biologic markers, molecular staging of prostate

cancer, translating basic research studies on potential markers into clinical studies that evaluate their

potential utility, nuclear magnetic resonance (NMR) to define prostate differentiation, prostate cancer

characterization with ultrasonic imaging, and examination of micrometastases. In accordance with the

PRG’s recommendation, most of the projects on this list involve noninvasive diagnosis and less-invasive

prognostics.

X Nine 2002 projects addressed the PRG recommendation to characterize prostatic intraepithelial

neoplasia (PIN) and prostate tumor heterogeneity.

X This priority was addressed by the NCI-sponsored workshop Applications of Bioinformatics in Cancer

Detection (ABCD), which was held on August 6–7, 2002.

X NCI initiatives addressing this priority included Cooperative Prostate Cancer Tissue Resource (CPCTR),

Prostate Specialized Programs of Research Excellence (SPOREs), Cancer Genome Anatomy Project

(CGAP), Clinical Proteomics Program, Director’s Challenge: Toward a Molecular Classification of Cancer,

and Tissue Array Resource Program (TARP).

PRG Priority: What biologic

determinants, independent of

stage, can provide a better definition of the malignant phenotype,

natural history, and prognosis with

various therapeutic interventions?

0

20

60

100

120

1998 1999 2000 2001

NCISupported

Projects

per

Year

2002

80

40

Table 5-1. NCI Efforts Responsive to PRG Priorities in Prostate Cancer

Early Detection, Diagnosis, and Prognosis Researcha

a A given project may map to more than one PRG Priority One question and therefore be represented in more than one figure. Projects active in

2002 are listed by Principal Investigator’s name for each PRG Priority One question in Appendix B (Tables B-21–B-26).
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Chapter 5 Prostate Cancer Early Detection, Diagnosis, and Prognosis

NCI Efforts:

X In FY 2002, active areas of investigation included assessing the impact of PSA screening on prostate

cancer incidence and mortality.

X NCI initiatives addressing this priority included PIVOT and PLCO Cancer Screening Trial.

PRG Priority: What are the effects of

early detection on morbidity and quality

of life?b

0

2

4

6

10

1998 1999 2000 2001

NCISupported

Projects

per

Year

2002

8

NCI Efforts:

X In FY 2002, active areas of investigation included the impact of PSA screening on prostate cancer

mortality, U.S. prostate cancer trends, approaches to modeling and predicting therapeutic benefit of

surveillance, and correlation of telomere DNA content assay results to patient survival.

X NCI initiatives addressing this priority included Prostate Cancer Intervention Versus Observation Trial

(PIVOT) and Prostate, Lung, Colorectal & Ovarian (PLCO) Cancer Screening Trial.

PRG Priority: Does early detection

change mortality from prostate

cancer?b

0

3

6

9

15

1998 1999 2000 2001

NCISupported

Projects

per

Year

2002

12

NCI Efforts:

X In FY 2002, active areas of investigation included studying biologic markers, including HK2 and the

androgen receptor, molecular profiling analysis, new tools to predict tumor growth and metastatic potential,

and utilizing cytogenetics.

X NCI initiatives addressing this priority included Prostate SPOREs.

PRG Priority: What biologic

determinants characterize the

growth rate and/or tumor-doubling

time during the progression of

prostate cancer?

0

10

20

30

1998 1999 2000 2001

NCISupported

Projects

per

Year

2002

15

5

25

Table 5-1. (cont.)

b See p. 8-3 for related priority “What is the impact of early detection and screening on outcomes?”
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Chapter 5 Prostate Cancer Early Detection, Diagnosis, and Prognosis

NATIONAL CANCER INSTITUTE

NCI Efforts:

X In FY 2002, active areas of investigation included developing and refining imaging technologies such as

magnetic resonance imaging (MRI), gamma probes, and spectroscopy; measurement of seminal zinc as

a cancer detection tool; and development of prodrugs to release probes as diagnostic agents.

Additional early detection, diagnosis, and prognosis projects that

did not address the PRG priority

questions already listed in this

table.

0

10

20

30

1998 1999 2000 2001

NCISupported

Projects

per

Year

2002

15

5

25

Table 5-1. (cont.)

The initiatives relevant to research on prostate cancer early detection, diagnosis, and prognosis

between FY 1998 and FY 2002 include the following list of general initiatives that are described in

Table 2-11

 (Chapter 2) and the category-specific initiatives that are listed and described in Table 5-2:2

X Applications of Innovative Technologies for the Molecular Analysis of Cancer

X Cancer Genome Anatomy Project (CGAP)

X Cancer Imaging Program (CIP)

X Cancer Molecular Analysis Project (CMAP)

X Cancer Prognosis and Prediction

X Cancer Research Training, Career Development, and Education Opportunities

X Clinical Trials Cooperative Group Program

X Cooperative Human Tissue Network (CHTN)

X Cooperative Prostate Cancer Tissue Resource (CPCTR)

X Diagnostic Imaging and Guided Therapy in Prostate Cancer

X Director’s Challenge: Toward a Molecular Classification of Cancer

X Exploratory Grants for Correlative Laboratory Studies and Clinical Trials

X Improving DNA, RNA, and Protein Availability in Fixed Tissue

X In Vivo Cellular and Molecular Imaging Centers (ICMICs)

X Minority Institution/Cancer Center Partnership (MI/CCP) Program

X Molecular Profiling Initiative (MPI)

X NCI Center for Bioinformatics (NCICB)

X Program for the Assessment of Clinical Cancer Tests (PACCT)

X Prostate Cancer Intervention Versus Observation Trial (PIVOT)

X Prostate, Lung, Colorectal & Ovarian (PLCO) Cancer Screening Trial

X Prostate Specialized Programs of Research Excellence (SPOREs)

X Shared Resources for Scientists outside NCI Cancer Centers

X Specimen Resource Locator

1 Initiatives that impact multiple categories of prostate cancer research.

2 Initiatives unique to the research category of early detection, diagnosis, and prognosis.
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Chapter 5 Prostate Cancer Early Detection, Diagnosis, and Prognosis

Table 5-2. NCI Initiatives Relevant to Prostate Cancer Research:

Early Detection, Diagnosis, and Prognosis

INITIATIVES WITH PROSTATE CANCER-RELEVANT COMPONENTS

Clinical Proteomics Program (http://ncifdaproteomics.com/index.php)

Objective: A collaboration between the NCI and the Food and Drug Administration for providing access to

raw proteomics data and models.

Relevant Resource Resulting from This Initiative: Prostate spectra available for download derived from

322 samples categorized according to disease status and PSA levels.

Development of Clinical Imaging Drugs and Enhancers (DCIDE)(http://www3.cancer.gov/bip/dcide.htm)

Objective: Facilitate promising investigational imaging enhancers (contrast agents) or molecular probes

from the laboratory to Investigational New Drug status.

Relevant Program, Resource, and/or Research Projects Resulting from This Initiative: Pending

Development of Novel Technologies for In Vivo Imaging (PAR-01-101) (PAR-01-102)

Objective: Develop and evaluate feasibility of novel image acquisition or enhancement methods.

Relevant Research Project Resulting from this PA: NMR Imaging of Prostate Cancer Using Ligands

Early Detection Research Network (EDRN) (http://www3.cancer.gov/prevention/cbrg/edrn/)

Objective: Collaborative development and testing of promising biomarkers or technologies, with rapid

dissemination of results.

Relevant Program Resulting from This PA: A consortium that currently includes 18 biomarker development

laboratories (3 address prostate cancer); 3 biomarker validation laboratories; 9 clinical and epidemiologic

centers (2 address prostate cancer); and 1 data management coordinating center.

Exploratory Studies in Cancer Detection, Prognosis, and Prediction (PA-01-010)

Objective: Innovative strategies for the early detection, assessment of prognosis, or prediction of response

to cancer treatment.

Relevant Research Projects Resulting from This PA:

X Human Kallikrein 4 (hK4): A New Prostatic Biomarker?

X Human RNA Binding Protein as a Cancer Marker

X Neural Network Prediction of Prostate Cancer Progression

X Proteomic Study of Androgen Independent Prostate Cancer

Exploratory Studies in Diagnostics (PA-98-022)

Objective: Novel studies in cancer diagnostics.

Relevant Research Projects Resulting from This PA:

X Characterization of Prostate Cancer with HRMAS 1HMRS

X hTERT Expression as a Marker for Early Cancer Detection

X Molecular Markers for Prostate Cancer

X Molecular Markers for Prostate Cancer Detection
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Table 5-2. (cont.)

Exploratory/Developmental Grants for Diagnostic Cancer Imaging (PA-01-030)

Objective: Highly innovative research concepts in diagnostic cancer imaging.

Relevant Research Projects Resulting from This PA:

X Aptamers as Cellular Targeting Agents

X Diagnostic Freehand Elastographic Imaging of Cancer

X High Spectral and Spatial Resolution MRI of Rodent Tumors

X Improved Prostate Cancer Staging with Dual Mode Imaging

X NMR Detection of Prostate Tumor Differentiation

X Prostate Cancer and BPH Ablation Using HIFU Waveguide

X Seed Localizer for Image-Guided Prostate Brachytherapy

X Sodium MRI for Assessing Early Chemotherapy Response

Gene Expression Data Portal (GEDP) (http://gedp.nci.nih.gov/dc/index.jsp)

Objective: A public source of microarray research that also provides online data annotation and analysis

tools.

Relevant Data Generated by the Following Research Projects:

X Alterations in Gene Expression Profiles during Prostate Cancer Progression

X Comprehensive Gene Expression Analysis of Prostate Cancer Reveals Distinct Transcriptional Programs

Associated with Metastatic Disease

X Gene Expression Correlates of Clinical Prostate Cancer Behavior

X Molecular Classification of Prostate Cancer

Innovative Technologies for the Molecular Analysis of Cancer (PAR-01-104) (PAR-01-105)

Objective: Develop novel technologies that will support the molecular analysis of cancers and their host

environment in support of basic, clinical, and epidemiological research.

Relevant Research Projects Resulting from These PAs:

X Androgen Receptor Biochip—Prostate Cancer Management

X Messenger RNA Profiling by Single Molecule Counting

X Imaging Alternative Splicing during Tumor Progression

X In Vivo Analysis of Tumor Peptide Secretion

X Live Sensors for Molecular Profiling in Prostate Cancer

X Optomechanical Chips for Molecular Profiling of Cancer

X Phosphoinositide 3-Kinase Assays in Cancer Diagnosis

X Technology to Detect Genome-Wide DNA Methylation Changes

Tissue Arrray Resource Program (TARP) (http://ccr.cancer.gov/tech_initiatives/tarp/)

Objective: Develop and disseminate multi-tumor tissue microarray slides and related technology to cancer

research investigators.

Relevant Resource Resulting from This Initiative: The fifth-generation prostate cancer slide includes 79

samples of prostatic adenocarcinoma.
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Chapter 5 Prostate Cancer Early Detection, Diagnosis, and Prognosis

Ongoing NCI Research: Recent Progress in Prostate

Cancer Early Detection, Diagnosis, and Prognosis

Novel Biologic Markers

Through the use of new technologies, the rate at which new biologic markers are being identified has

significantly increased. New biologic markers have been identified in human serum, urine, prostatic fluid,

and tissue samples. Over the last 3 years, the result has been the identification of scores of novel prostate

cancer markers. Through NCI initiatives such as CGAP, numerous genes that are unique to prostate

cancer and pre-cancerous prostate have been identified. Many of these genes are being further investigated to determine if they can be used as markers or therapeutic targets for prostate cancer. The following NCI-supported research represents examples of recently identified biologic markers for prostate

cancer that may become clinically useful.

X Alpha-Methylacyl-CoA Racemase (AMACR) is an enzyme that normally functions in a digestive

system pathway; AMACR is required for bile acid synthesis and breaking down complex fatty

acids, such as those found in dairy products and beef. Increased expression of AMACR has been

observed in prostate cancer tissues compared to normal prostate or benign prostatic hyperplasia

(BPH) (Luo et al., 2002; Rubin et al., 2002). In two studies, samples representing different stages

of prostate cancer progression were analyzed. No correlation was observed between AMACR

and stage, grade, tumor size, or surgical margin status. However, high-grade prostatic

intraepithelial neoplasia (HGPIN) had increased levels of AMACR. This suggests AMACR may

be a valuable marker for early detection of prostate cancer.

X Caveolin-1 (Cav-1) is a protein that plays an important role in communication within a cell in both

signal transduction pathways and lipid transport. In some studies, increased levels of Cav-1 have

been associated with prostate cancer metastasis, biochemical recurrence after radical prostatectomy, and androgen insensitivity (Yang et al., 1999; Li et al., 2001). Additionally, some preliminary

results suggest that differences in Cav-1 expression may underlie the observed difference in the

virulence of prostate cancer in African American versus white patients (Yang et al., 2000). To

serve as an effective marker or prognostic indicator, it is important to understand how Cav-1

functions. Recent investigations have clarified how the Cav-1 gene is turned on and, once the

protein is produced, what downstream effects are mediated by Cav-1 (Cui et al., 2001; Tahir et

al., 2001). While still being developed, Cav-1 shows promise as a marker for detection and

prognosis and as a target for therapeutic interventions.

X Ribonuclease L (RNAseL) normally functions as a regulator in cell growth and cell death pathways. Recently, the RNAseL gene has been identified as a candidate gene for a form of familial

prostate cancer (Carpten et al., 2002). Two different mutations have been identified that were

previously linked to a chromosome 1 gene, known as the hereditary prostate cancer 1 locus. The

role of RNAseL in prostate cancer was further supported by a second study on noninherited

forms of prostate cancer (Casey et al., 2002). This analysis implicated a third variant of RNAseL

as a contributing factor in as many as 13 percent of prostate cancer cases. Men with a specific

variant of the RNAseL gene had two to four times the risk of developing prostate cancer compared to individuals without the variant. Thus, RNAseL shows the potential for use as a genetic

and diagnostic marker for prostate cancer and a potential target for therapeutic interventions.

X Prostate-Specific Stem Cell Antigen (PSCA) is a protein that is found on cell surfaces, is predominantly expressed in prostate cells, and may play a role in the normal development of the prostate

gland (Reiter et al., 1998). Published studies have shown a high correlation (64%–94%) between

increased PSCA expression and prostate cancer. The protein is also expressed in HGPIN and

BPH. PSCA expression is maintained in androgen-independent prostate cancer and is highly
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Chapter 5 Prostate Cancer Early Detection, Diagnosis, and Prognosis

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expressed in metastatic disease (Gu et al., 2000). In a recent study, anti-PSCA monoclonal

antibodies have been shown to inhibit tumor growth and metastasis formation in mouse models of

prostate cancer (Ross et al., 2002). Thus, PSCA shows promise as both a diagnostic/prognostic

marker for prostate cancer and a potential therapeutic target.

X Epidermal Growth Factor Receptor (EGFR) is a protein involved in cell growth and differentiation

signaling. Using immunohistochemical studies, EGFR expression appeared to be increased in

androgen-insensitive prostate cancer and in some prostate cells in advanced disease (Sherwood et

al., 1998; Leav et al., 1998). Since the expression of EGFR is deregulated in advanced disease,

several research groups are examining EGFR inhibitors as potential therapeutic agents. EGFR is

inhibited by a number of agents including C225 (cetuximab), which blocks the ligand-binding

domain of EGFR. OSI774, ZD1839 (Iressa), PKI166, and CI1033 prevent the protein from

performing its enzymatic functions by inhibiting the EGFR tyrosine kinase (Sirotnak et al., 2000;

Karashima et al., 2002). Selection of treatment with any of these agents would follow pretreatment analysis of samples to determine the extent of EGFR expression and determine whether

treatment with any of these agents would be efficacious. Several NCI-sponsored trials to determine the efficacy of EGFR pathway inhibitors are currently under way.

X The Telomerase Reverse-Transcriptase (TERT) gene encodes the protein component of telomerase,

the ribonucleoprotein that maintains the telomeric ends of chromosomes. Published reports demonstrate TERT activity levels in most prostate cancers and in some cases of high-grade PIN (HGPIN)

and that TERT is consistently absent from normal prostate tissues (Sommerfield et al., 1996;

Koeneman et al., 1998). The process of cancer development from normal cells through precancerous cells appears to be correlated to the shortening of telomeres (Meeker et al., 2002), the

stimulation of TERT expression (Guo et al., 2003; Moore et al., 2003), and the maintenance of

cellular longevity by active telomerase. Further evaluation of TERT expression following telomere

shortening may reveal a niche for its use as a supplement to diagnostic PSA testing.

Imaging Technologies

Transrectal ultrasonography (TRUS) became a standard technique for imaging the prostate by the

late 1980s. As tests that detect elevated PSA became commonly employed, cancers could be detected

below the limit of sensitivity of TRUS. In the past decade, the sensitivity and specificity of detecting

prostate cancers by TRUS have been significantly enhanced with three-dimensional Doppler imaging,

spectral analysis, and computer-aided image analysis (Moskalik et al., 2001; Balaji et al., 2002).

Research in magnetic resonance imaging (MRI) is also enhancing the potential for noninvasive

cancer detection. Advances in equipment design and newer analytic methods are being examined in

animal models. In addition, novel contrast agents and molecular probes are being examined to enhance the

specificity and selectively of MRI to detect prostate cancers and to differentiate metastatic from nonmetastatic tumors (Karczmar et al., 2000; Fan et al., 2001). MRI is also being employed to detect the

uptake of drugs, which will enhance the ability to predict drug effectiveness (Artemov et al., 2001).

Molecular Profiling

Molecular profiling involves determination of an individual tumor’s gene and protein expression patterns

through the use of technologies such as cDNA microarray and proteomic analyses. These high-throughput

techniques have only been developed in the past

decade and are still being optimized. Gene expression microarray and proteomic approaches have

been examined as complementary techniques to

study androgen-induced prostate cancer gene

expression and protein level changes (Nelson et al.,

2000; Nelson et al., 2002). In evaluating normal,

The challenge will be to select the

most promising markers and to

determine how to validate and

develop them into diagnostic tests.

- National Institutes of Health, Prostate Cancer

Research Plan for FY 2003–2008
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Chapter 5 Prostate Cancer Early Detection, Diagnosis, and Prognosis

Figure 5-3. NIH’s FY 2003–2008 prostate cancer early detection, diagnosis,

and prognosis research objectives build upon the 1998 PRG priorities.

BPH, PIN, and carcinoma cell lines, cancer stage-specific gene expression patterns have been detected, and

both novel genes and previously characterized proteins have been identified from these analyses (Chakrabarti

et al., 2002). Patterns of multiple proteins detected by mass spectrometry have proven more selective and

specific in identifying prostate cancers than the measurement of any single protein (Cazares et al., 2002).

Novel bioinformatics algorithms are being coupled to the newer mass spectrometry techniques to optimize the

selective identification of cancer cells versus non-cancer cells derived from microdissected tissues or serum

(Petricoin et al., 2002; Qu et al., 2002; Yasui et al., 2003). In the future, molecular profiles will be used to

classify tumors and define subsets of patients so that treatment can be tailored for individuals.

Continuing Needs and Evolution

The development of comprehensive approaches to molecular analysis and the validation of prostate

cancer markers remain high priorities. Currently, there are several new markers whose potential utility

must be validated in large clinical studies. NCI’s current investments will provide a foundation and the

infrastructure to support large validation studies. Multi-institutional studies will be required to accumulate

adequate sample sizes, and appropriate controls will be necessary along with standardization procedures

that will eliminate site-to-site differences in assay results. Future studies will likely include a focus on

early disease detection, prognosis of disease course, prediction of response to treatment, or other parameters such as risk of disease recurrences or overall disease-free survival.

NCI’s Future Investment in Prostate Cancer Early

Detection, Diagnosis, and Prognosis

The NIH Prostate Cancer Research Plan for FY 2003–2008 describes the NCI’s planned objectives

for early detection, diagnosis, and prognosis research pertaining to prostate cancer. The evolving nature of

science and NCI’s adaptations to changing needs are evident when the 1998 PRG report is compared to

the FY 2003–2008 Research Plan. The three FY 2003–2008 early detection, diagnosis, and prognosis

objectives and their alignment to the PRG priorities are summarized in Figure 5-3. Figure 5-3 also shows

how two PRG priorities in early detection, diagnosis, and prognosis align with an FY 2003–2008 objective

under the category of cancer control, survivorship, and outcomes.

PRG Priorities

What biologic determinants, independent of

stage, can provide a better definition of the

malignant phenotype, natural history, and 

prognosis with various therapeutic 

interventions?

Identify and validate biologic markers of premalignant, early-stage, latent, and potentially

aggressive disease.

Use knowledge of etiology and molecular

profiles at different stages of development to

improve tumor classification and identify

patient subgroups.

Develop, evaluate, and apply new technologies that more precisely characterize the

biological properties of prostatic lesions and 

will aid in predicting clinical behavior.

Cancer Control, Survivorship, and Outcomes:

Evaluate the outcomes of screening and treatment interventions, with special emphasis on

the impact of the quality of cancer care. (See 

Figure 8-3, Chapter 8.)

How should prognostic markers be validated?

What biologic determinants characterize the

growth rate and/or tumor-doubling time during

the progression of prostate cancer?

Does early detection change mortality from

prostate cancer?

What are the effects of early detection on 

morbidity and quality of life?

FY 2003–2008 Objectives
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Chapter 5 Prostate Cancer Early Detection, Diagnosis, and Prognosis

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NCI-Supported Research Referenced in Chapter 5

Artemov D, Solaiyappan M, Bhujwalla ZM. Magnetic resonance pharmacoangiography to detect and predict

chemotherapy delivery to solid tumors. Cancer Res. 2001 Apr 1;61(7):3039–44.

Balaji KC, Fair WR, Feleppa EJ, Porter CR, Tsai H, Liu T, Kalisz A, Urban S, Gillespie J. Role of advanced 2 and

3-dimensional ultrasound for detecting prostate cancer. J Urol. 2002 Dec;168(6):2422–5.

Carpten J, Nupponen N, Isaacs S, Sood R, Robbins C, Xu J, Faruque M, Moses T, Ewing C, Gillanders E, Hu P,

Bujnovszky P, Makalowska I, Baffoe-Bonnie A, Faith D, Smith J, Stephan D, Wiley K, Brownstein M, Gildea D,

Kelly B, Jenkins R, Hostetter G, Matikainen M, Schleutker J, Klinger K, Connors T, Xiang Y, Wang Z, De Marzo A,

Papadopoulos N, Kallioniemi OP, Burk R, Meyers D, Gronberg H, Meltzer P, Silverman R, Bailey-Wilson J,

Walsh P, Isaacs W, Trent J. Germline mutations in the ribonuclease L gene in families showing linkage with HPC1.

Nat Genet. 2002 Feb;30(2):181–4.

Casey G, Neville PJ, Plummer SJ, Xiang Y, Krumroy LM, Klein EA, Catalona WJ, Nupponen N, Carpten JD,

Trent JM, Silverman RH, Witte JS. RNAseL Arg462Gln variant is implicated in up to 13% of prostate cancer cases.

Nat Genet. 2002 Dec;32(4):581–3.

Cazares LH, Adam BL, Ward MD, Nasim S, Schellhammer PF, Semmes OJ, Wright GL Jr. Normal, benign, preneoplastic,

and malignant prostate cells have distinct protein expression profiles resolved by surface enhanced laser desorption/

ionization mass spectrometry. Clin Cancer Res. 2002 Aug;8(8):2541–52.

Chakrabarti R, Robles LD, Gibson J, Muroski M. Profiling of differential expression of messenger RNA in normal,

benign, and metastatic prostate cell lines. Cancer Genet Cytogenet. 2002 Dec;139(2):115–25.

Cui J, Rohr LR, Swanson G, Speights VO, Maxwell T, Brothman AR. Hypermethylation of the caveolin-1 gene

promoter in prostate cancer. Prostate. 2001 Feb 15;46(3):249–56.

Fan X, River JN, Zamora M, Tarlo K, Kellar K, Rinker-Schaeffer C, Karczmar GS. Differentiation of nonmetastatic and

metastatic rodent prostate tumors with high spectral and spatial resolution MRI. Magn Reson Med. 2001

Jun;45(6):1046–55.

Gu Z, Thomas G, Yamashiro J, Shintaku IP, Dorey F, Raitano A, Witte ON, Said JW, Loda M, Reiter RE. Prostate stem

cell antigen (PSCA) expression increases with high Gleason score, advanced stage and bone metastasis in prostate

cancer. Oncogene. 2000 Mar 2;19(10):1288–96.

Guo C, Armbruster BN, Price DT, Counter CM. In vivo regulation of hTERT expression and telomerase activity by

androgen. J Urol. 2003 Aug;170(2 Pt 1):615-8.

Karashima T, Sweeney P, Slaton JW, Kim SJ, Kedar D, Izawa JI, Fan Z, Pettaway C, Hicklin DJ, Shuin T,

Dinney CP. Inhibition of angiogenesis by the antiepidermal growth factor receptor antibody ImClone C225 in

androgen-independent prostate cancer growing orthotopically in nude mice. Clin Cancer Res. 2002 May;8(5):1253–

64.

Karczmar GS, Fan X, Al-Hallaq HA, Zamora M, River JN, Rinker-Schaeffer C, Zaucha M, Tarlo K, Kellar K. Uptake of a

superparamagnetic contrast agent imaged by MR with high spectral and spatial resolution. Magn Reson Med. 2000

May;43(5):633–9.

Koeneman KS, Pan CX, Jin JK, Pyle JM 3rd, Flanigan RC, Shankey TV, Diaz MO. Telomerase activity, telomere length,

and DNA ploidy in prostatic intraepithelial neoplasia (PIN). J Urol. 1998 Oct;160(4):1533-9.

Leav I, McNeal JE, Ziar J, Alroy J. The localization of transforming growth factor alpha and epidermal growth factor

receptor in stromal and epithelial compartments of developing human prostate and hyperplastic, dysplastic, and

carcinomatous lesions. Hum Pathol. 1998 Jul;29(7):668–75.

Li L, Yang G, Ebara S, Satoh T, Nasu Y, Timme TL, Ren C, Wang J, Tahir SA, Thompson TC. Caveolin-1 mediates

testosterone-stimulated survival/clonal growth and promotes metastatic activities in prostate cancer cells. Cancer

Res. 2001 Jun 1;61(11):4386–92.

Luo J, Zha S, Gage WR, Dunn TA, Hicks JL, Bennett CJ, Ewing CM, Platz EA, Ferdinandusse S, Wanders RJ,

Trent JM, Isaacs WB, De Marzo AM. Alpha-methylacyl-CoA racemase: a new molecular marker for prostate cancer.

Cancer Res. 2002 Apr 15;62(8):2220–6.

Meeker AK, Hicks JL, Platz EA, March GE, Bennett CJ, Delannoy MJ, De Marzo AM. Telomere shortening is an early

somatic DNA alteration in human prostate tumorigenesis. Cancer Res. 2002 Nov 15;62(22):6405-9.
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Chapter 5 Prostate Cancer Early Detection, Diagnosis, and Prognosis

Moore MG, Wetterau LA, Francis MJ, Peehl DM, Cohen P. Novel stimulatory role for insulin-like growth factor

binding protein-2 in prostate cancer cells. Int J Cancer. 2003 May 20;105(1):14-9.

Moskalik AP, Rubin MA, Wojno KJ, Bree R, Rubin JM, Fowlkes JB, Montie JE, Manley S, Carson PL. Analysis of

three-dimensional Doppler ultrasonographic quantitative measures for the discrimination of prostate cancer.

J Ultrasound Med. 2001 Jul;20(7):713–22.

Nelson PS, Clegg N, Arnold H, Ferguson C, Bonham M, White J, Hood L, Lin B. The program of androgen-responsive

genes in neoplastic prostate epithelium. Proc Natl Acad Sci U S A. 2002 Sep 3;99(18):11890–5. Epub 2002 Aug 16.

Nelson PS, Han D, Rochon Y, Corthals GL, Lin B, Monson A, Nguyen V, Franza BR, Plymate SR, Aebersold R, Hood L.

Comprehensive analyses of prostate gene expression: convergence of expressed sequence tag databases, transcript

profiling and proteomics. Electrophoresis. 2000 May;21(9):1823–31.

Petricoin EF 3rd, Ornstein DK, Paweletz CP, Ardekani A, Hackett PS, Hitt BA, Velassco A, Trucco C, Wiegand L,

Wood K, Simone CB, Levine PJ, Linehan WM, Emmert-Buck MR, Steinberg SM, Kohn EC, Liotta LA. Serum

proteomic patterns for detection of prostate cancer. J Natl Cancer Inst. 2002 Oct 16;94(20):1576–8.

Qu Y, Adam BL, Yasui Y, Ward MD, Cazares LH, Schellhammer PF, Feng Z, Semmes OJ, Wright GL Jr. Boosted

decision tree analysis of surface-enhanced laser desorption/ionization mass spectral serum profiles discriminates

prostate cancer from noncancer patients. Clin Chem. 2002 Oct;48(10):1835–43.

Reiter RE, Gu Z, Watabe T, Thomas G, Szigeti K, Davis E, Wahl M, Nisitani S, Yamashiro J, Le Beau MM, Loda M,

Witte ON. Prostate stem cell antigen: a cell surface marker overexpressed in prostate cancer. Proc Natl Acad Sci

USA. 1998 Feb 17;95(4):1735–40.

Ross S, Spencer SD, Holcomb I, Tan C, Hongo J, Devaux B, Rangell L, Keller GA, Schow P, Steeves RM, Lutz RJ,

Frantz G, Hillan K, Peale F, Tobin P, Eberhard D, Rubin MA, Lasky LA, Koeppen H. Prostate stem cell antigen as therapy

target: Tissue expression and in vivo efficacy of an immunoconjugate. Cancer Res. 2002 May 1;62(9):2546-53.

Rubin MA, Zhou M, Dhanasekaran SM, Varambally S, Barrette TR, Sanda MG, Pienta KJ, Ghosh D,

Chinnaiyan AM. Alpha-methylacyl coenzyme A racemase as a tissue biomarker for prostate cancer. JAMA. 2002 Apr

3;287(13):1662–70.

Sherwood ER, Van Dongen JL, Wood CG, Liao S, Kozlowski JM, Lee C. Epidermal growth factor receptor activation in

androgen-independent but not androgen-stimulated growth of human prostatic carcinoma cells. Br J Cancer. 1998

Mar;77(6):855–61.

Sirotnak FM, Zakowski MF, Miller VA, Scher HI, Kris MG. Efficacy of cytotoxic agents against human tumor xenografts is markedly enhanced by coadministration of ZD1839 (Iressa), an inhibitor of EGFR tyrosine kinase. Clin

Cancer Res. 2000 Dec;6(12):4885–92.

Sommerfeld HJ, Meeker AK, Piatyszek MA, Bova GS, Shay JW, Coffey DS. Telomerase activity: a prevalent marker of

malignant human prostate tissue. Cancer Res. 1996 Jan 1;56(1):218-22.

Tahir SA, Yang G, Ebara S, Timme TL, Satoh T, Li L, Goltsov A, Ittmann M, Morrisett JD, Thompson TC. Secreted

caveolin-1 stimulates cell survival/clonal growth and contributes to metastasis in androgen-insensitive prostate

cancer. Cancer Res. 2001 May 15;61(10):3882–5.

Yang G, Addai J, Ittmann M, Wheeler TM, Thompson TC. Elevated caveolin-1 levels in African-American versus

white-American prostate cancer. Clin Cancer Res. 2000 Sep;6(9):3430–3.

Yang G, Truong LD, Wheeler TM, Thompson TC. Caveolin-1 expression in clinically confined human prostate cancer:

a novel prognostic marker. Cancer Res. 1999 Nov 15;59(22):5719–23.

Yasui Y, Pepe M, Thompson ML, Adam BL, Wright GL Jr, Qu Y, Potter JD, Winget M, Thornquist M, Feng Z.

A data-analytic strategy for protein biomarker discovery: profiling of high-dimensional proteomic data for cancer

detection. Biostatistics. 2003 Jul;4(3):449–63.
6-1

Chapter 6 Scientific Model Systems for Prostate Cancer

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CHAPTER

6

Scientific Model Systems for

Prostate Cancer: NCI’s 

Investment and Recent Progress

The NCI supports utilization of various cell, organ, animal, and

mathematical models for studying mechanisms of prostate cancer

development and progression along with testing prevention and

treatment strategies. To maximize utility for prostate cancer research,

a scientific model needs to be fully characterized, validated for both

consistency and applicability to human disease, and readily available to

researchers.

In their 1998 report, the Prostate Cancer PRG described

the advantages and limitations of existing models for research

on prostate cancer and the need for additional models. Although

there are a variety of models that mimic one or more aspects of

prostate cancer in humans, there is no single model that replicates the

full spectrum of human disease development and progression.

Furthermore, our limited understanding of prostate cancer etiology,

progression, and metastasis complicates the validation of existing

models and development of new models.

The Prostate Cancer PRG identified four1

 Priority One research

questions that apply to the category of scientific model systems. The

questions and their accompanying recommendations addressed the

need for models that better simulate important aspects of human

prostate cancer (e.g., progression to androgen independence and affinity for bone) and models that are

better suited for testing new therapies, including the novel and targeted

therapies that are currently being pursued (e.g., gene and immunologic

therapies and other biologics).

The NCI has been responsive to the PRG’s recommendations. Model development, validation, and access have been addressed

by a major new initiative—the Mouse Models of Human Cancers

Consortium (MMHCC)—and supplements to existing NCI grants. Since

1998, emphasis has also been placed on the use of models to study

specific genes and pathways that are thought to play a role in prostate

cancer development and progression and to develop interventions

directed at these genes and their gene products.

A laboratory model

ideally simulates all of

the properties of

prostate cancer in

humans, but this is

difficult to achieve in

practice.

– Defeating Prostate

Cancer: Crucial Directions

for Research - Report of the

Prostate Cancer Progress

Review Group, August

1998.

1 Although the Laboratory and Clinical Models section of the PRG report actually included five questions, one of the questions

(Can models of human prostate cancer metastases be developed to mimic the affinity of human prostate cancer for bone

marrow?) has been combined with a second related question (Can models be designed to display the carcinogenic characteristics of human prostate cancer [i.e., its genetic characteristics, host–tumor interactions, micro-environment, angiogenesis, and

progression]?).
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Chapter 6 Scientific Model Systems for Prostate Cancer

Figure 6-1. NCI’s extramural investment in scientific model systems

pertaining to prostate cancer: 1998–2002 (in millions of dollars).

NCI’s responsiveness is summarized in Table 6-1 for the four Prostate Cancer PRG Priority One

research questions pertaining to scientific model systems.

NCI Efforts:

X In FY 2002, active areas of investigation included keratinocyte growth factor and fibroblast growth factor

receptors in the transgenic adenocarcinoma of the mouse prostate (TRAMP) and derived cell lines,

transgenic mouse models that closely mimic human progression using different genes, identity of stagespecific gene expression patterns in mice, early prostate cancer events and progression in Nkx3.1

mutant mice, role of integrins in bone metastasis, and bone effects in promoting growth of metastatic

tumors.

X The NCI portfolio addressed the following recommended actions to improve prostate cancer models:

- Six projects to identify genes that drive the initiation process of prostate cancer development

- Three projects to develop new prostate cancer cell lines

- Nineteen projects to develop new animal models, including four projects specifically developing

models that mimic prostate metastasis to bone

- Two projects to study the interaction of bone cells and prostate cells

X NCI initiatives addressing this priority included Prostate Specialized Programs of Research Excellence

(SPOREs), MMHCC, and Competing Supplements for Organotypic Models of Cancer.

PRG Priority: Can models be designed to

display the carcinogenic characteristics of

human prostate cancer (i.e., genetics,

host–tumor interactions, micro-environment, angiogenesis, and progression)?

Importantly, can models that mimic bone

marrow metastases be developed? 0

10

20

30

1998 1999 2000 2001

NCISupported

Projects

per

Year

2002

15

5

25

Table 6-1. NCI Efforts Responsive to PRG Priorities in

Scientific Model Systems of Prostate Cancera

a A given project may map to more than one PRG Priority One question and therefore be represented in more than one figure. Projects active in

2002 are listed by Principal Investigator’s name for each PRG Priority One question in Appendix B (Tables B-27–B-31).

0

2

4

6

8

12

1998 1999 2000 2001 2002

Fiscal Year

Millions of Dollars10

NCI’s Investment and Response

From fiscal year (FY) 1998 to FY 2002, NCI’s extramural investment in scientific model systems

relevant to prostate cancer has increased from $3.6 million (M) to $11.3M (Figure 6-1).
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Chapter 6 Scientific Model Systems for Prostate Cancer

NATIONAL CANCER INSTITUTE

NCI Efforts:

X In FY 2002, active areas of investigation included topoisomerase I inhibitors, mechanisms of anti-tubulin

and anti-phosphatase agents, anti-cancer properties of natural products and their derivatives, preclinical

and clinical evaluation of peptides against angiogenesis and metastasis, thermal-sensitive liposomal

drug delivery, and green fluorescent protein-tagged proteins in rodent model transplants to examine

metastasis and angiogenesis.

X NCI initiatives addressing this priority included Cancer Therapy-Related Use of Genetically Engineered

Mice, Prostate SPOREs, and MMHCC.

NCI Efforts:

X In FY 2002, active areas of investigation included hormone effects in an early prostate cancer mouse

model, estradiol-17-beta and testosterone mechanisms of tumor progression, inhibitors of androgen

receptor and androgen metabolizing enzymes, and hormone-induced carcinogenesis and cancer

progression in retinoblastoma (Rb)-knockout and conditionally Rb-deleted mice.

X Five projects addressed the PRG recommendation to study the mechanism of hormone action in

prostate cell lines and animal models.

X Three projects addressed the PRG recommendation to study the mechanism by which prostate cancer

cells become refractory to androgens.

X NCI initiatives addressing this priority included Prostate SPOREs and MMHCC.

PRG Priority: Can models be designed to

display the hormone responsiveness of

human prostate cancer and its progression to hormone independence?

PRG Priority: Can laboratory models

be used to screen potential chemotherapeutic agents, clarify dose/

response relationships, and understand chemotherapy resistance and

mechanisms of therapeutic response?

0

3

6

9

15

1998 1999 2000 2001

NCISupported

Projects

per

Year

2002

12

0

10

20

30

1998 1999 2000 2001

NCISupported

Projects

per

Year

2002

15

5

25

Table 6-1. (cont.)
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Chapter 6 Scientific Model Systems for Prostate Cancer

NCI Efforts:

X In FY 2002, active areas of investigation included T-cell-stimulated cytotoxic response, anti-angiogenesis

antibodies in combination with conventional chemotherapy or hormonal therapy, immunization of TRAMP

mice with tumor-associated antigen, immunization of transgenic models with peptides of human

telomerase, gene therapy vector delivery, and herpes simplex virus thymidine kinase gene therapy with

valacyclovir or ganciclovir.

X Eight projects addressed the PRG recommendation to develop vectors for gene therapy.

X Three projects addressed the PRG recommendation to define the immune components of prostate

cancer cells.

X Twenty-three projects addressed the PRG recommendation to test novel therapeutic approaches in

animal models.

X NCI initiatives addressing this priority included Cancer Therapy-Related Use of Genetically Engineered

Mice, Prostate SPOREs, and MMHCC.

NCI Efforts:

X In FY 2002, active areas of investigation included evaluation of dietary carcinogens; development,

validation, and dissemination of TRAMP and other mouse models; and mouse models used to develop

positron emission tomography imaging techniques.

Additional scientific model systems

projects that did not address the PRG

priority questions in this table.

0

2

4

6

10

1998 1999 2000 2001

NCISupported

Projects

per

Year

2002

8

Table 6-1. (cont.)

The initiatives relevant to research on prostate cancer scientific model systems between FY 1998

and FY 2002 include the following list of general initiatives that are described in Table 2-12

 (Chapter 2) and

the category-specific initiatives that are listed and described in Table 6-2:3

X Cancer Research Training, Career Development, and Education

Opportunities

X Cancer Therapy-Related Use of Genetically Engineered Mice

X Cooperative Prostate Cancer Tissue Resource (CPCTR)

X Improving DNA, RNA, and Protein Availability in Fixed Tissue

2 Initiatives that impact multiple categories of prostate cancer research.

3 Initiatives that are unique to the scientific model systems research category.

PRG Priority: Can models be used to

test novel therapeutic approaches

(e.g., cancer vaccines, gene therapy,

and immunological therapies)?

0

10

20

40

1998 1999 2000 2001

NCISupported

Projects

per

Year

2002

15

5

30

25

35
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Chapter 6 Scientific Model Systems for Prostate Cancer

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Table 6-2. NCI Initiatives Relevant to Prostate Cancer Research:

Scientific Model Systems

Ongoing NCI Research:

Recent Progress in Scientific Model Systems

Transgenic Animal Models

In recent years, notable advances have been made in utilizing existing and developing new

transgenic, xenograft, and knockout models. The TRAMP model was first described in 1995 (Greenberg

et al., 1995). Recently, it has been used for preclinical testing of therapeutic strategies (Shariat et al.,

2001; Arap et al., 2002) and chemopreventive agents (Gupta et al., 2000) and for studying the events that

lead to androgen independence at the molecular level (Buchanan et al., 2001; Han et al., 2001).

INITIATIVES WITH PROSTATE CANCER-RELEVANT COMPONENTS

Competing Supplements for Organotypic Models of Cancer (PAR-02-052)

Objective: Development and use of alternate model systems that more closely resemble normal tissue or

emerging tumors than do dispersed cells cultured on plastic.

Relevant Research Projects Resulting from This Program Announcement:

X Cathepsin B and Tumor Invasion

X Cell Motility in Prostate Tumor Invasion

Mouse Models of Human Cancers Consortium (MMHCC) (http://emice.nci.nih.gov/)

Objective: Accelerate the pace at which mice with heritable malignancies that are accurate, reproducible

models of human cancers are made available to the research community.

Relevant Research Project Resulting from This Initiative: A collaborative project that makes information

and tools available to the public via its eMICE website, which includes a section on Prostate Cancer Models

and a Mouse Tumor Biology Database. The consortium includes a Prostate Cancer Committee that is

charged with developing mouse models of prostate cancer that faithfully simulate the human disease. In

addition, there are four strains of mice specific to prostate cancer and one specific to both prostate and

breast cancer* that can be ordered for use in research:

X *C3(1)/Tag (FVB-Tg(C3-1-TAg)cJeg)

X Nkx3.1 null (B6.129-Nkx3-1tm1Mms)

X Nkx3.1 null (FVB.129-Nkx3-1tm1Mms)

X PB-Cre4 (B6;D2-Tg(PB-Cre)4Prb)

X TRAMP (C57BL/6-Tg(TRAMP)8247Ng)

Additional Relevant Research Projects Resulting from This Initiative:

X Mouse Cancer Models by Regulated Inactivation of Tumor Suppressors

X Mouse Cancer Models via TGF-Beta RII Loss

X A Mouse Model for Prostate Cancer

X Mouse Models for Prostate Cancer

X Transgenic Mouse Models of Prostate Cancer

X In Vivo Cellular and Molecular Imaging Centers (ICMICs)

X Prostate Specialized Programs of Research Excellence (SPOREs)

X Specimen Resource Locator
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Chapter 6 Scientific Model Systems for Prostate Cancer

In its quest to rapidly advance

prostate cancer research, NCI is

committed to develop more accurate

models of prostate cancer.

– National

Institutes of

Health,

Prostate

Cancer

Research

Plan for FY

2003–2008.

Prior to development of the TRAMP model, transgenic animals designed as models of prostate

cancer developed tumors at sites other than (Schaffner et al., 1995) or in addition to (Maroulakou et al.,

1994) the prostate. The TRAMP model is the first to consistently develop prostate cancer. It is based on

inclusion of gene sequences not normally present in the mouse—the overlapping large T and small t

antigen-coding sequences (Tag sequences) of the SV40 simian virus and the promoter region of the rat

probasin gene, a gene that is specific to prostate epithelial cells and regulated by androgen. The transgene

sequences affect mouse prostate epithelial cells by blocking transcription of the normally expressed mouse

p53 and Rb tumor suppressor genes (via the expressed large T SV40 antigen) and inactivating the MAP

kinase pathway enzyme protein phosphatase 2A (via the expressed small t SV40 antigen). This results in

mice that consistently display pathological changes leading to high-grade prostatic intraepithelial neoplasia

(PIN), adenocarcinoma (by 12 weeks of age), and metastasis (by 30 weeks of age) (Gingrich et al., 1999).

The TRAMP mice develop metastases to the regional lymph nodes and lungs and infrequently develop

skeletal metastasis. Studies have shown that the prostate tumors that spontaneously develop in TRAMP

mice progress to androgen independence and that one or more mutations can be found in the androgen

receptor gene sequences of each mouse that has become androgen independent (Han et al., 2001).

New transgenic strains that are variants of the TRAMP model have been developed and characterized in recent years. The LADY model, which is under rat probasin promoter control but fails to express

the small t SV40 antigen, develops prostate cancers that are less aggressive than those in TRAMP

(Kasper et al., 1998; Masumori et al., 2001). While these mice develop low- and high-grade PIN lesions

and adenocarcinoma, progression to distant metastases is rarely observed. However, following androgen

deprivation therapy, the tumors in LADY mice initially regress but then grow further and progress to

metastatic disease.

Transgenic strains that rely on other insertional elements, including the rat probasin promoter and

mouse androgen receptor gene (Stanbrough et al., 2001), have also been recently developed. These

strains develop hyperplasia and low-grade PIN, but do not progress to prostatic adenocarcinoma.

Xenografted Animal Models

Xenografted mouse models, in which characterized human prostate cancer cell lines are implanted

subcutaneously or intra-prostatically (orthotopically) in immunodeficient animals, such as nude mice, were

first described in the mid-1970s (Schroeder et al., 1976). Numerous human prostate cancer cell lines (e.g.,

LNCaP, LuCAP, CWR22, DU145, and PC-3) derived from different sources ranging from primary tumors

to distant site metastases have been used for this purpose. These cell lines display different genetic

backgrounds, androgen sensitivities, and metastatic potential. Further influencing the behavior of the cells

is the site of implantation. PC-3 cells lead to metastases following orthotopic placement in the prostate but

not following subcutaneous implantation (Glinskii et

al., 2003).

Xenografted animals have recently been used

to study inducers of apoptosis (Dhanalakshmi et al.,

2003; Xiao et al., 2003) and other therapeutic

interventions (Denmeade et al., 2003). They have

also been employed in microarray analysis of gene

expression in normal versus diseased prostate

(Glinsky et al., 2003).
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Chapter 6 Scientific Model Systems for Prostate Cancer

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The drawbacks of xenograft models include the absence of bone metastasis (although tumors can

appear in bone following direct implantation) and the internal milieu of immunodeficient animals, which is

different from that of wild-type animals and the vast majority of men who develop prostate cancer.

Furthermore, because the cell lines used in implantation are already malignant, xenografted models are not

suitable for studying the initiating events in prostate carcinogenesis.

Knockout Animal Models

Knockout mouse models, in which a specific gene has been inactivated due to deletion or other

mutation, have been developed for studying the involvement of specific gene products and regulator

sequences in prostate cancer development and progression (Ruan et al., 1999; Kim et al., 2002). An

important feature of knockout models is that they provide a tailored environment for testing targeted gene

therapies and other therapies based on gene product replacement.

Knockout models based on the tumor suppressor Nkx3.1 and/or Pten genes have been found to

display prostatic abnormalities such as hyperplasia, PIN, and, when the two deletions are combined,

possible progression to adenocarcinoma (Di Cristofano et al., 1998; Bhatia-Gaur et al., 1999; Kim et al.,

2002; Park et al., 2002; Abate-Shen et al., 2003). A recent study has shown that the high-grade PIN

lesions removed from Nkx3.1/Pten compound knockout mice result in adenocarcinoma and lymph node

metastases following transplantation into immunodeficient animals (Abate-Shen et al., 2003).

Another recent study has shown that when Pten is preferentially deleted from prostate epithelial

cells, the PIN lesions are followed by progression to invasive carcinoma and subsequent metastasis in the

regional lymph nodes and lungs. These metastases were androgen receptor positive. This is the first

animal model in which deletion of an endogenous gene leads to metastatic prostate cancer. Since the

initiating oncogenic event is androgen independent, the Pten conditional deletion mice may provide a unique

opportunity to address the mechanisms of resistance to androgen ablation therapy (Wang et al., 2003).

Continuing Needs and Evolution

A continuing need in the area of scientific model systems is model validation (1) to determine the

extent to which scientific model systems are similar to and different from the human disease state and

(2) to understand the significance of these similarities and differences for preclinical assessment of

pathways/mechanisms and preventive and therapeutic interventions. Proteomic analysis has shown that

there are substantive differences between (1) prostate tumor cells obtained via laser capture microdissection and (2) both commonly used and same patient-derived cell lines that are maintained in vitro

(Ornstein et al., 2000).

NCI’s Future Investment in Scientific Model Systems

The NIH Prostate Cancer Research Plan for FY 2003–2008 describes the NCI’s planned objectives

for research on scientific model systems of prostate cancer. The objectives are based on the priorities

identified by the PRG and advances that have taken place since completion of the PRG’s work. The three

FY 2003–2008 objectives and their alignment to the four PRG priorities in the area of scientific model

systems and additional PRG priorities in the areas of resources needed, and etiology and prevention are

summarized in Figure 6-2.

One of the FY 2003–2008 objectives, which does not align with any of the five PRG priorities,

recognizes an advancement in the area—the ability to leverage mouse and other models to refine knowledge of molecular and cellular processes initially gleaned from human subjects and patients. Key to this

objective is the NCI initiative that supports disease site-specific model development (i.e., the MMHCC).
NATIONAL CANCER INSTITUTE

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Chapter 6 Scientific Model Systems for Prostate Cancer

NCI-Supported Research Referenced in Chapter 6

Abate-Shen C, Banach-Petrosky WA, Sun X, Economides KD, Desai N, Gregg JP, Borowsky AD, Cardiff RD,

Shen MM. Nkx3.1; Pten mutant mice develop invasive prostate adenocarcinoma and lymph node metastases. Cancer

Res. 2003 Jul 15;63(14):3886–90.

Arap W, Haedicke W, Bernasconi M, Kain R, Rajotte D, Krajewski S, Ellerby HM, Bredesen DE, Pasqualini R,

Ruoslahti E. Targeting the prostate for destruction through a vascular address. Proc Natl Acad Sci (USA).2002;

99(3):1527–31.

Bhatia-Gaur R, Donjacour AA, Sciavolino PJ, Kim M, Desai N, Young P, Norton CR, Gridley T, Cardiff RD,

Cunha GR, Abate-Shen C, Shen MM. Roles for Nkx3.1 in prostate development and cancer. Genes Dev. 1999 Apr

15;13(8):966–77.

Buchanan G, Greenberg NM, Scher HI, Harris JM, Marshall VR, Tilley WD. Collocation of androgen receptor gene

mutations in prostate cancer. Clinical Cancer Research. 2001; (7)1273–81.

Denmeade SR, Jakobsen CM, Janssen S, Khan SR, Garrett ES, Lilja H, Christensen SB, Isaacs JT. Prostate-specific

antigen-activated thapsigargin prodrug as targeted therapy for prostate cancer. J Natl Cancer Inst. 2003 Jul

2;95(13):990–1000.

Dhanalakshmi S, Agarwal R, Agarwal C. Inhibition of NF-kappaB pathway in grape seed extract-induced apoptotic

death of human prostate carcinoma DU145 cells. Int J Oncol. 2003 Sep;23(3):721–7.

Figure 6-2. NIH’s FY 2003–2008 prostate cancer scientific model systems

research objectives build and expand upon the 1998 PRG priorities.

PRG Priorities

Can models be designed to display the

carcinogenic characteristics of human prostate

cancer (i.e., genetics, host–tumor interactions,

microenvironment, angiogenesis, and progression)? Importantly, can models that mimic

bone marrow metastases be developed?

Identify and design models that can accurately

mimic the natural progression of human

prostate cancer, namely, its genetic characteristics, interactions with the host, microenvironment, progression, and metastasis.

FY 2003–2008 Objectives

Can models be designed to display the

hormone responsiveness of human prostate

cancer and its progression to hormone 

independence?

Can laboratory models be used to screen

potential chemotherapeutic agents, clarify

dose/response relationships, and understand

chemotherapy resistance and mechanisms of

therapeutic response?

Can models be used to test novel therapeutic

approaches (e.g., cancer vaccines, gene 

therapy, and immunological therapies)?

Resources Needed: Preclinical Models (See

Figure 2-1, Chapter 2.)

Etiology and Prevention: What is the potential 

of new animal models for testing of potential

chemopreventive agents? (See Figure 4-2, 

Chapter 4.)

Use mouse and other models to characterize

molecular and cellular processes in human

prostate cancer and disseminate this 

information widely to the research community.

Use validated models to identify and test

preventive, detection, and therapeutic agents.
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Chapter 6 Scientific Model Systems for Prostate Cancer

NATIONAL CANCER INSTITUTE

Di Cristofano A, Pesce B, Cordon-Cardo C, Pandolfi PP. Pten is essential for embryonic development and tumour

suppression. Nat Genet. 1998 Aug;19(4):348–55.

Gingrich JR, Barrios RJ, Foster BA, Greenberg NM. Pathologic progression of autochthonous prostate cancer in the

TRAMP model. Prostate Cancer and Prostatic Diseases. 1999; 2:70–5.

Glinskii AB, Smith BA, Jiang P, Li XM, Yang M, Hoffman RM, Glinsky GV. Viable circulating metastatic cells produced

in orthotopic but not ectopic prostate cancer models. Cancer Res. 2003 Jul 15;63(14):4239–43.

Glinsky GV, Krones-Herzig A, Glinskii AB, Gebauer G. Microarray analysis of xenograft-derived cancer cell lines

representing multiple experimental models of human prostate cancer. Mol Carcinog. 2003 Aug;37(4):209–21.

Greenberg NM, DeMayo FJ, Finegold M, Medina D, Tilley W, Aspinall JO, Cunha GR, Donjacour AA, Matusik RJ,

Rosen JM. Prostate cancer in a transgenic mouse. Proc Natl Acad Sci USA. 1995; 92(8):3439–43.

Gupta S, Ahmad N, Marengo SR, MacLennan GT, Greenberg NM, Mukhtar H. Chemoprevention of prostate carcinogenesis by alpha- difluoromethylornithine in TRAMP mice. Cancer Res. 2000; 60(18):5125–33.

Han G, Foster BA, Mistry S, Buchanan G, Harris JM, Tilley WD, Greenberg NM. Hormone status selects for spontaneous somatic androgen receptor variants that demonstrate specific ligand and cofactor dependent activities in

autochthonous prostate cancer. J Biol Chem. 2001 Apr 6;276(14):11204–13.

Kasper S, Sheppard PC, Yan Y, Pettigrew N, Borowsky AD, Prins GS, Dodd JG, Duckworth ML, Matusik RJ. Development, progression, and androgen-dependence of prostate tumors in probasin-large T antigen transgenic mice: A

model for prostate cancer. Lab Invest. 1998;78(6):i–xv.

Kim MJ, Cardiff RD, Desai N, Banach-Petrosky WA, Parsons R, Shen MM, Abate-Shen C. Cooperativity of Nkx3.1

and Pten loss of function in a mouse model of prostate carcinogenesis. Proc Natl Acad Sci USA. 2002 Mar

5;99(5):2884–9.

Maroulakou IG, Anver M, Garrett L, Green JE. Prostate and mammary adenocarcinoma in transgenic mice carrying a rat

C3(1) simian virus 40 large tumor antigen fusion gene. Proc Natl Acad Sci USA. 1994 Nov 8;91(23):11236–40.

Masumori N, Thomas TZ, Chaurand P, Case T, Paul M, Kasper S, Caprioli RM, Tsukamoto T, Shappell SB,

Matusik RJ. A probasin-large T antigen transgenic mouse line develops prostate adenocarcinoma and neuroendocrine carcinoma with metastatic potential. Cancer Res. 2001;61(5)2239–49.

Ornstein DK, Gillespie JW, Paweletz CP, Duray PH, Herring J, Vocke CD, Topalian SL, Bostwick DG, Linehan WM,

Petricoin EF 3rd, Emmert-Buck MR. Proteomic analysis of laser capture microdissected human prostate cancer and in

vitro prostate cell lines. Electrophoresis. 2000 Jun;21(11):2235–42.

Park JH, Walls JE, Galvez JJ, Kim M, Abate-Shen C, Shen MM, Cardiff RD. Prostatic intraepithelial neoplasia in

genetically engineered mice. Am J Pathol. 2002 Aug;161(2):727–35.

Ruan W, Powell-Braxton L, Kopchick JJ, Kleinberg DL. Evidence that insulin-like growth factor I and growth hormone

are required for prostate gland development. Endocrinology. 1999 May;140(5):1984–9.

Schaffner DL, Barrios R, Shaker MR, Rajagopalan S, Huang SL, Tindall DJ, Young CY, Overbeek PA, Lebovitz RM,

Lieberman MW. Transgenic mice carrying a PSArasT24 hybrid gene develop salivary gland and gastrointestinal tract

neoplasms. Lab Invest. 1995 Mar;72(3):283–90.

Stanbrough M, Leav I, Kwan PW, Bubley GJ, Balk SP. Prostatic intraepithelial neoplasia in mice expressing an

androgen receptor transgene in prostate epithelium. Proc Natl Acad Sci USA. 2001 Sep 11;98(19):10823–8.

Xiao W, Zhang Q, Jiang F, Pins M, Kozlowski JM, Wang Z. Suppression of prostate tumor growth by U19, a novel

testosterone-regulated apoptosis inducer. Cancer Res. 2003 Aug 1;63(15):4698–704.

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Chapter 7 Prostate Cancer Treatment

NATIONAL CANCER INSTITUTE

CHAPTER

7

Prostate Cancer Treatment:

NCI’s Investment and Recent

Progress

The ultimate goal of prostate

cancer treatment is to reduce

prostate cancer-specific

mortality.

– Defeating Prostate Cancer: Crucial

Directions for Research - Report of

the Prostate Cancer Progress Review

Group, August 1998.

Research leading to improved cancer treatment plays a prominent role in NCI’s cancer portfolio. It

spans a spectrum of activities ranging from synthesis and discovery on the benchtop, to preclinical testing

of safety and efficacy in animal models, and ultimately, to clinical trials in increasing numbers of cancer

patients.

In their 1998 report, the Prostate Cancer PRG described promising directions and unmet

needs for staging and treatment of localized prostate cancer and for systemic treatment of

prostate cancer that cannot be cured by localized treatment modalities.

1

 For both localized and

advanced prostate cancer, the PRG stressed the importance of developing the following:

X Technologies for more precise disease staging,

treatment selection, and treatment optimization

X Targeted therapies, especially gene and cellular

therapies

Existing limitations on the ability to accurately assess

disease stage and treatment response have resulted in some

patients being “undertreated” for tumors that will ultimately

advance or recur and “overtreated” for tumors that will

remain indolent. Additionally, treatments for localized prostate

cancer are not always effective, nor are they free from side

effects. Therefore, research is needed to develop optimal

treatments for patients at different stages of prostate cancer.

The Prostate Cancer PRG identified 11 Priority One

research questions that apply to the category of treatment:

Four that pertain to staging and treatment of localized prostate

cancer and seven that pertain to systemic therapy.2

 The

questions and their accompanying recommendations addressed the need for improving existing approaches

and the potential promise of novel approaches.

The NCI’s broad approach to conducting and sponsoring research on treatment for

prostate cancer is responsive to these recommendations. This approach includes the following:

X Developing novel agents based on mechanism of action

X Developing molecularly targeted agents that influence key pathways implicated in prostate cancer

progression

X Optimizing promising hormonal and chemotherapeutic regimens

1 Although staging and treatment of localized prostate cancer and systemic therapy were addressed as two discrete categories of

research in the PRG report, this report addresses both under the single category entitled treatment. This approach is consistent

with the Common Scientific Outline (CSO) research categorization scheme that was adopted by the NCI for tracking dollar

investments, resources, and projects. (See discussion in Chapter 1.)

2 Although the PRG report actually included eight questions pertaining to the category of systemic therapy, one of the questions

(How can new targets be identified?) was also part of a second question (How can new targets be identified and what is the role

of novel therapeutic agents directed at these targets?).
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Chapter 7 Prostate Cancer Treatment

X Pursuing multidisciplinary approaches

X Developing new functional imaging tools

X Incorporating new technology

X Training new multidisciplinary investigators

NCI’s Investment and Response

From Fiscal Year (FY) 1998 to FY 2002, NCI’s extramural investment in research for prostate

cancer treatment grew from $16.9 million (M) to $57.6M (Figure 7-1). Much of this investment was

made in the form of increases in the number of projects that respond to PRG Priority One questions.

NCI’s responsiveness is summarized in Table 7-1 for the four Prostate Cancer PRG Priority One

research questions pertaining to staging and treatment of localized prostate cancer and in Table 7-2 for the

seven Priority One research questions pertaining to systemic therapy.

Figure 7-1. NCI’s extramural investment in prostate cancer

treatment research: 1998–2002 (in millions of dollars).

0

10

30

60

1998 1999 2000 2001 2002

Fiscal Year

Millions of Dollars50

20

40
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Chapter 7 Prostate Cancer Treatment

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NCI Efforts:

X In FY 2002, active areas of investigation included radiosensitization of tumor cells, MRI-guided ultrasound

ablation, computer-assisted photodynamic therapy, and imaging techniques for implanting brachytherapy

seeds and monitoring brachytherapy response.

X Ten projects addressed the PRG recommendation to develop novel staging tools; five projects and the

following two clinical trials addressed the PRG recommendation to further test and refine threedimensional conformal therapy:

- Phase II Study of High-Dose Three-Dimensional Conformal Radiotherapy (3D-CRT) in Patients with

Intermediate Prognostic Risk Adenocarcinoma of the Prostate (NCI-H97-0006)

- Phase III Randomized Study of High- versus Standard-Dose Three-Dimensional Conformal

Radiotherapy in Patients with Stage I or II Adenocarcinoma of the Prostate (RTOG-P-0126)

X Additional clinical trials addressing this priority included

- Phase I Study of High-Intensity Focused Ultrasound Using the Sonablate System in Patients with

Locally Recurrent Prostate Cancer (NCI-V01-1683)

- Phase II Neoadjuvant Study of Androgen Suppression and Transperineal Ultrasound-Guided

Brachytherapy after External Beam Radiotherapy in Patients with Locally Recurrent Prostate

Adenocarcinoma (NCCTG-N0052)

- Phase II Pilot Study of Magnetic Resonance-Guided High-Dose Rate Brachytherapy before and after

External Beam Radiotherapy in Patients with Prostate Cancer (NCI-02-C-0207)

- Phase II Study of Patient Positioning Using Multiple CT Scans in Patients with Prostate Cancer

Undergoing External Beam Radiotherapy (NCI-G01-1968)

- Phase I Study of Photodynamic Therapy with Lutetium Texaphyrin in Patients with Locally Recurrent

Prostate Adenocarcinoma (NCI-T99-0042)

- Phase II Study of Topical Amifostine for Rectal Protection during Radiotherapy in Patients with

Prostate Cancer (NCI-02-C-0215)

NCI Efforts:

X In FY 2002, active areas of investigation included iron-containing tracers coupled with magnetic separation

technology, microarray analyses to define stage-specific molecular profiles, high-resolution magnetic

resonance imaging (MRI), flow cytometry detection of circulating metastatic cells, and reverse transcriptase

polymerase chain reaction (RT-PCR)-based detection of prostate specific-antigen (PSA)-positive cells in

blood.

X Thirteen projects address the PRG recommendation that assays be developed for detecting circulating

cells and that the effects of investigational treatments on circulating cell levels be determined.

X NCI initiatives addressing this priority included Applications of Innovative Technologies for the Molecular

Analysis of Cancer and the Cancer Imaging Program (CIP).

PRG Priority: What new technologies can

detect clinically significant metastases

prior to treatment? What is the clinical

significance of circulating prostate cells

detected by molecular techniques and

their relationship to treatment failure and

metastases? 0

10

20

25

1998 1999 2000 2001

NCISupported

Projects

per

Year

2002

15

5

Table 7-1. NCI Efforts Responsive to PRG Priorities

in Staging and Treatment of Localized Prostate Cancera

PRG Priority: What technologies (e.g.,

new, irradiation therapy, and localization

techniques) can be developed to decrease morbidity and enhance efficacy of

therapy for the primary tumor?

0

20

40

60

100

1998 1999 2000 2001

NCISupported

Projects

per

Year

2002

80

a A given project may map to more than one PRG Priority One question and therefore be represented in more than one figure. Projects active

in 2002 are listed by Principal Investigator’s name for each PRG Priority One question in Appendix B (Tables B-32–B-35).
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Chapter 7 Prostate Cancer Treatment

NCI Efforts:

X In FY 2002, active areas of investigation included molecular modeling to engineer immunotoxins,

dendritic cells as immunotherapeutics, collagen delivery systems to optimize gene transfer, and

optimization of viral vectors for gene therapy.

X Clinical trials addressing this priority included the following:

- Phase I/II Study of Leuvectin in Patients with Locally Recurrent Organ-Confined Prostate Cancer after

Radiotherapy (NCI-G00-1721)

- Phase I Study of Recombinant Vaccinia Virus Expressing the PSA Antigen for Advanced

Adenocarcinoma of the Prostate Progressing after Hormonal Therapy (NCI-94-C-0118C)

- Phase I Study of Recombinant Vaccinia Virus That Expresses Prostate Specific Antigen in Metastatic

Adenocarcinoma of the Prostate (NCI-T95-0086H)

X Other NCI initiatives addressing this priority included Prostate SPORE, Clinical Cancer Therapy

Research, Rapid Access to Intervention Development (RAID) Program, and Therapeutic Modulation of

Angiogenesis in Disease.

NCI Efforts:

X In FY 2002, active areas of investigation included artificial neural networks and Bayesian analyses for

outcome prediction, antibody microarray expression analysis, and protein glycosylation electrophoresis

to detect metastasis.

X Three projects addressed the PRG recommendation to explore MRI spectroscopy; one project addressed

the PRG recommendation to identify markers that correlate with response to therapy.

X NCI initiatives addressing this priority included Prostate Specialized Programs of Research Excellence

(SPOREs) and Exploratory Grants for Correlative Laboratory Studies and Clinical Trials.

- Phase I Study of Oral Capecitabine as a Radiation Enhancer in Patients with Unresectable, Residual,

or Locally Recurrent Cancer Localized in the Pelvis (NCCTG-984652)

X NCI initiatives addressing this priority included CIP, Development and Applications of Imaging in

Therapeutic Studies, Diagnostic Imaging and Guided Therapy in Prostate Cancer, and Exploratory Grants

for Correlative Laboratory Studies and Clinical Trials.

X New Directions in Brachytherapy was a one and one-half day workshop held in March 2001 to assess the

current state of the science in brachytherapy.

X Between 1998 and 2002, NCI co-hosted three National Forums on Biomedical Imaging in Oncology

designed to facilitate the development of enhanced imaging devices to address the needs of clinicians

and research scientists.

Table 7-1. (cont.)

PRG Priority: What critical features of the

primary tumor determine treatment

success? What clinical, pathological, and

molecular determinants can be used as

markers of aggressiveness and “indolent” prostate cancer? How can multiple

test results be combined using

informatics?

0

10

20

30

1998 1999 2000 2001

NCISupported

Projects

per

Year

2002

15

5

25

PRG Priority: Which gene therapies,

including immunotherapeutic approaches, appear most suitable for

localized and systemic prostate cancer

treatment?b

0

10

20

30

50

1998 1999 2000 2001

NCISupported

Projects

per

Year

2002

40

Additional staging and treatment of localized prostate cancer projects that did not address the PRG priority

questions in this table. None.

b See p. 7-5 for related priority “What is the role of gene and cellular therapy for prostate cancer?”
7-5

Chapter 7 Prostate Cancer Treatment

NATIONAL CANCER INSTITUTE

NCI Efforts:

X In FY 2002, active areas of investigation included dendritic cell vaccines, immunotoxin design, and new

vectors for efficient and targeted gene delivery.

X Clinical trials addressing this priority included the following:

- Phase II Pilot Randomized Study of Fowlpox-Prostate-Specific Antigen Vaccine with or without

Docetaxel in Patients with Metastatic Androgen-Independent Prostate Cancer (NCI-02-C-0218)

- Phase I Study of Activated Autologous T Cells (Xcellerate) in Patients with Hormone-Refractory

Prostate Cancer (NCI-G02-2075)

- Phase II Study of Immunization with Prostate-Specific Membrane Antigen-Pulsed Autologous

Peripheral Blood Mononuclear Cells and Interleukin-12 in Patients with Metastatic HormoneRefractory Prostate Cancer (NCI-1192)

- Phase I Study of Autologous Dendritic Cells Transfected with Autologous Total Tumor RNA in Patients

with Metastatic Prostate Cancer (DUMC-000759-00-4R1)

- Phase I Study of Recombinant Prostate-Specific Membrane Antigen (rPSMA)-Pulsed Autologous

Dendritic Cells (CaPVax) in Patients with Metastatic Hormone-Refractory Prostate Cancer (NCI-G00-

1802)

NCI Efforts:

X In FY 2002, active areas of investigation included androgen receptor mutations associated with

resistance to hormonal therapy, genes associated with resistance to chemotherapy, and mechanisms of

action and resistance of nucleoside analog drugs.

X Clinical trials addressing this priority include these examples designed to (a) optimize radiotherapy,

(b) optimize neoadjuvant or adjuvant hormonal therapy, (c) investigate novel chemotherapeutics in

resistant models, and (d) reduce metastases by concurrent hormone and chemotherapies:

- Phase I Study of Oral Capecitabine as a Radiation Enhancer in Patients with Unresectable, Residual,

or Locally Recurrent Cancer Localized in the Pelvis (NCCTG-984652)

- Phase I Study of High-Intensity Focused Ultrasound Using the Sonablate System in Patients with

Locally Recurrent Prostate Cancer (NCI-V01-1683)

- Phase III Randomized Study of Neoadjuvant Total Androgen Suppression and Radiotherapy in

Patients with Intermediate-Risk Adenocarcinoma of the Prostate (RTOG-9910)

- Phase II Study of BMS-247550 in Patients with Hormone-Refractory Prostate Cancer (SWOG-S0111)

- Phase III Randomized Study of Adjuvant Androgen Deprivation Therapy with or without Mitoxantrone

and Prednisone after Radical Prostatectomy in Patients with High-Risk Adenocarcinoma of the

Prostate (SWOG S9921)

X NCI initiatives addressing this priority included Cooperative Human Tissue Network (CHTN), Cooperative

Prostate Cancer Tissue Resource, and Prostate SPOREs.

Table 7-2. NCI Efforts Responsive to PRG Priorities in Systemic Therapya

PRG Priority: What are the mechanisms

associated with resistance to hormone

therapy, immunotherapy, radiation, and

chemotherapy?

0

5

10

15

20

1998 1999 2000 2001

NCISupported

Projects

per

Year

2002

PRG Priority: What is the role of gene

and cellular therapy for prostate cancer?b

0

10

20

30

60

1998 1999 2000 2001

NCISupported

Projects

per

Year

2002

40

50

a A given project may map to more than one PRG Priority One question and therefore be represented in more than one figure. Projects active

in 2002 are listed by Principal Investigator’s name for each PRG Priority One question in Appendix B (Tables B-36–B-43). b See p. 7-4 for related priority “Which gene therapies, including immunotherapeutic approaches, appear most suitable for localized and systemic

prostate cancer treatment?”
NATIONAL CANCER INSTITUTE

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Chapter 7 Prostate Cancer Treatment

NCI Efforts:

X In FY 2002, active areas of investigation included anti-cancer agents that target various biological

mechanisms such as angiogenesis, DNA repair, cell-cycle checkpoints, apoptosis, DNA methylation, and

cancer cell adhesion; bioinformatics models for rational drug design and evaluation; radioisotopes for

therapy and detection; activation mechanisms for prodrugs and probes; high-throughput screens to

identify new lead interventions; and immunologic and vaccine development.

PRG Priority: How can new targets be

identified and what is the role of novel

therapeutic agents directed at these

targets?

0

40

60

80

120

1998 1999 2000 2001

NCISupported

Projects

per

Year

2002

100

20

NCI Efforts:

X In FY 2002, active areas of investigation included surrogate endpoint validation, PSA endpoint correlation

to quality of life and time to progression, and RT-PCR-based detection of PSA-positive cells in blood.

X The PRG recommended that the NCI encourage novel trial designs. Intermittent androgen therapy, which

may delay the onset of androgen independence and prolong survival (Oliver et al., 2000), is forming the

basis of a novel clinical trial design whereby investigational agents are evaluated in a placebo-controlled

fashion for their effects on progression-free survival during hormonal rest periods.

X The PRG recommended that clinical trials be used to determine whether PSA levels correlate with

survival outcomes. The NCI’s current strategy is to incorporate PSA-based intermediate endpoints into

large, randomized trials in such a way that they can be reported early to support clinical decision making

and planning of subsequent studies. Because the trials are large, the eventual outcome data can be

used to validate conclusions based on the intermediate PSA endpoint.

X The NCI is participating in a working group with the Food and Drug Administration (FDA), American

Association for Cancer Research (AACR), and American Society of Clinical Oncology (ASCO) to review

and identify appropriate endpoints for clinical trials conducted in prostate cancer patients.

Recommendations that address surrogate markers, definitions of clinical benefit, and time-to-event

endpoints are expected to be raised at open public FDA Advisory Committee Meetings.

- Phase I Study of Recombinant Vaccinia Virus Expressing the PSA Antigen for Advanced

Adenocarcinoma of the Prostate Progressing after Hormonal Therapy (NCI-94-C-0118C)

- Phase I Study of Recombinant Vaccinia Virus That Expresses Prostate Specific Antigen in Metastatic

Adenocarcinoma of the Prostate (NCI-T95-0086H)

- Phase I/II Study of Active Immunotherapy with Prostate Specific Antigen RNA Pulsed Autologous

Dendritic Cells in Patients with Metastatic Prostate Cancer (NCI-G99-1655)

- Phase I Study of Autologous Dendritic Cells Transfected with Autologous Total Tumor RNA in Patients

with Metastatic Prostate Cancer (NCI-G00-1910)

X NCI initiatives addressing this priority included Prostate SPOREs, Quick-Trials for Prostate Cancer

Therapy, National Cooperative Drug Discovery Groups (NCDDGs), and RAID Program.

Table 7-2. (cont.)

PRG Priority: What are the relevant

endpoints for clinical trials of systemic

therapies (e.g., PSA levels, time to

progression, quality of life, and survival)?

How can endpoints be validated? What is

the impact of treatment on survival?

0

5

10

15

20

1998 1999 2000 2001

NCISupported

Projects

per

Year

2002
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Chapter 7 Prostate Cancer Treatment

NATIONAL CANCER INSTITUTE

NCI Efforts:

X In FY 2002, active areas of investigation included angiogenesis inhibitors, arsenic compounds, IGF

signaling pathway factors that potentiate androgen-independent growth, screening isolates from

traditional Chinese herbal medicines, and surrogate markers to measure disease progression.

X Among the 75 active NCI-sponsored prostate cancer treatment trials in early 2003, 19 were being

conducted in patients with hormone-refractory disease. Included among these were

- Phase II Randomized Study of BMS-275291 [an angiogenesis inhibitor] in Patients with HormoneRefractory Prostate Cancer (NCI-5615)

- Phase II Study of Arsenic Trioxide in Patients with Metastatic Hormone-Refractory Prostate Cancer

(NCI-T99-0077)

- Phase II Study of Monoclonal Antibody ABX-EGF in Patients with Hormone-Resistant Prostate Cancer

with Elevated PSA Levels without Metastasis (UCLA-0206074)

PRG Priority: What is the optimal treatment for androgen-independent disease?

0

10

20

30

1998 1999 2000 2001

NCISupported

Projects

per

Year

2002

15

5

25

X During the years 1998-2002, NCI’s Cancer Therapy Evaluation Program (CTEP) initiated 33 Phase II

trials to explore the activity of new agents directed at targets that included all the following:

- Growth signaling pathways (vascular endothelial growth factor [VEGF] and other angiogenesis targets

and farnesyl transferase)

- Differentiation (retinoids)

- Arachidonic acid-associated pro-apoptosis signaling (selective cyclooxygenase-2 inhibitors)

- Steroid sex hormone signaling (Her-2/neu).

Additional Phase II trials were conducted by the Prostate SPOREs and intramural NCI programs.

X In direct response to the PRG priority, CTEP established a policy that, barring a mechanistic

contraindication, all novel therapeutics under development or co-development by the NCI would be tested

for activity in prostate cancer.

X The PRG recommended that NCI convene a consensus conference every 3 years, with industry

participation, to discuss the newest molecular targets and drug development in prostate cancer. In

November 1999, the NCI sponsored the state-of-the-science workshop Prostate Cancer: Molecular

Targets. In December 2002, the NCI co-sponsored the Society for Urologic Oncology’s SUO2/NCI

Urologic Oncology Meeting: Extraordinary Opportunities for Discovery.

X NCI initiatives addressing this priority included Quick-Trials for Prostate Cancer Therapy, Prostate

SPOREs, CIP, Cancer Molecular Analysis Project (CMAP), Cancer Therapy-Related Use of Genetically

Engineered Mice, Cooperative Human Tissue Network (CHTN), Cooperative Prostate Cancer Tissue

Resource, Drug Discovery for Cancer Flexible System to Advance Innovative Research for Cancer Drug

Discovery by Small Businesses (FLAIR), Interdisciplinary Research Teams for Molecular Target

Assessment, National Cooperative Drug Discovery Groups (NCDDGs), Molecular Target Drug Discovery

for Cancer, National Cooperative Drug Discovery Groups (NCDDGs), RAID Program, and Therapeutic

Modulation of Angiogenesis in Disease.

Table 7-2. (cont.)
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Chapter 7 Prostate Cancer Treatment

NCI Efforts:

X In FY 2002, active areas of investigation included microvessel density determinations as a prognostic

marker, synergism of anti-angiogenic plus cytostatic agents in advanced prostate cancer, targeted

delivery of genes to angiogenic vasculature, tissue factor-mediated angiogenesis, angiogenesis

inhibitors and differentiation agents, and compounds that inhibit VEGF production by human cancer cells.

X Clinical trials are being conducted in patients across all stages of prostate cancer. Various trials include

proof-of-principle studies administering agents in the neo-adjuvant, Phase I or Phase II setting with

correlative science components for future trial designs and populations. In addition, clinical trials of

activity are being conducted in men who have a rising PSA and in men with either hormone-sensitive or -

insensitive metastatic disease. Examples of clinical trials addressing this priority included the following:

- Phase I Study of SU5416 [an angiogenesis inhibitor] with Standard Androgen Ablation and

Radiotherapy in Patients with Intermediate or Advanced-Stage Prostate Cancer (NCI-4390)

- Phase II Study of Trastuzumab (Herceptin) in Patients with Progressive Androgen Dependent and

Independent Prostate Cancer (NCI-G99-1493)

- Phase II Study of R115777 in Patients with Progressive, Metastatic, Hormone Refractory Prostate

Cancer (FCCC-99031)

- Phase II Randomized Study of Radiotherapy with or without Vaccine Containing Recombinant

Vaccinia Prostate Specific Antigen (PSA) and rV-B7.1 Plus Recombinant Fowlpox PSA Vaccine in

Patients with Localized Prostate Cancer (NCI-00-C-0154)

- Phase II Study of Paclitaxel and Bryostatin 1 in Patients with Hormone-Refractory, Metastatic

Adenocarcinoma of the Prostate (MSGCC-9948)

- Phase II Study of Green Tea Extract in Patients with Androgen-Independent Metastatic Prostate

Cancer (NCCTG-N9951)

- Phase II Study of APC8015 (Provenge) and Bevacizumab in Patients with Progressive Prostate

Cancer (UCSF-0155-01)

NCI Efforts:

X In FY 2002, active areas of investigation included PSA-screening effectiveness in reducing prostate

cancer mortality.

X Ongoing clinical trials addressing all stages of prostate cancer include these trials examining

asymptomatic recurrence measured by a rising PSA (i.e., biochemical recurrence):

- Phase III Randomized Study of Zoledronate and Standard Therapy vs. Placebo and Standard

Therapy in Patients with Asymptomatic Recurrent Prostate Cancer Who Have Castrate Levels of

Testosterone and Rising PSA Levels (NCI-G00-1722)

- Phase III Randomized Study of Second-Line Hormonal Therapy (Ketoconazole and Hydrocortisone)

versus Combination Chemotherapy (Docetaxel and Estramustine) in Asymptomatic Patients with

Prostate Cancer and a Rising PSA after Androgen Suppression (E-1899)

Table 7-2. (cont.)

PRG Priority: At what point in the progression of prostate cancer should novel

therapeutic agents be initiated (e.g., antiangiogenic and anti-metastatic agents)?

0

5

10

15

20

1998 1999 2000 2001

NCISupported

Projects

per

Year

2002

PRG Priority: When should a patient with

a rising PSA be treated?

0

2

4

6

10

1998 1999 2000 2001

NCISupported

Projects

per

Year

2002

8
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Chapter 7 Prostate Cancer Treatment

NATIONAL CANCER INSTITUTE

NCI Efforts:

X In FY 2002, active areas of investigation included pharmacology models to improve dose schedules in

Phase II and Phase III trials and structure-based therapeutic discovery.

X The NCI participated in the panel of experts that developed consensus criteria for use of PSA to monitor

patients following radiation therapy (American Society for Therapeutic Radiation and Oncology [ASTRO])

and convened a panel of experts to determine eligibility and response in pilot or Phase II trials of new

agents in androgen independent prostate cancer (Bubley et al., 1999). These standards have been

generally adopted in both drug and radiation trials expanding the number of patients considered eligible

and, therefore, the capacity of the clinical trial infrastructure to accommodate new agents.

Table 7-2. (cont.)

Additional treatment projects that did not

address the PRG priority questions in this

table.

0

2

4

6

10

1998 1999 2000 2001

NCISupported

Projects

per

Year

2002

8

Clinical trials comprised a considerable portion of the NCI’s responsiveness to PRG priorities and

recommended actions. Over the years 1998–2002, the NCI sponsored3 104 new early-phase4 trials and

18 new Phase III trials in prostate cancer patients. Included among the 83 active treatment trials in 2002

were 67 early-phase trials examining the safety and/or effectiveness of new therapies.

The initiatives that impacted research on prostate cancer treatment between FY 1998 and FY 2002

include the following list of general initiatives that are described in Table 2-15

 (Chapter 2) and the category-specific initiatives that are listed and described in Table 7-3:6

X Applications of Innovative Technologies for the Molecular Analysis of Cancer

X Cancer Centers Program

X Cancer Imaging Program (CIP)

X Cancer Molecular Analysis Project (CMAP)

X Cancer Prognosis and Prediction

X Cancer Research Training, Career Development, and Education Opportunities

X Cancer Therapy-Related Use of Genetically Engineered Mice

X Clinical Trials Cooperative Group Program

X Common Data Elements (CDE) Initiative

X Community Clinical Oncology Program (CCOP)

3 An NCI-sponsored clinical trial in the Physician Data Query (PDQ) database meets one or more of the following criteria: the protocol

(1) has been reviewed and approved by NCI’s CTEP Protocol Review Committee or by an approved NCI-designated Cancer Center

Protocol Review and Monitoring System and/or (2) receives support through an NCI Grant or cooperative agreement. Information on

ongoing treatment trials for the different stages of prostate cancer can be obtained via the NCI’s Search for Clinical Trials webpage. To

limit one’s search to only those trials that are sponsored by the NCI, it is necessary to use the advanced search function.

4 Early-phase trials include those that are in Phase I, II, or I/II.

5 Initiatives that impact multiple categories of prostate cancer research.

6 Initiatives that are unique to the treatment research category.
NATIONAL CANCER INSTITUTE

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Chapter 7 Prostate Cancer Treatment

INITIATIVES FOCUSED ON PROSTATE CANCER

Quick-Trials for Prostate Cancer Therapy (PA-00-047)

Objective: Established in 1999 as a rapid grant review process to facilitate pilot studies of innovative,

mechanism-based therapeutics not yet tested in humans. First made available for prostate cancer trials

and subsequently open to other cancers, this is a pilot program to provide investigators with rapid access to

support for pilot, Phase I, and Phase II cancer clinical trials along with patient monitoring and laboratory

studies to ensure the timely development of new therapeutic approaches. In 2002, the program was

expanded into Quick-Trials for Novel Cancer Therapies, which pertains to all cancer sites.

Relevant Research Projects Resulting from This Program Announcement (PA):

X Ad-OC-TK/Val Gene Therapy Clinical Correlates

X Arsenic Trioxide in Advanced Prostate Cancer

X Biologic Effects of 17AA Geldanamycin

X Calcitriol in Recurrent Prostate Cancer

X Combinatorial Approaches for Novel Anticancer Agents

X Dendritic Cell Vaccine in Metastatic Prostate Cancer

X A Feasibility Study of L-Selenomethionine and Alpha-Tocopherol

X Molecular Correlates of Soy in Humans

X Cooperative Human Tissue Network (CHTN)

X Cooperative Prostate Cancer Tissue Resource (CPCTR)

X Diagnostic Imaging and Guided Therapy in Prostate Cancer

X Exploratory Grants for Correlative Laboratory Studies and Clinical Trials

X Flexible System to Advance Innovative Research for Cancer Drug Discovery by Small Businesses (FLAIR)

X Improving DNA, RNA, and Protein Availability in Fixed Tissue

X Interdisciplinary Research Teams for Molecular Target Assessment

X In Vivo Cellular and Molecular Imaging Centers (ICMICs)

X Minority Institution/Cancer Center Partnership (MI/CCP) Program

X Minority-Based Community Clinical Oncology Program (MBCCOP)

X Molecular Profiling Initiative (MPI)

X Molecular Target Drug Discovery for Cancer

X NCI Center for Bioinformatics (NCICB)

X Program for the Assessment of Clinical Cancer Tests (PACCT)

X Prostate Cancer Intervention Versus Observation Trial (PIVOT)

X Prostate, Lung, Colorectal & Ovarian Cancer Screening Trial (PLCO)

X Prostate Specialized Programs of Research Excellence (SPOREs)

X Shared Resources for Scientists outside NCI Cancer Centers

X Small Animal Imaging Resource Program (SAIRP)

X Special Populations Networks (SPNs)

X Specimen Resource Locator

Table 7-3. NCI Initiatives Relevant to Prostate Cancer Research: Treatment
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Chapter 7 Prostate Cancer Treatment

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Table 7-3. (cont.)

X Phase I Study of Combined Viral and Suicide Gene Therapies

X Phase I Trial of PDT in Patients with Prostate Carcinoma

X Phase II Trial of Tetrathiomolybdate in Prostate Cancer

X A Pilot Phase IB Trial of a PSA Peptide Vaccine

X Radionuclide Therapy of Skeletal Metastases from Cancer

INITIATIVES WITH PROSTATE CANCER-RELEVANT COMPONENTS

Cancer Drug Discovery: Diversity Generation and Smart Assays (RFA-CA-98-009)

Objective: Innovative approaches to the generation of structural diversity, such as (a) combinatorial synthesis, parallel synthesis, or genetic manipulation of biosynthetic pathways in producer organisms and (b)

Smart assay development for cancer drug discovery.

Relevant Research Project Resulting from This Request for Applications (RFA): Combinatorial Creation of

New Anticancer Agents

Cancer Trials Support Unit (CTSU) (http://www.ctsu.org)

Objective: A national network of physicians to participate in NCI-sponsored Phase III treatment trials that

include randomized trials for all clinical states as well as protocols offering a variety of treatment modalities.

Relevant Program Resulting from This Initiative: A pilot program initiated in 2000, prostate cancer trials

were the first for which this mechanism was activated. In early 2003, there were eight CTSU-listed trials for

prostate cancer:

X Phase III Randomized Study of Second-Line Hormonal Therapy (Ketoconazole and Hydrocortisone)

versus Combination Chemotherapy (Docetaxel and Estramustine) in Asymptomatic Patients with Prostate

Cancer and a Rising PSA after Androgen Suppression (E-1899)

X Phase III Randomized Trial Comparing Intermittent versus Continuous Androgen Suppression for

Patients with Prostate-Specific-Antigen Progression in the Clinical Absence of Distant Metastases

Following Radiotherapy for Prostate Cancer (CAN-NCIC-PR7)

X Prospective Randomized Phase III Trial Comparing Consolidation Therapy with or without Strontium-89

Following Induction Chemotherapy in Androgen-Independent Prostate Cancer (NCI-3410)

X Phase III Protocol of Androgen Suppression (AS) and Radiation Therapy (RT) vs. AS and RT Followed by

Chemotherapy with Paclitaxel, Estramustine, and Etoposide (TEE) for Localized, High-Risk Prostate

Cancer (RTOG-99-02)

X Phase III Trial to Evaluate the Duration of Neoadjuvant Total Androgen Suppression (TAS) and Radiation

Therapy (RT) in Intermediate-Risk Prostate Cancer (RTOG-99-10)

X Phase III Randomized Study of Adjuvant Therapy for High Risk pT2-3N0 Prostate Cancer (CAN-NCICPR9)

X Phase III Randomized Study of Patients with High Risk, Hormone-Naive Prostate Cancer: Androgen

Blockade with 4 Cycles of Immediate Chemotherapy versus Androgen Blockade with Delayed

Chemotherapy (RTOG-P-0014)

X Adjuvant Androgen Deprivation versus Mitoxantrone Plus Prednisone Plus Androgen Deprivation in

Selected High Risk Prostate Cancer Patients Following Radical Prostatectomy: Phase III (S9921)

Clinical Cancer Therapy Research (PA-02-002)

Objective: Translate insights in cancer biology and the development of new agents into innovative cancer

therapeutic studies.

Relevant Research Project Resulting from This PA: Telomerase RNA Transfected Dendritic Cell Vaccines

Development and Applications of Imaging in Therapeutic Studies (RFA-CA-98-024)

Objective: Apply imaging technologies in the assessment of investigational cancer therapeutic agents.

Relevant Research Project Resulting from This RFA: TNT Imaging to Monitor the Efficacy of Cancer

Therapy
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Chapter 7 Prostate Cancer Treatment

Table 7-3. (cont.)

Ongoing NCI Research: Recent Progress in Prostate

Cancer Treatment

Progress in Preclinical Models

Recent advances in the development of complementary transgenic and xenograft mouse models

displaying aspects of prostate cancer disease progression, including bone metastasis, have led to changes

in the way promising therapeutic agents are tested. (See Chapter 6 for more details.) Agents recently

studied in transgenic mouse models include the vitamin D analog EB 1089 (Perez-Stable et al., 2002) and

the nonsteroidal anti-inflammatory drug E-7869 (R-flurbiprofen) (Wechter et al., 2000). NCI-funded

researchers are also using transgenic models to assess the effectiveness of novel agents for the treatment

of prostate cancer. In recent years, immunodeficient mice xenografted with prostate cancer cell lines

have been used for testing all types of agents, including stimulators of apoptosis, angiogenesis inhibitors,

gene therapies, and prodrugs.

Expanded Participation Project (EPP) (http://spitfire.emmes.com/study/epp)

Objective: Demonstration project for providing broader access to Cooperative Group Phase III trials for

prostate and three other cancer types.

Relevant Program Resulting from This Initiative: Twenty-eight participating institutions were recruited to

pilot centralized access to clinical trials, which included two prostate cancer trials. After the goals of the EPP

were reached, most of these institutions elected to continue with centralized access by joining the CTSU.

National Cooperative Drug Discovery Groups (NCDDGs) (http://dtp.nci.nih.gov/branches/gcob/

gcob_web3.html)

Objective: Discovery of new and more effective anticancer treatments.

Relevant Research Project Resulting from This Initiative: A Vaccine for Prostate Cancer (Provenge)

Rapid Access to Intervention Development (RAID) Program (http://dtp.nci.nih.gov/docs/raid/

raid_index.html)

Objective: Assist translation to the clinic of novel anticancer therapies deriving from academia.

Relevant Research Projects Resulting from This Initiative:

X Enzymatic Activation of a Thapsigargin Prodrug by Prostate-Specific Antigen (PSA) as Treatment for

Metastatic Prostate Cancer

X A Novel Gene Therapy Approach for the Treatment of Prostate Cancer: A Preclinical to Clinical Transition

X A Prolactin Growth Antagonist as a Potential Therapeutic for Androgen-Independent Prostate Cancer

X Tumor-Specific Targeting of WT p53 by Anti-Transferrin Receptor Single-Chain Antibody: New Therapeutic

Strategy for Prostate Cancer Treatment

Therapeutic Modulation of Angiogenesis in Disease (PAR-98-096)

Objective: Translate basic knowledge of the angiogenic process into therapeutic applications.

Relevant Research Projects Resulting from This PA:

X Novel Angiogenesis Inhibitor from Cartilage

X Targeted Delivery of Genes to Angiogenic Vasculature

Translational Research Initiative (http://ctep.cancer.gov/resources/trf-overview.html)

Objective: Conduct correlative studies with material from or examinations of patients participating in NCIsponsored early-phase clinical trials with CTEP Investigational New Drug (IND) agents.

Relevant Clinical Trial Supported by This Initiative: Phase II Study of Zoledronate and BMS-275291 in

Patients with Hormone-Refractory Prostate Cancer (NCI-5361)
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Chapter 7 Prostate Cancer Treatment

NATIONAL CANCER INSTITUTE

Early-Stage Disease

The incidence of prostate cancer in the United States increased noticeably following the introduction

of the PSA screening assay. (See Chapter 1, Figure 1-1.) Cause-specific mortality initially increased as

well, peaking in 1992; however, the rate has since fallen to levels observed in the early 1970s. (See

Chapter 1, Figure 1-2.) The following explanations have been proposed to address this decline in mortality:

(1) Diagnosis occurs at an earlier stage of cancer due to PSA screening (see Chapter 5 for progress

related to early detection and diagnosis) and/or (2) the impact of treatment on localized disease has

changed with the greatly enhanced use of hormonal therapy. Several recent developments provide support

for the hypothesis that treatment has a major impact on survival:

X Results of an NCI-sponsored trial support the hypothesis that early initiation of hormonal therapy

can prolong survival in men at high risk for recurrence (Messing et al., 1999). Patients who were

found to have microscopic metastases in their lymph nodes at the time of prostatectomy were

assigned to either receive immediate hormonal therapy or to undergo observation until the time of

disease progression. Prostate cancer-related mortality and disease recurrence were significantly

lower in men receiving the hormonal therapy than in the observational group after a median of 7.1

years following treatment. This finding has led to a change in the standard of care for nodepositive prostate cancer patients.

X Follow-up data from multiple randomized trials conducted by the RTOG have matured (Horwitz et

al., 2001 and Pilepich et al., 2001) and together with results from the EORTC (Bolla et al., 1997

and 2002) provide strong evidence that the addition of androgen-deprivation therapy to external

beam radiotherapy can improve cause-specific and overall survival in subsets of patients with

poorly differentiated or locally advanced disease.

X The Prostate Cancer Intervention Versus Observation Trial (PIVOT) was conducted in the United

States in 44 VA Medical Centers and 8 NCI sites, completing accrual in 2002. Data are not yet

mature, but the results from PIVOT are expected to clarify whether surgery can improve outcomes in individuals diagnosed in the early stages of disease due to PSA screening.

Since prostate cancer is a heterogeneous disease, an important area of research is the development

and validation of prognostic nomograms, not only to provide information for an individual patient but also to

facilitate data interpretation and the appropriate design of subsequent trials. Recent relevant publications

address the utility of considering the percentage of positive prostate biopsies (D’Amico et al., 2000), the

prognostic significance of Gleason score (Chan et al., 2000), the importance of pretreatment blood

biomarker levels as determined by RT-PCR (Shariat et al., 2002), the development of a continuous probability model (Kattan et al., 1998), and nomograms following surgery or radiotherapy (D’Amico et al.,

1999).

Biochemical Recurrence

The practice of monitoring PSA levels after treatment of patients with curative intent has created a

new asymptomatic patient population whose only evidence of disease is a rising PSA. Since these patients

have minimal disease, are asymptomatic, and may live a long time after a rising PSA, clinical trial methodology specific to this population needs to be considered. In 2001 and 2002, NCI (CTEP) joined investigators from Memorial Sloan-Kettering Cancer Center and Prostate Cancer Foundation to organize and

participate in a working group to address drug development paradigms, clinical trial methodology, and

reporting standards for this population. Proceedings are to be published in the Journal of Clinical

Oncology.
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Chapter 7 Prostate Cancer Treatment

A variety of Phase II and Phase III NCI-sponsored protocols are open to this population, including

the following:

X Phase III Randomized Crossover Study of Oral Thalidomide versus Placebo in Patients with

Androgen Dependent Prostate Cancer Following Limited Hormonal Ablation (T99-0053)

X Phase III Randomized Study of Intermittent versus Continuous Androgen Suppression in

Patients with PSA Progression after Prior Radiotherapy (SWOG JPR7)

X Phase III Randomized Study of Second-Line Hormonal Therapy (Ketoconazole and Hydrocortisone) versus Docetaxel/Estramustine in Asymptomatic Patients and a Rising PSA after

Androgen Suppression (ECOG 1899)

X Phase II trials of anti-angiogenesis agents, immunotherapy, an alkylphospholipid, and differentiating

agents

In general, large randomized trials in the adjuvant setting or in patients with biochemical recurrence

(i.e., those trials in which the endpoint of survival will require long-term follow-up) are prospectively

designed for analysis and reporting of biochemical outcomes prior to their survival data. This approach is

intended to expedite clinical research, as well as to eventually provide information on the correlation of

PSA levels with outcome.

Advanced Disease

The identification of active treatments for androgen-independent disease is a major challenge, in part

due to the prior lack of standardization of PSA response definitions (Dawson, 1998). In 1999, NCI convened

a PSA working group composed of expert clinical investigators in an effort to standardize eligibility and

response criteria for Phase II clinical trials in androgen-independent disease. The resulting consensus

guidelines have become the standard for the conduct of clinical trials in this patient population (Bubley et al.,

1999). A majority of Phase II treatment trials sponsored by the NCI now utilize PSA-based endpoints when

evaluating and prioritizing new therapies for use in larger-scale and/or definitive clinical tests.

A hallmark of prostate cancer is its propensity to metastasize to bone, with evidence of bone metastases at autopsy in up to 85 percent of men with prostate cancer (Galasko, 1981). Research into the

biology of bone metastases and tumor cell–stromal interactions is being conducted in multiple disciplines

using in vitro and in vivo model systems (Chapters 3 and 6). To facilitate crossdisciplinary communication

and translation to the clinic, NCI sponsored a workshop entitled “Mechanisms of Tumor Metastasis to the

Bone: Challenges and Opportunities” in November 2000 and co-sponsored the Third International Conference on Cancer-Induced Bone Diseases with the Paget Foundation in 2001.

NCI-supported clinical researchers are exploring a variety of approaches for targeting bone metastases, and are studying the use of bisphosphonates, matrix metalloproteinase inhibitors, integrin antagonists, growth factor receptor inhibitors and antiangiogenesis agents alone and in combination for treatment

of metastases.

X Zoledronic acid (Zometa®), which targets cancers that metastasize to bone by inhibiting osteoclast

function and skeletal calcium release, was the first bisphosphonate to be approved by the FDA for

use in prostate cancer. A new national trial sponsored by NCI will evaluate men with hormonesensitive prostate cancer metastatic to bone to determine whether early use of zoledronic acid

(i.e., before androgen independence) can delay the progression of bone disease as well as skeletal

complications and androgen-associated osteoporosis.

X NCI-supported investigators also tested whether the use of radioisotopes in addition to standard

treatment could improve the outcome of bone-targeted therapy in patients with clinically symptomatic bone metastases (Tu et al., 2001). Patients responding to chemotherapy were selected at

random to receive either additional chemotherapy alone or in combination with radiostrontium (Sr89). Sr-89 is a radioactive calcium analogue that is targeted to the site of osteoblastic metastases.
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Chapter 7 Prostate Cancer Treatment

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Although the study was small, the median survival of patients who received Sr-89 was approximately 65 percent longer than that of patients who received chemotherapy alone. These results

suggest that targeting the growth of bone metastases and/or altering their capacity to develop

resistance to chemotherapy could prolong survival in addition to providing symptomatic relief. This

finding is currently being followed up in a larger, national, randomized Phase III study (Phase III

Randomized Study of Consolidation Therapy with or without Strontium Chloride Sr-89 after

Induction Chemotherapy in Patients with Androgen-Independent Prostate Cancer - NCI3410) to definitively determine whether the approach works and, if so, whether markers can be

identified that predict development and progression of bone metastases.

After many years in which the value of chemotherapy in prostate cancer treatment was questionable, the FDA approved the use of the combination regimen mitoxantrone and prednisone for the palliation

of symptomatic bone metastases in 1996. Subsequently, microtubulin inhibitors such as estramustine and

the taxane drugs, particularly when used in combination, were found to produce significant responses as

measured by both the soft-tissue disease and surrogate endpoint of reduced PSA levels (Hudes et al.,

1995; Pienta and Smith,1997; Petrylak et al., 1999). Various chemotherapy-based approaches are now

being tested in large, randomized trials that include patients in each of the clinical states, such as those with

localized disease at high risk for recurrence following prostatectomy or radiotherapy, those with biochemical recurrence, and patients with metastatic disease. Some examples are as follows:

X Phase III Protocol of Androgen Suppression (AS) and Radiation Therapy (RT) versus AS

and RT Followed by Chemotherapy with Paclitaxel, Estramustine, and Etoposide (TEE) in

Localized, High-Risk Prostate Cancer (RTOG-9902)

X Phase III Randomized Study of Adjuvant Androgen Deprivation Therapy with or without

Mitoxantrone and Prednisone after Radical Prostatectomy in Patients with High-Risk

Adenocarcinoma of the Prostate (SWOG S9921)

X Phase III Randomized Study of Second-line Hormonal Therapy (Ketoconazole and Hydrocortisone) versus Docetaxel/Estramustine in Asymptomatic Patients and a Rising PSA after

Androgen Suppression (ECOG 1899)

X Phase III Randomized Study of Docetaxel and

Estramustine versus Mitoxantrone and Prednisone

in Patients with Hormone-Refractory, Metastatic

Adenocarcinoma of the Prostate (SWOG 9916)

Continuing Needs and Evolution

Although genuine options are available for curing prostate

cancer when it is localized, tools to more accurately assess both

risk for recurrence and response to treatment in an individual

patient are needed. As the genetic machinery that governs the

behavior of prostate cancer cells evolves, novel agents can be

rationally designed to target critical pathways in each clinical state. To ensure that novel therapeutics can be

adequately explored, there remains a need for translational research and early-phase clinical trials. Larger

scale, randomized trials will be needed to validate biomarkers and surrogate endpoints, as well as to confirm

and extend promising findings. Adequate infrastructure is needed to allow for the acquisition, storage, and

use of clinically annotated tissue banks in all stages of trials in order to support translational research. Although in its infancy, functional imaging holds promise for oncology clinical trials in areas such as diagnosis,

initial staging, risk classification, and detection of biochemical recurrence, as well as for the prediction of

response to therapy based on function before structural changes are detectable and even in sites traditionally

difficult to assess (e.g., bone).

The National Cancer

Institute’s goal for prostate

cancer treatment over the

next five years is to

“accelerate development

and validation of optimal

treatments that target the

molecular and cellular

characteristics of prostate

cancer.”

– National Institutes of Health,

Prostate Cancer Research Plan for

FY 2003–2008.
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Chapter 7 Prostate Cancer Treatment

NCI’s Future Investment in Prostate Cancer Treatment

The NIH Prostate Cancer Research Plan for FY 2003–2008 describes the NCI’s planned objectives

for research on treatment of prostate cancer. The plans are based on the priorities that were identified by

the PRG and the advances that have taken place since completion of the PRG’s work. The four FY

2003–2008 objectives and their alignment to the 12 PRG priorities are summarized in Figure 7-2.

These objectives encompass all 12 PRG treatment priorities, with one objective consolidating the

issues addressed by seven of the PRG priorities and another objective addressing a PRG priority in the

area of resources needed. Over the next few years, the NCI will continue to invest in research and

support new initiatives that address the objectives listed in Figure 7-2. Emphasis will be placed on

research addressing reliable means to predict the behavior of individual cancers and optimal treatments for

all stages of prostate cancer.

NCI-Supported Research Referenced in Chapter 7

Bolla M, Collette L, Blank L, Warde P, Dubois JB, Mirimanoff RO, Storme G, Bernier J, Kuten A, Sternberg C,

Mattelaer J, Lopez Torecilla J, Pfeffer JR, Lino Cutajar C, Zurlo A, Pierart M. Long-term results with immediate

androgen suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study):

A phase III randomised trial. Lancet. 2002 Jul 13;360(9327):103-6.

Bolla M, Gonzalez D, Warde P, Dubois JB, Mirimanoff RO, Storme G, Bernier J, Kuten A, Sternberg C, Gil T, Collette L,

Pierart M. Improved survival in patients with locally advanced prostate cancer treated with radiotherapy and

goserelin. N Engl J Med. 1997 Jul 31;337(5):295–300.

Bubley GJ, Corducci M, Dahuw W, et al. Eligibility and response guidelines for phase II clinical trials in androgenindependent prostate cancer: Recommendations from the prostate-specific antigen working group. J Clin Oncol.

1999 17:3461–67.

Chan TY, Partin AW, Walsh PC, Epstein JI. Prognostic significance of Gleason score 3+4 versus Gleason score 4+3

tumor at radical prostatectomy. Urology. 2000 Nov 1;56(5):823–7.

D’Amico AV, Whittington R, Malkowicz SB, Fondurulia J, Chen MH, Kaplan I, Beard CJ, Tomaszewski JE,

Renshaw AA, Wein A, Coleman CN. Pretreatment nomogram for prostate-specific antigen recurrence after radical

prostatectomy or external-beam radiation therapy for clinically localized prostate cancer. J Clin Oncol. 1999

Jan;17(1):168–72.

D’Amico AV, Whittington R, Malkowicz SB, Schultz D, Fondurulia J, Chen MH, Tomaszewski JE, Renshaw AA,

Wein A, Richie JP. Clinical utility of the percentage of positive prostate biopsies in defining biochemical outcome after

radical prostatectomy for patients with clinically localized prostate cancer. J Clin Oncol. 2000 Mar;18(6):1164–72.

Dawson NA. Apples and oranges: Building a consensus for standardized eligibility criteria and end points in prostate

cancer clinical trials. J Clin Oncol. 1998 Oct;16(10):3398–405.

Galasko CSB. The anatomy and pathways of skeletal metastases. In: Weiss L, Gilbert HA, eds. Bone metastases.

Vol. 6. Boston: GK Hall, 1981:49–63.

Horwitz EM, Winter K, Hanks GE, Lawton CA, Russell AH, Machtay M. Subset analysis of RTOG 85-31 and 86-10

indicates an advantage for long-term vs. short-term adjuvant hormones for patients with locally advanced nonmetastatic

prostate cancer treated with radiation therapy. Int J Radiat Oncol Biol Phys. 2001 Mar 15;49(4):947–56.

Hudes GR, Obasaju C, Chapman A, Gallo J, McAleer C, Greenberg R. Phase 1 study of paclitaxel and estramustine:

Preliminary activity in hormone-refractory prostate cancer. Semin Oncol. 1995 Jun;22(3 Suppl 6):6–11.

Kattan MW, Eastham JA, Stapleton AM, Wheeler TM, Scardino PT. A preoperative nomogram for disease recurrence

following radical prostatectomy for prostate cancer. J Natl Cancer Inst. 1998 May 20;90(10):766–71.

Messing EM, Manola J, Sarosdy M, Wilding G, Crawford ED, Trump D. Immediate hormonal therapy compared with

observation after radical prostatectomy and pelvic lymphadenectomy in men with node-positive prostate cancer. N

Engl J Med. 1999 Dec 9;341(24):1781–8.
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Chapter 7 Prostate Cancer Treatment

NATIONAL CANCER INSTITUTE

Figure 7-2. NIH’s FY 2003–2008 prostate cancer treatment

research objectives build upon the 1998 PRG priorities.

PRG Priorities

What new technologies can detect clinically

significant metastases prior to treatment? 

What is the clinical significance of circulating

prostate cells detected by molecular techniques and their relationship to treatment 

failure and metastases?

Identify and validate new targets, novel

therapeutic agents, and optimal intervention

approaches by disease stage in a clinical

setting.

Identify promising tools for enhancing and 

evaluating the effectiveness of new therapies.

Identify and validate intermediate endpoints

for clinical trials of local and systemic 

therapies.

Strengthen clinical trial infrastructure including

design and patient recruitment to increase the

number of rigorous clinical trials that are

pivotal to developing and testing novel 

therapeutics.

What technologies (e.g., new, irradiation 

therapy and localization techniques) can be

developed to decrease morbidity and enhance

efficacy of therapy for the primary tumor?

What critical features of the primary tumor

determine treatment success? What clinical,

pathological, and molecular determinants can

be used as markers of aggressiveness and 

"indolent" prostate cancer? How can multiple

test results be combined using informatics?

Which gene therapies, including immunotherapeutic approaches, appear most suitable

for localized and systemic prostate cancer

treatment?

FY 2003–2008 Objectives

What are the mechanisms associated with

resistance to hormone therapy, immunotherapy, radiation, and chemotherapy?

What is the role of gene and cellular therapy

for prostate cancer?

What are the relevant endpoints for clinical

trials of systemic therapies (e.g., PSA levels, 

time to progression, quality of life, and 

survival)? How can endpoints be validated?

What is the impact of treatment on survival?

How can new targets be identified and what is

the role of novel therapeutic agents directed at

these targets?

What is the optimal treatment for androgenindependent disease?

At what point in the progression of prostate

cancer should novel therapeutic agents be

initiated (e.g., anti-angiogenic and antimetastatic agents)?

When should a patient with a rising PSA be

treated?

Resources Needed: Clinical Trials (See Figure

2-1, Chapter 2.)
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Chapter 7 Prostate Cancer Treatment

Oliver RT, Farrugia D, Ansell W, Williams G, Chinegwundoh F. Potential of intermittent hormone therapy for M+ and

M0 prostate cancer patients. Prostate Cancer Prostatic Dis. 2000 Dec;3(4):286–9.

Perez-Stable CM, Schwartz GG, Farinas A, Finegold M, Binderup L, Howard GA, Roos BA. The G gamma / T-15

transgenic mouse model of androgen-independent prostate cancer: Target cells of carcinogenesis and the effect of

the vitamin D analogue EB 1089. Cancer Epidemiol Biomarkers Prev. 2002 Jun;11(6):555–63.

Petrylak DP, MaCarthur RB, O’Connor J, Shelton G, Judge T, Balog J, Pfaff C, Bagiella E, Heitjan D, Fine R,

Zuech N, Sawczuk I, Benson M, Olsson CA. Phase I trial of docetaxel with estramustine in androgen-independent

prostate cancer. J Clin Oncol. 1999 Mar; 17(3):958–67.

Pienta KJ, Smith DC. Paclitaxel, estramustine, and etoposide in the treatment of hormone-refractory prostate cancer.

Semin Oncol. 1997 Oct;24(5 Suppl 15):S15-72–77.

Pilepich MV, Winter K, John MJ, Mesic JB, Sause W, Rubin P, Lawton C, Machtay M, Grignon D. Phase III radiation

therapy oncology group (RTOG) trial 86-10 of androgen deprivation adjuvant to definitive radiotherapy in locally

advanced carcinoma of the prostate. Int J Radiat Oncol Biol Phys. 2001 Aug 1;50(5):1243–52.

Shariat SF, Gottenger E, Nguyen C, Song W, Kattan MW, Andenoro J, Wheeler TM, Spencer DM, Slawin KM.

Preoperative blood reverse transcriptase-PCR assays for prostate-specific antigen and human glandular kallikrein for

prediction of prostate cancer progression after radical prostatectomy. Cancer Res. 2002 Oct 15;62(20):5974–9.

Tu SM, Millikan RE, Mengistu B, Delpassand ES, Amato RJ, Pagliaro LC, Daliani D, Papandreou CN, Smith TL, Kim J,

Podoloff DA, Logothetis CJ. Bone-targeted therapy for advanced androgen-independent carcinoma of the prostate: A

randomised Phase II trial. Lancet. 2001 Feb 3;357(9253):336–41.

Wechter WJ, Leipold DD, Murray ED Jr, Quiggle D, McCracken JD, Barrios RS, Greenberg NM. E-7869 (Rflurbiprofen) inhibits progression of prostate cancer in the TRAMP mouse. Cancer Res. 2000;60(8)2203–8.
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Chapter 8 Prostate Cancer Control, Survivorship, and Outcomes

NATIONAL CANCER INSTITUTE

CHAPTER

8

Prostate Cancer Control,

Survivorship, and Outcomes: NCI’s

Investment and Recent Progress

Although curing

prostate cancer is one

criterion of successful

cancer therapy,

understanding the

long-term impact on

quality of life will

ultimately determine

the effectiveness of

new and existing

treatments.

– Defeating Prostate

Cancer: Crucial Directions

for Research - Report of the

Prostate Cancer Progress

Review Group, August

1998.

Most men diagnosed with prostate cancer die with the disease

rather than from the disease. As shown in Figure 8-1, after adjusting

for other causes of death, over 80 percent of men who were diagnosed

with prostate cancer in 19901

 were still alive in 2000.

1 The most recent year for which SEER 10-year survival data are available.

2 Definition derived from the NCI Division of Extramural Activities (DEA) Cancer Control Review Group.

3 Definition derived from the NCI Division of Cancer Control and Population Sciences (DCCPS).

4 Definition derived from the NCI DEA Cancer Control Review Group.

In order to improve the lives of men who are at risk or who have already been diagnosed with

prostate cancer, the NCI supports the following relatively new areas of research:

X Cancer Control Research: Basic and applied research in the behavioral, social, and population

sciences to create or enhance interventions that, independently or in combination with biomedical

approaches, reduce cancer risk, incidence, morbidity, and mortality.2

X Survivorship Research: Research that encompasses the

physical, psychosocial, and economic sequelae of cancer diagnosis and its treatment among survivors of cancer.3

X Outcomes Research: Research that describes, interprets, and

predicts the impact of various influences, especially (but not

exclusively) interventions on endpoints that matter to decision

makers: patients, providers, private payers, government agencies,

accrediting organizations, or society at large.4

0

20

40

60

100

80

012 3 4 5 6 7 8 9 10

Years after Diagnosis

Percent of

Men Living

Figure 8-1. Survival of U.S. men who were diagnosed

with prostate cancer in 1990.

Rates have been adjusted to exclude causes of death other than prostate cancer.

This figure uses data derived from Table XXII-5 in SEER Cancer Statistics Review, 1975-2001,

SEER Program, National Cancer Institute.
NATIONAL CANCER INSTITUTE

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Chapter 8 Prostate Cancer Control, Survivorship, and Outcomes

In their 1998 report, the Prostate Cancer PRG described promising directions and unmet

needs in the area of outcomes research. The report indicated that methodologies have recently

become available to quantitatively evaluate both clinical outcomes, such as overall and disease-free

survival, and patient-focused outcomes, such as quality of life, treatment-related morbidity, economic

outcomes, and access to care, in a systematic way. Although assessments of patient-focused outcomes

had already been incorporated into most large clinical trials, the absence of standardized methodology

hindered comparison of results between trials. Furthermore, few NCI-sponsored projects had been

focused on long-term morbidity, late complications, or supportive care—issues that had increased in

importance following the dissemination of screening and treatment approaches that were believed to, but

had not yet been proven to, extend the lives of men with prostate cancer.

The Prostate Cancer PRG identified three Priority One questions affecting the area of cancer

control, survivorship, and outcomes. The questions and their accompanying recommendations addressed

the need for refining, standardizing, and applying the new methodologies and for determining

the impact of prostate cancer screening and treatment on the population as a whole, and on racial/ethnic

minorities and medically underserved populations.

The NCI has responded to the three PRG Priority One questions and recommendations.

In fiscal years (FYs) 1998 through 2002, NCI increased its dollar investment in cancer control, survivorship, and outcomes research more than threefold. Recent results from NCI-sponsored research have

reshaped our knowledge of the long-term effects of prostate cancer therapy and PSA screening.

NCI’s Investment and Response

From FY 1998 to FY 2002, NCI’s extramural investment in cancer control, survivorship, and outcomes research grew from $6.5 million (M) to $20.3M (Figure 8-2). Much of this investment was made

in the form of increases in the number of projects that respond to PRG Priority One questions. Table 8-1

summarizes NCI’s response to the three Prostate Cancer PRG Priority One research questions in this

area.

0

5

10

15

20

25

1998 1999 2000 2001 2002

Fiscal Year

Millions of Dollars

Figure 8-2. NCI’s extramural investment in cancer control, survivorship,

and outcomes research: 1998–2002 (in millions of dollars).
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Chapter 8 Prostate Cancer Control, Survivorship, and Outcomes

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NCI Efforts:

X In FY 2002, active areas of investigation included prospective clinical trials, retrospective analysis,

modeling and characteristics of health insurance, and managed care plans that influence the practice of

cancer screening.

X The ongoing Prostate, Lung, Colorectal & Ovarian Cancer Screening Trial (PLCO) is determining whether

PSA screening reduces mortality from prostate cancer.

X Other NCI initiatives addressing this priority included the Cancer Intervention and Surveillance Modeling

Network (CISNET) and the Cancer Surveillance Using Health Claims-Based Data System.

PRG Priority: What is the impact

of early detection and screening

on outcomes?b

NCI Efforts:

X In FY 2002, active areas of investigation included development, validation, and introduction of quality-oflife survey instruments and effectiveness, costs, and cost effectiveness of screening and treatment.

X The NCI Cancer Outcomes Measurement Working Group (COMWG) was established in 2001 to assess

and improve measurement of key patient outcomes in prostate and three other cancer sites. This

working group addresses the PRG recommendations to identify key patient-focused variables and to

encourage common mechanisms for reporting patient outcomes.

NCI Efforts:

X In FY 2002, active areas of investigation included quality-of-life determinations in prostate cancer patients

and long-term survivors, with emphasis on elderly men and African American men; underlying causes for

the observed racial/ethnic disparities in prostate cancer incidence and mortality; and new tools for

disseminating information on treatments and their outcomes to patients and family members.

X NCI initiatives addressing this priority included the Prostate Cancer Intervention Versus Observation Trial

(PIVOT) and the Prostate Cancer Outcomes Study (PCOS).

PRG Priority: What is the impact on outcomes of treatment, community settings

versus clinical trials/centers of excellence,

and provider characteristics (e.g., volume

and expertise)? How do benefits differ

among patient subsets (e.g., age and race)?

How do patients value tradeoffs between

length of survival and quality of life?

PRG Priority: How are different types

of outcomes defined and standardized (e.g., quality of life, morbidity, and

patient satisfaction)?

0

10

20

25

1998 1999 2000 2001

NCISupported

Projects

per

Year

2002

15

5

0

2

4

6

10

1998 1999 2000 2001

NCISupported

Projects

per

Year

2002

8

0

2

4

6

10

1998 1999 2000 2001

NCISupported

Projects

per

Year

2002

8

Table 8-1. NCI Efforts Responsive to PRG Priorities in

Prostate Cancer Control, Survivorship, and Outcomesa

a A given project may map to more than one PRG Priority One question and therefore be represented in more than one figure. Projects active in

2002 are listed by Principal Investigator’s name for each PRG Priority One question in Appendix B (Tables B-44–B-47).

b See p. 5-4 for related priorities “Does early detection change mortality from prostate cancer?” and “What are the effects of early detection on

morbidity and quality of life?”
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Chapter 8 Prostate Cancer Control, Survivorship, and Outcomes

NCI Efforts:

X In FY 2002, active areas of investigation included characteristics of successful social support systems for

men, influence of market forces on cancer care, cancer information and education programs tailored to

specific communities, and clinical trials of behavioral and pharmacological interventions to counteract

fatigue, improve quality of life, and improve physical health in patients.

Additional cancer control,

surveillance, and outcomes projects

Table 8-1. (cont.)

0

10

20

30

1998 1999 2000 2001

NCISupported

Projects

per

Year

2002

15

5

25

Initiatives comprised a considerable portion of NCI’s response to the PRG’s priorities and recommended actions. The initiatives relevant to research on prostate cancer control, survivorship, and outcomes between FYs 1998 and 2002 include the following list of general initiatives that are described in

Table 2-15 (Chapter 2) and the category-specific initiatives that are listed and described in Table 8-2:6

X Cancer Research Training, Career Development, and Education Opportunities

Y Cancer Prevention, Control, Behavioral, and Population Sciences Career Development Award

Y Established Investigator Award in Cancer Prevention, Control, Behavioral, and Population

Research

X Clinical Trials Cooperative Group Program

X Community Clinical Oncology Program (CCOP)

X Minority Institution/Cancer Center Partnership (MI/CCP) Program

X Minority-Based Community Clinical Oncology Program (MBCCOP)

X Prostate Cancer Intervention Versus Observation Trial (PIVOT)

X Prostate, Lung, Colorectal & Ovarian Cancer Screening Trial (PLCO)

X Prostate Specialized Programs of Research Excellence (SPOREs)

X Special Populations Networks (SPNs)

5 Initiatives relevant to multiple categories of prostate cancer research.

6 Initiatives unique to the research category of cancer control, survivorship, and outcomes.
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Chapter 8 Prostate Cancer Control, Survivorship, and Outcomes

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Table 8-2. NCI Initiatives Relevant to Prostate Cancer Research:

Cancer Control, Survivorship, and Outcomes

INITIATIVES FOCUSED ON PROSTATE CANCER

Prostate Cancer Outcomes Study (PCOS) (http://healthservices.cancer.gov/pcos)

Objective: Determine the impact of primary prostate cancer treatments on quality of life.

Relevant Program Resulting from This Initiative: Program was begun in 1994. Six cancer registries that

are part of NCI’s Surveillance, Epidemiology, and End Results (SEER) program collect supplemental data

from patients diagnosed with prostate cancer to support study of the extent of treatment-induced urinary,

bowel, and sexual complications. PCOS data sets and data collection instruments are available to outside

investigators.

INITIATIVES WITH PROSTATE CANCER-RELEVANT COMPONENTS

Cancer Intervention and Surveillance Modeling Network (CISNET) (http://cisnet.cancer.gov/about)

Objective: Collaborative research using simulation and other modeling techniques to describe the impact

of prevention, screening, and/or treatment interventions in population-based settings.

Relevant Resource Resulting from This Initiative: Begun in 1999, CISNET was expanded in 2002 to

include its fourth cancer site and additional prostate cancer projects. To disseminate results and facilitate

comparisons of the models developed by different CISNET investigators, the web-based Model Profiler tool

was developed for capturing details that are generally not included in journal articles.

Relevant Research Projects Resulting from This Initiative:

X PSA Screening and U.S. Prostate Cancer Trends

X Survival Effects of Prostate Cancer Surveillance

Cancer Outcomes Measurement Working Group (COMWG) (http://outcomes.cancer.gov/methods/

measures/comwg)

Objective: Evaluate existing endpoint measures and instruments and formulate alternative strategies for

identifying valid, reliable, sensitive, and feasible clinical and patient-centered endpoint measures for use in

quality of cancer care studies.

Relevant Resource Resulting from This Initiative: Established in 2001, the COMWG focuses on prostate

and three other cancer types. The Working Group’s findings have been reported to the NCI and will be

published as the book Outcomes Assessment in Cancer.

Cancer Research Network (CRN) (http://cancercontrol.cancer.gov/bb/can_research.html)

Objective: Stimulate research on cancer prevention, early detection, long-term care, and post-diagnosis

monitoring.

Relevant Resource Resulting from This Initiative: Initiated in 1999, the CRN is comprised of 10 managed

care research organizations. The CRN is developing integrated data systems to support studies that will

include the use of hormonal therapies in prostate cancer patients.

Cancer Surveillance Using Health Claims-Based Data System (http://dccps.nci.nih.gov/ARP/

research/health.asp)

Objective: Investigate health claims information as a reporting source for assessing cancer burden.

Relevant Research Project Resulting from This Initiative: Managed Care Penetration and Cancer Care

Economic Studies in Cancer Prevention, Screening, and Care (http://cancercontrol.cancer.gov/

ARP/research/economic.asp)

Objective: Increase knowledge of the economic aspects of cancer prevention, screening, and care.

Relevant Research Project Resulting from This Initiative: Use of Cancer Screening in a Managed Care

Environment

Exploratory Grants for Behavioral Research in Cancer Control (PA-99-163)

Objective: Test novel or creative ideas to advance behavioral research in cancer prevention and control.

Relevant Research Project Resulting from This Initiative: A Multimedia Prostate Cancer Intelligent Expert System
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Chapter 8 Prostate Cancer Control, Survivorship, and Outcomes

Table 8-2. (cont.)

Minority and Underserved Cancer Survivors (http://dccps.nci.nih.gov/ocs/underserved)

Objective: Promote survivorship research among minority and underserved populations, and enhance

communication between these communities and cancer centers.

Relevant Research Project Resulting from This Initiative: Partner-Assisted Coping Skills Training for

Prostate Cancer Survivors

SEER–Medicare Linked Database (http://healthservices.cancer.gov/seermedicare)

Objective: Linkage of two large population-based data sources that provide detailed information about

elderly persons with cancer.

Relevant Resource Resulting from This Initiative: The current SEER–Medicare linkage, completed in

December 2001, includes all Medicare-eligible persons appearing in the SEER data through 1999 and their

Medicare claims through 2001. Because the database is large and complex, the initiative’s website includes a section on analytic support to assist researchers who use the database.

SEER Patterns of Care/Quality of Care (POC/QOC) Initiative (http://cancercontrol.cancer.gov/bb/

seer_pattern.html)

Objective: Evaluate the dissemination of state-of-the-art therapy into community practice, disseminate

research findings into scientific journals and professional meetings, and work with professional organizations to develop relevant educational or training opportunities.

Relevant Program Resulting from This Initiative: Program began in 1987. In 2001, a mechanism was

established whereby POC/QOC studies would be performed by the SEER registries every 3–5 years for the

major cancer sites (including prostate). Cancer sites with emerging new treatments or concerns regarding

provision of state-of-the-art therapy would be conducted in the alternate years.

Small Grants Program for Behavioral Research in Cancer Control (http://dccps.nci.nih.gov/

smallgrants/index.html)

Objective: Facilitate the growth of a nationwide cohort of scientists with expertise in behavioral research

addressing cancer prevention and control.

Relevant Research Projects Resulting from This Initiative:

X Disparities in Prostate Cancer Decision-Making and Quality of Life

X Dyadic Social Support for Men with Prostate Cancer

X Family Members and the Survivorship Phase of Cancer

X Prostate Cancer Survivor Narratives and Doctors’ Responses

X A Training Curriculum Guide for Prostate Cancer Control

Surveillance, Epidemiology, and End Results (SEER) (http://seer.cancer.gov/)

Objective: Collect, analyze, and publish information on cancer incidence and survival.

Relevant Resource Resulting from This Initiative: Begun in 1973, its most recent expansion was in 2001.

SEER currently collects and publishes data from 11 population-based cancer registries and three supplemental registries; approximately 26 percent of the U.S. population, including a substantial portion of racial/

ethnic minorities and other medically underserved populations, is covered. In 1999, SEER published the

monograph Prostate Cancer Trends, 1973–1995.
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Chapter 8 Prostate Cancer Control, Survivorship, and Outcomes

NATIONAL CANCER INSTITUTE

Ongoing NCI Research: Recent Progress in Prostate

Cancer Control, Survivorship, and Outcomes

Survivorship and Outcomes

The lingering uncertainty about the superiority of any single treatment modality for clinically localized

prostate cancer and the relatively long survivorship of men diagnosed with this disease have stimulated

progress in the area of cancer control, survivorship, and outcomes. Much of the literature on this topic in

the past 3 years has emphasized patient-focused outcomes such as quality of life and patient satisfaction,

rather than clinical outcomes such as recurrence and survival. The primary focus has been on the longterm complications of prostate cancer treatment, particularly urinary, sexual, and bowel dysfunction.

Although most studies have used patient surveys to examine these outcomes (Stanford et al., 2000; Bacon

et al., 2001; Hamilton et al., 2001; Potosky et al., 2001b; Bacon et al., 2002; Potosky et al., 2002; Penson

et al., 2003), claims data have also been used (Begg et al., 2002).

During the late 1980s and early 1990s, the complication rates for the most common initial prostate

cancer treatment modalities—watchful waiting, external beam radiation, and prostatectomy—were

derived mainly from studies involving small numbers of patients in large, academic medical centers. In

these studies, the complication rates were relatively low (e.g., 10–20 percent impotence rates following

radical prostatectomy). More recent results, from the large PCOS (Stanford et al., 2000; Potosky et al.,

2001b) and other studies (Bacon et al., 2001; Bacon et al., 2002) involving patients who better represent

general clinical practice, have shown complication rates that are much higher (e.g., impotence rates in

excess of 60 percent following radical prostatectomy). Starting in October 1999, analyses of PCOS data

were published on topics that included the following:

X Quality of life following androgen deprivation (AD) therapy or no therapy for localized prostate

cancer

X Urinary, bowel, and sexual function after prostatectomy or radiotherapy for localized prostate

cancer

X Factors associated with selection of various initial therapy approaches for localized prostate

cancer

X Factors associated with initial presentation of advanced prostate cancer in different minority

populations

X Impact of decrements in urinary and sexual function on quality of life

X Effects of treatments on patient satisfaction with care

Due to the rapid adoption of injectable AD during the past decade, a particularly important area of

progress has been determining the effects of AD therapy on sexual function and other quality-of-life

measures (Potosky et al., 2001b; Potosky et al., 2002). There has also been research examining the

complications associated with newer forms of radiotherapy, particularly conformal-beam radiotherapy

(Hanlon et al., 2001) and brachytherapy (Lee et al., 2000; Bacon et al., 2001; Eton et al., 2001; Hollenbeck

et al., 2002). A recent review article (Eton et al., 2001) has addressed the many factors that affect quality

of life in men with prostate cancer.
NATIONAL CANCER INSTITUTE

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Chapter 8 Prostate Cancer Control, Survivorship, and Outcomes

An important advance in the study of patient-focused outcomes has been the development of a new

questionnaire, the Expanded Prostate Cancer Index Composite (EPIC). This 50-item survey instrument,

which is an expansion of an older 20-item instrument, may be adopted as a standard approach for measuring urinary, sexual, bowel, and hormonal symptoms following prostate cancer therapy (Wei et al., 2000).

EPIC is currently being used in a number of multi-institutional trials funded by the NCI and other

organizations.

Statistical Trends and Surveillance of Practice Patterns

In addition to the emphasis on patient-focused outcomes, there has been effort devoted to assessment and analysis of the trends in prostate cancer incidence (Etzioni et al., 1999; Hankey et al., 1999;

Schwartz et al., 1999; Etzioni et al., 2002) and mortality (Feuer et al., 1999; Cronin and Feuer, 2000)

rates.7

 One current perspective is that PSA screening might be an important contributory factor to the

mortality decline that began in the mid-1990s. Pending results from ongoing screening trials, it is possible

to speculate that other potential reasons for the mortality decline include changes in treatment patterns

(such as increasing use of hormonal therapy) and cause of death misclassification. These issues were

addressed in a recent review (Potosky et al., 2001a), and in more detail in a three-part series of articles

analyzing SEER Program data published in the Journal of the National Cancer Institute (Etzioni et al.,

1999; Feuer et al., 1999; Hankey et al., 1999).

Another important area of focus has been racial disparities. Recent studies have explored differences among whites, African Americans, and other racial/ethnic groups in screening (Etzioni et al., 2002a),

stage at diagnosis (Hoffman et al., 2001), treatment (Harlan et al., 2001; Polednak, 2001; Zietman et al.,

2001; Shavers and Brown, 2002), treatment complications (Eton et

al., 2001), and survival (Polednak, 2001; Thompson et al., 2001;

Clegg et al., 2002; Lin et al., 2002). It is clear that African American men are diagnosed at more advanced stages of disease, have

poorer survival8

 and survival duration, and are sometimes treated

less aggressively than men who are white or of other racial/ethnic

groups. However, it is not clear why differences in treatment

translate to increased mortality, since randomized trials have not

established the superiority of any single treatment strategy. Several

investigators have explored the reasons underlying increased

prostate cancer incidence and mortality in African American men

(Montie and Pienta, 1999; Polednak, 2001).

Continuing Needs and Evolution

Prostate cancer mortality rates displayed a long-term gradual

increase up until the early 1990s that was followed by a decline (see

Chapter 1, Figure 1-2). There have also been dramatic improvements in the survival of men after diagnosis. There continues to be

scientific debate over whether the improvement in mortality and

survival is due primarily to changes in the nature of the prostate

cancers being detected (see Chapter 5, Figure 5-1 for prostate cancer incidence rates by grade during the

years 1975–2000) or to the increased use of interventions that are used to screen for and treat prostate

The National Cancer

Institute’s goal for

prostate cancer control,

survivorship, and

outcomes over the next

five years is to “achieve

a continuously improved

understanding of the

impact of prostate

cancer and its care on

individuals, families and

populations with special

emphasis on enhancing

survivorship, improving

quality of care, and

steadily reducing

disparities in both care

and outcomes.”

- National Institutes of Health,

Prostate Cancer Research Plan

for FY 2003–2008.

7 Overall and racial/ethnic group-specific rates for prostate cancer incidence and mortality can be viewed in Figure 1-1 and

Figure 1-2 of Chapter 1.

8 Ibid.
8-9

Chapter 8 Prostate Cancer Control, Survivorship, and Outcomes

NATIONAL CANCER INSTITUTE

cancer. It is still not known whether PSA screening, as currently practiced, is of ultimate benefit to the

many U.S. men who opt for the test.

Until definitive information is reported from randomized controlled trials of screening and treatment,

interpretations of the reasons for these population trends in mortality and survival will remain uncertain.

Additional results concerning these issues will come to light following the completion of data collection for

the NCI-sponsored PLCO trial in 2007 and the European Randomized Study of Screening for Prostate

Cancer (ERSPC), which will complete a third round of screening in 2007. With knowledge that PSA

screening leads to likely prostate cancer overdiagnosis (Etzioni et al., 2002b), there is a need to know to

what extent the overdiagnosed are being overtreated. As initial PIVOT findings and ultimately final results

are published, we will know more about the long-term (up to 15-year) clinical and patient-focused outcomes of expectant observation.9

Research on cancer control, survivorship, and outcomes is made more challenging by the long length

of time that is often required for data collection and the changes that are adopted in treatment, supportive

care, and cancer control practices during the course of data collection. With new knowledge that the longterm side effects of prostate cancer therapy are more prevalent than originally thought, many patients and

physicians want to know whether recently adopted practice changes and supportive care measures (e.g.,

nerve-sparing prostatectomy, increasing use of LHRH agonists for primary therapy for early-stage

disease, conformal-beam radiotherapy, brachytherapy, and Viagra®) are efficacious at preventing or

alleviating these effects.

NCI’s Future Investment in Prostate Cancer Control,

Survivorship, and Outcomes

The NIH Prostate Cancer Research Plan for FY 2003–2008 describes NCI’s planned objectives for

cancer control, survivorship, and outcomes research pertaining to prostate cancer. The objectives are

based on the priorities that were identified by the PRG and the advances that have taken place since

completion of the PRG’s work. The five FY 2003–2008 objectives and their alignment to the three

prostate cancer control, survivorship, and outcomes PRG priorities are summarized in Figure 8-3.

The objectives developed for the 2003–2008 plan emphasized the need for research on quality of life,

quality of care, and the impact of screening and treatment—areas that were emphasized by the Prostate

Cancer PRG in both outcomes and early detection, diagnosis, and prognosis. However, compared to the

PRG’s plan, the 2003–2008 plan placed greater emphasis on the dissemination of research findings

(addressed in a specific PRG recommendation but not a PRG research priority) and surveillance research

(not specifically addressed by the PRG).

Greater emphasis on dissemination of research findings is warranted because of the results that are

now emerging from outcomes analyses and the widespread adoption of new multimedia and interactive

technologies. Greater emphasis on surveillance research is needed because of the stabilization in prostate

cancer incidence and the decline in prostate cancer mortality that have taken place since 1995—the last

year for which retrospective SEER data were available to the Prostate Cancer PRG.

9 With expectant observation, interventions are reserved for symptomatic or confirmed metastatic disease.
NATIONAL CANCER INSTITUTE

8-10

Chapter 8 Prostate Cancer Control, Survivorship, and Outcomes

NCI-Supported Research Referenced in Chapter 8

Bacon CG, Giovannucci E, Testa M, Glass TA, Kawachi I. The association of treatment-related symptoms with qualityof-life outcomes for localized prostate carcinoma patients. Cancer. 2002 Feb 1;94(3):862–71.

Bacon CG, Giovannucci E, Testa M, Kawachi I. The impact of cancer treatment on quality of life outcomes for patients

with localized prostate cancer. J Urol. 2001 Nov;166(5):1804–10.

Begg CB, Riedel ER, Bach PB, Kattan MW, Schrag D, Warren JL, Scardino PT. Variations in morbidity after radical

prostatectomy. N Engl J Med. 2002 Apr 11;346(15):1138–44.

Clegg LX, Li FP, Hankey BF, Chu K, Edwards BK. Cancer survival among U.S. whites and minorities: a SEER (Surveillance, Epidemiology, and End Results) program population-based study. Arch Intern Med. 2002 Sep 23;162(17):1985–

93.

Cronin KA, Feuer EJ. Cumulative cause-specific mortality for cancer patients in the presence of other causes: A crude

analogue of relative survival. Stat Med. 2000 Jul 15;19(13):1729–40.

Eton DT, Lepore SJ, Helgeson VS. Early quality of life in patients with localized prostate carcinoma: An examination of

treatment-related, demographic, and psychosocial factors. Cancer. 2001 Sep 15;92(6):1451–9.

Etzioni R, Berry KM, Legler JM, Shaw P. Prostate-specific antigen testing in black and white men: An analysis of

Medicare claims from 1991-1998. Urology. 2002a Feb;59(2):251–5.

Figure 8-3. NIH’s FY 2003–2008 prostate cancer control, survivorship,

and outcomes research objectives build upon the 1998 PRG priorities.

PRG Priorities

What is the impact of treatment on 

outcomes? How do the benefits differ in

subsets of patients by age, morbidity,

race, etc.? What are the outcomes in the

community setting compared with those

from clinical trials or centers of excellence?

How do provider characteristics (e.g., volume

and expertise) affect outcomes? How do

patients value tradeoffs between length of

survival and quality of life?

Expand the channels for dissemination and

diffusion of cancer research findings.

Conduct biobehavioral research to understand how patient preferences and behaviors

affect treatment decisions and outcomes and

test interventions based on findings.

Evaluate the outcomes of screening and

treatment interventions, with special emphasis

on the impact of the quality of cancer care.

Assess quality of life for prostate cancer 

survivors and interventions to ameliorate

symptoms associated with treatment and

survival.

Conduct, apply, and disseminate surveillance

research to describe and understand trends

in the burden of prostate cancer, in screening,

and in medical practice.

How are different types of outcomes defined?

What are the standardized measures of 

outcomes (e.g., quality of life, morbidity, and

patient satisfaction)?

What is the impact of early detection and 

screening on outcomes?

Early Detection, Diagnosis, and Prognosis:

Does early detection change mortality from

prostate cancer? (See Figure 5-3, Chapter 5.)

Early Detection, Diagnosis, and Prognosis:

What are the effects of early detection on

morbidity and quality of life? (See Figure 5-3, 

Chapter 5.)

FY 2003–2008 Objectives
8-11

Chapter 8 Prostate Cancer Control, Survivorship, and Outcomes

NATIONAL CANCER INSTITUTE

Etzioni R, Legler JM, Feuer EJ, Merrill RM, Cronin KA, Hankey BF. Cancer surveillance series: Interpreting trends in

prostate cancer—part III: Quantifying the link between population prostate-specific antigen testing and recent

declines in prostate cancer mortality. J Natl Cancer Inst. 1999 Jun 16;91(12):1033–9.

Etzioni R, Penson DF, Legler JM, di Tommaso D, Boer R, Gann PH, Feuer EJ. Overdiagnosis due to prostate-specific

antigen screening: Lessons from U.S. prostate cancer incidence trends. J Natl Cancer Inst. 2002b Jul 3;94(13):981–90.

Feuer EJ, Merrill RM, Hankey BF. Cancer surveillance series: Interpreting trends in prostate cancer—part II: Cause of

death misclassification and the recent rise and fall in prostate cancer mortality. J Natl Cancer Inst. 1999 Jun

16;91(12):1025–32.

Hamilton AS, Stanford JL, Gilliland FD, Albertsen PC, Stephenson RA, Hoffman RM, Eley JW, Harlan LC,

Potosky AL. Health outcomes after external-beam radiation therapy for clinically localized prostate cancer: Results

from the Prostate Cancer Outcomes Study. J Clin Oncol. 2001 May 1;19(9):2517–26.

Hankey BF, Feuer EJ, Clegg LX, Hayes RB, Legler JM, Prorok PC, Ries LA, Merrill RM, Kaplan RS. Cancer surveillance series: Interpreting trends in prostate cancer—part I: Evidence of the effects of screening in recent prostate

cancer incidence, mortality, and survival rates. J Natl Cancer Inst. 1999 Jun 16;91(12):1017–24.

Hanlon AL, Watkins Bruner D, Peter R, Hanks GE. Quality of life study in prostate cancer patients treated with threedimensional conformal radiation therapy: Comparing late bowel and bladder quality of life symptoms to that of the

normal population. Int J Radiat Oncol Biol Phys. 2001 Jan 1;49(1):51–9.

Harlan LC, Potosky A, Gilliland FD, Hoffman R, Albertsen PC, Hamilton AS, Eley JW, Stanford JL, Stephenson RA.

Factors associated with initial therapy for clinically localized prostate cancer: Prostate cancer outcomes study. J Natl

Cancer Inst. 2001 Dec 19;93(24):1864–71.

Hoffman RM, Gilliland FD, Eley JW, Harlan LC, Stephenson RA, Stanford JL, Albertson PC, Hamilton AS,

Hunt WC, Potosky AL. Racial and ethnic differences in advanced-stage prostate cancer: The Prostate Cancer

Outcomes Study. J Natl Cancer Inst. 2001 Mar 7;93(5):388–95.

Hoffman RM, Hunt WC, Gilliland FD, Stephenson RA, Potosky AL. Patient satisfaction with treatment decisions for

clinically localized prostate cancer: Results from the Prostate Cancer Outcomes Study. Cancer. 2003;97:1653–62.

Hollenbeck BK, Dunn RL, Wei JT, McLaughlin PW, Han M, Sanda MG. Neoadjuvant hormonal therapy and older age

are associated with adverse sexual health-related quality-of-life outcome after prostate brachytherapy. Urology. 2002

Apr;59(4):480–4.

Lee WR, McQuellon RP, McCullough DL. A prospective analysis of patient-reported quality of life after prostate

brachytherapy. Semin Urol Oncol. 2000 May;18(2):147–51.

Lin SS, Clarke CA, Prehn AW, Glaser SL, West DW, O’Malley CD. Survival differences among Asian subpopulations

in the United States after prostate, colorectal, breast, and cervical carcinomas. Cancer. 2002 Feb 15;94(4):1175–82.

Montie JE, Pienta KJ. A unifying model to explain the increased incidence and higher mortality of prostate cancer in

black men. Urology. 1999 Jun;53(6):1073–6.

Penson DF, Feng Z, Kuniyuki A, McClerran D, Albertsen PC, Deapen D, Gilliland FD, Hoffman RM,

Stephenson RA, Potosky AL, Stanford JL. General quality of life 2 years following treatment for prostate cancer:

What influences outcomes? Results from the Prostate Cancer Outcomes Study. J Clin Oncol. 2003;21:1147–54.

Polednak AP. Association of African American ethnic background with survival in men with metastatic prostate

cancer. J Natl Cancer Inst. 2001 Aug 1;93(15):1174–5.

Potosky AL, Feuer EJ, Levin DL. Impact of screening on incidence and mortality of prostate cancer in the United

States. Epidemiol Rev. 2001a;23(1):181–6. Review.

Potosky AL, Knopf K, Clegg LX, Albertsen PC, Stanford JL, Hamilton AS, Gilliland FD, Eley JW, Stephenson RA,

Hoffman RM. Quality-of-life outcomes after primary androgen deprivation therapy: Results from the Prostate Cancer

Outcomes Study. J Clin Oncol. 2001b Sep 1;19(17):3750–7.

Potosky AL, Reeve BB, Clegg LX, Hoffman RM, Stephenson RA, Albertsen PC, Gilliland FD, Stanford JL. Quality of

life following localized prostate cancer treated initially with androgen deprivation therapy or no therapy. J Natl

Cancer Inst. 2002 Mar 20;94(6):430–7.

Schwartz KL, Grignon DJ, Sakr WA, Wood DP Jr. Prostate cancer histologic trends in the metropolitan Detroit area,

1982 to 1996. Urology. 1999 Apr;53(4):769–74.
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Chapter 8 Prostate Cancer Control, Survivorship, and Outcomes

Shavers VL, Brown ML. Racial and ethnic disparities in the receipt of cancer treatment. J Natl Cancer Inst. 2002 Mar

6;94(5):334–57.

Stanford JL, Feng Z, Hamilton AS, Gilliland FD, Stephenson RA, Eley JW, Albertsen PC, Harlan LC, Potosky AL.

Urinary and sexual function after radical prostatectomy for clinically localized prostate cancer: The Prostate Cancer

Outcomes Study. JAMA. 2000 Jan 19;283(3):354–60.

Thompson I, Tangen C, Tolcher A, Crawford E, Eisenberger M, Moinpour C. Association of African American ethnic

background with survival in men with metastatic prostate cancer. J Natl Cancer Inst. 2001 Feb 7;93(3):219–25.

Wei JT, Dunn RL, Litwin MS, Sandler HM, Sanda MG. Development and validation of the expanded prostate cancer

index composite (EPIC) for comprehensive assessment of health-related quality of life in men with prostate cancer.

Urology. 2000 Dec 20;56(6):899–905.

Zietman A, Moughan J, Owen J, Hanks G. The Patterns of Care Survey of radiation therapy in localized prostate

cancer: Similarities between the practice nationally and in minority-rich areas. Int J Radiat Oncol Biol Phys. 2001 May

1;50(1):75–80.
A-1

Chapter 8 Prostate Cancer Control, Survivorship, and Outcomes: NCI’s Investment and Recent Progress

NATIONAL CANCER INSTITUTE

APPENDIX

A

Prostate Cancer

Working Group

Membership Roster

James Corrigan Ph.D.

Office of Science Planning and Assessment

National Cancer Institute

William D. Figg, Sr., Pharm.D., M.B.A.

Center for Cancer Research

National Cancer Institute

Richard B. Hayes, Ph.D.

Division of Cancer Epidemiology

 and Genetics

National Cancer Institute

Andrew Hruszkewycz, M.D., Ph.D.

Organ Systems Branch

National Cancer Institute

James W. Jacobson, Ph.D.

Division of Cancer Treatment and Diagnosis

National Cancer Institute

Richard Kaplan, M.D.

Division of Cancer Treatment and Diagnosis

National Cancer Institute

Alison Martin, M.D.

Division of Cancer Treatment and Diagnosis

National Cancer Institute

Suresh Mohla, Ph.D.

Division of Cancer Biology

National Cancer Institute

Cherie Nichols, M.B.A.

Office of Science Planning and Assessment

National Cancer Institute

Howard Parnes, M.D.

Division of Cancer Prevention

National Cancer Institute

Arnold L. Potosky, Ph.D.

Division of Cancer Control and Population

 Sciences

National Cancer Institute

James V. Tricoli, Ph.D.

Division of Cancer Treatment and Diagnosis

National Cancer Institute

B-1

Appendix B NCI-Supported Research Projects Relevant to Prostate Cancer That Were Active in 2002

NATIONAL CANCER INSTITUTE

APPENDIX

B

NCI-Supported Research Projects

Relevant to Prostate Cancer That

Were Active in 2002

FY 2002 Biology Projects (Tables B-1–B-11) ....................................................................................... B-3

FY 2002 Etiology and Prevention Projects (Tables B-12–B-20) ...........................................................B-25

FY 2002 Early Detection, Diagnosis, and Prognosis Projects (Tables B-21–B-26) ..............................B-41

FY 2002 Scientific Model Systems Projects (Tables B-27–B-31).........................................................B-51

FY 2002 Treatment Projects (Tables B-32–B-43)................................................................................. B-57

FY 2002 Cancer Control, Survivorship, and Outcomes Projects (Tables B-44–B-47) ..........................B-77

These tables list all of the prostate cancer-relevant projects that were active in 2002. The projects

that are listed directly relate to the specific priority questions addressed in the body of this report and are

grouped according to their appearance in each chapter. Within each table, projects are sorted alphabetically according to the Principal Investigator’s name. Projects that were supported through a Request for

Applications (RFA) or a Program Announcement (PA) list an RFA or a PA number next to the project’s

title. Investigator-initiated projects do not list an RFA or a PA number. Project IDs (grant numbers) are

indicated in the last column.
NATIONAL CANCER INSTITUTE

B-2

Appendix B NCI-Supported Research Projects Relevant to Prostate Cancer That Were Active in 2002
B-3

Appendix B NCI-Supported Research Projects Relevant to Prostate Cancer That Were Active in 2002

NATIONAL CANCER INSTITUTE

Principal

Investigator Title RFA or PA Project ID

Bai, Wenlong AR-PTEN Antagonism in Prostate Cell Growth and Apoptosis CA93666

Balk, Steven The Androgen Receptor in Hormone Refractory Disease PAR-99-167 CA90381-Sub-05

Barrack, Evelyn R Project 3: Androgen Receptor Gene Structure and

Function in Human Prostate Cancer CA-94-031 CA58236-Sub-03

Chang,

Chawnshang AR-Associated Proteins in Prostate Carcinogenesis CA77532

Chang,

Chawnshang T- vs. DHT-Specific Antiandrogens in Prostate Cancer CA55639

Cohen, Pinchas Interactions between IGFBPs and Nuclear Receptors in

Prostate Cancer PAR-99-167 CA92131-Sub-03

Dalton, James Nonsteroidal Affinity Ligands for the Androgen Receptor CA68096

De Vere White,

Ralph hAR Alterations and Androgen Independent Prostate Cancer CA92069

Emmert-Buck,

Michael R Genetic Progression of Cancer SC10437

Everson, Richard Receptor Gene Polymorphisms in Prostate Cancer CA81240

Farrar, William L Molecular Mechanisms of Growth Factor Modulated Proliferation BC10253

Feldman, David Androgen-Independent Prostate Cancer: Mechanisms and Treatment PA-99-081 CA92238

Fletterick, Robert J Inhibition of Androgen Receptor Activation PAR-01-045 CA95324

Gao, Allen STAT3 in Androgen Receptor Signaling in Prostate Cancer CA90271

Gelmann, Edward Beta Catenin in Prostate Cancer PA-99-081 CA87855

Gelmann,

Edward P Beta Catenin in Prostate Cancer CA96854

Hager, Gordon L Function of Steroid Receptors in Subcellular Compartments BC10027

Hamburger, Anne EBP1 Control of Prostate Cancer Cell Growth PA-99-081 CA88882

Hayward, Simon Hormonal Carcinogenesis in Rb-Knockout Mouse Prostate CA96403

Imperato-McGinley,

Julianne Androgens Regulate IGF Pathway and Prostate Diseases PAR-98-023 CA85435

Johnson, Candace Glucocorticoids and Vitamin D: Role in Anti-Tumor Effects CA85142

Kakar, Sham Molecular Characterization of GnRH Receptors CA60871

Knudsen, Karen E Bis-Phenol A: Signaling and Mitogenesis in the Prostate CA93404

Lange, Paul H Mechanisms and Markers of Prostate Cancer Metastases CA85859

Liao, Shutsung Molecular Mechanisms of Growth Control—Prostate Cancer CA58073

FY 2002 Biology Projects

Table B-1

NCI Projects Supported in 2002 Addressing the PRG Priority:

What are the potential roles of nuclear receptors, their interactive proteins,

and ligand-metabolizing enzymes on prostate growth,

tissue interactions, and development?
NATIONAL CANCER INSTITUTE

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Appendix B NCI-Supported Research Projects Relevant to Prostate Cancer That Were Active in 2002

Principal

Investigator Title RFA or PA Project ID

Libermann, Towia Role of a New Ets Factor, PDEF, in Prostate Cancer PA-99-081 CA85467

Lu, Michael L Molecular Regulation of Androgen Receptor Activation PA-99-081 CA87997

Mohler, James Prostate Cancer: Transition to Androgen-Independence CA77739

Mueller, Elisabetta PPAR as a Target of Therapy for Prostate Cancer PAR-99-167 CA90381-Sub-02

Navone, Nora Growth Regulation of Prostatic Cells by Androgen CA75499

Penning, Trevor Human Aldo-Keto Reductases and Steroid Hormone Action CA90744

Pestell, Richard Cyclin D1 Function in Prostate Cancer PA-99-081 CA86072

Rosenfeld,

Michael G Repressors in Prostate Cancer PA-99-081 CA97134

Stearns, Mark IL-10 and IGF1 Receptor Axis in Prostate Cancer CA90397

Sun, Zijie Androgen Receptor Associated Proteins in Prostate Cancer CA70297

Sun, Zijie TGF-Beta/Smads and Androgen Signaling in Prostate Cancer PA-99-081 CA87767

Tsai, Ming-Jer Project 7: Endocrinology and the Role of Stroma Genes in

Prostate Cancer PAR-00-087 CA58204-Sub-07

Yamamoto, Keith Gene Regulation by Steroid Receptor Proteins CA20535

Yamamoto, Keith Project 1: Mechanisms of Hormone Resistance in Prostate Cancer PAR-99-167 CA89520-Sub-01

Young, Charles Y Growth Control of Prostate Cancer Cells by Plant Phenols PA-99-081 CA88900

Zhang, Xiao-Kun TR3/Nur77 in Survival and Death of Cancer Cells CA87000

Table B-1 (cont.)
B-5

Appendix B NCI-Supported Research Projects Relevant to Prostate Cancer That Were Active in 2002

NATIONAL CANCER INSTITUTE

Principal

Investigator Title RFA or PA Project ID

Abato, Paul Validation of Prostate Cancer Oncogenes CA96276

Aebersold, Ruedi Novel Quantitative, Comprehensive Proteomic Technology CA-01-011 CA93302

Agus, David The Role of the Her-Kinase Axis in Emergence of Androgen

Independence in Human Prostate Cancer PAR-99-167 CA92131-Sub-04

Arap, Wadih Project 4: Exploring the Molecular Diversity of Blood Vessels for

Diagnostic and Therapeutic Targeting in Prostate Cancer PAR-99-167 CA90270-Sub-04

Barrett, J Carl A Metastasis Suppressor Gene for Prostatic Cancer BC10431

Beitz, Alvin J In Vivo Analysis of Tumor Peptide Secretion PAR-01-106 CA86330

BeranovaGiorgianni, Sarka Cancer Relevant Proteins in the Human Prostate Proteome PAR-00-025 CA91254

Boss, Gerry R Analysis of Ras and Rho Activation in Prostate Cancer PA-00-080 CA90932

Bova, G Modes of Prostate Cancer Progression—Role of p53 Pathway PA-99-081 CA92234

Brothman, Arthur Molecular and Cytogenetic Analysis of Prostate Carcinoma CA46269

Cavalieri, Ercole Molecular Origin Cancer—Catechol Estrogen-3,4-Quinones CA49210

Chakrabarti, Ratna Molecular Markers for Prostate Cancer CA81329

Chang,

Chawnshang AR-Associated Proteins in Prostate Carcinogenesis CA77532

Chang, David D Expression and Function of Eplin CA90498

Cheng, Leo Characterization of Prostate Cancer with HRMAS 1HMRS PA-98-022 CA80901

Cher, Michael Prostate Cancer, Bone Metastasis, and Metalloproteinases PA-99-081 CA88028

Chinnadurai,

Govindaswamy Oncogenic and Chemoresistance by BCL-2 CA73803

Chinnaiyan, Arul M The Role of Polycomb Group Proteins in Prostate Cancer CA97063

Chung, Leland Extracellular Matrix Integrin Signaling in Prostate Cancer CA76620

Coffey, Donald Models of Prostate Cancer—Cell Structure and Dynamics CA15416

Coffey, Donald Project 4: Human Prostate Cancer Nuclei: Abnormalities in

Structure and the Development of New Molecular Markers CA-94-031 CA58236-Sub-04

Cohen, Michael B Trail Mediated Apoptosis in Prostate Cancer CA93870

Cohen, Pinchas Interactions between IGFBPs and Nuclear Receptors in

Prostate Cancer PAR-99-167 CA92131-Sub-03

Couch, Fergus p21 Induction by BRCA2 CA78878

Demarzo, Angelo Inflammation and Atrophy in Prostate Carcinogenesis PA-99-005 CA84997

Ellis, William Genomic and Gene Expression Profiling of Disseminated

Prostate Cancer PAR-00-087 CA97186-Sub-02

Emmert-Buck,

Michael R Genetic Progression of Cancer SC10437

Epner, Daniel GAPDH—Novel Regulator of Cell Structure and Migration CA78355

Table B-2

NCI Projects Supported in 2002 Addressing the PRG Priority:

What are the molecular determinants that govern cancer invasion,

migration, and metastasis?
NATIONAL CANCER INSTITUTE

B-6

Appendix B NCI-Supported Research Projects Relevant to Prostate Cancer That Were Active in 2002

Principal

Investigator Title RFA or PA Project ID

Falzon, Miriam PTH-Related Peptide and Vitamin D in Prostate Cancer Growth CA83940

Farrar, William L Molecular Mechanisms of Growth Factor Modulated Proliferation BC10253

Feldman, David Androgen-Independent Prostate Cancer: Mechanisms and Treatment PA-99-081 CA92238

Fidler, Isiah Project 1: The Biology of Human Prostate Cancer Metastasis PAR-99-167 CA90270-Sub-01

Figg, William D Development of Angiogenesis Inhibitors Using Prostate Cancer

as a Tumor Model SC06538

Fisher, Paul Novel Prostate Cancer Gene and Monoclonal Antibody CA74468

Freeman, Michael Prostate Cancer-Bone Interaction—Secretion of EGFR PA-97-019 CA77386

Gelman, Irwin H PKC/PKA Regulation in Prostate Cancer by SSeCKS/Gravin CA94108

Gelmann, Edward P Beta Catenin in Prostate Cancer CA96854

Gerald, William Molecular Classification of Prostate Cancer CA-98-027 CA84999

Giovannucci, Genetic and Serologic Determinants of Prostate Cancer Risk and

Edward Progression PAR-99-167 CA90381-Sub-01

Gleave, Martin Characterization of Anti-Apoptotic Genes Induced during Androgen

Independent Progression and Chemotherapy PAR-00-087 CA97186-Sub-03

Glinsky, Gennadi Transcriptome of Metastatic Prostate Cancer CA89827

Golub, Todd Genomic Expression Analysis of Tumors after Radical Prostatectomy PAR-99-167 CA90381-Sub-04

Green, Jeffrey E Transgenic Models for Prostate and Breast Cancer BC05740

Gupta, Smiti NF-kB: A Marker for Cellular Oxidative Stress CA91658

Hixson, Douglas Molecular Determinants of Multicellular Organization CA42714

Holt, Jeffrey Mechanisms of Carcinogenesis in BRCA2 Mutant Cells CA85269

Hood, Leroy Transcriptome and Proteome Stratification of Prostate

Adenocarcinoma Phenotypes PAR-00-087 CA97186-Sub-04

Hoosein, Naseema Neuroendocrine Factors in Prostate Cancer CA63225

Jenkins, Robert Biologic and Clinical Studies of Overrepresented 8q24 Region

Associated with Prostate Cancer Progression PAR-99-167 CA91956-Sub-03

Kelly, Kathleen ERK-Dependent Growth and Differentiation Pathways SC09358

Koff, Andrew p27Kip1 Expression, a Prognostic Indicator—But Why? CA89563

Kung, Hsing-Jien ErbB Kinase Activation and Transformation CA39207

Lange, Paul H Mechanisms and Markers of Prostate Cancer Metastases CA85859

Languino, Lucia Integrin Signaling Pathways in Prostate Cancer PA-99-081 CA89720

Lauffenburger,

Douglas Cell Motility in Prostate Tumor Invasion PAR-02-052 CA88865

Lee, Chung Project 1: Clusterin as a Negative Prognostic Indicator in Prostate

Cancer PAR-99-167 CA90386-Sub-01

Lin, Sue-Hwa Regulation of Angiogenesis by C-CAM1 CA86342

Table B-2 (cont.)
B-7

Appendix B NCI-Supported Research Projects Relevant to Prostate Cancer That Were Active in 2002

NATIONAL CANCER INSTITUTE

Principal

Investigator Title RFA or PA Project ID

Livingston, David Gene Expression Analysis of Prostate and Lung Cancer CA-98-027 CA84995

Lu, Michael L Molecular Regulation of Androgen Receptor Activation PA-99-081 CA87997

Lynch, Kevin Lysophosphatidic Acid and the Progression of Prostate Cancer CA88994

Malins, Donald FT-IR/GC-MS Models for Predicting Prostate Cancer CA79690

Mason, Ralph MR Measurement of Tumor pH, pO2, and Vascularity In Vivo CA79515

Moore, Bethany CXC Chemokine Regulation of Prostate Cancer Angiogenesis CA79046

Morton, Ronald E-Cadherin—Marker of Prostate Cancer Progression CA74290

Moscatelli, David A Angiopoietins in Prostate Biology and Disease PA-99-081 CA90593

Muschel, Ruth Molecular Mechanisms of Metastasis CA46830

Nagle, Raymond Prostate Carcinoma—Invasion and Metastasis Factors CA56666

Nelson, Peter Serine Proteases in Prostate Cancer Metastasis PA-99-081 CA85286

Ornstein, David K Proteomic Study of Androgen Independent Prostate Cancer PA-01-010 CA93759

Pandolfi, Pier Paolo Molecular Analysis of Carcinogenesis in the Mouse and Human Prostate PAR-99-167 CA92629-Sub-02

Parkos, Charles Phage Display and Prostate Neoplasia Progression PAR-99-102 CA91435

Pasqualini, Renata Project 2: Targeting Prostate Cancer Bone Metastasis PAR-99-167 CA90270-Sub-02

Petros, John A Mitochondrial DNA in Mutations in Prostate Cancer CA96994

Pienta, Kenneth Project 5: Inhibition of Human Prostate Cancer Metastasis CA-94-031 CA69568-Sub-05

Pretlow, Thomas Cytogenetics and Biochemistry of Prostate Cancer CA57179

Qiu, Yun IL-6 and Neuroendocrine Differentiation of Prostate Cancer CA85380

Reiter, Robert Prostate Stem Cell Antigen (PSCA) in the Biology and

Therapy of Prostate Cancer PAR-99-167 CA92131-Sub-01

Rinker-Schaeffer,

Carrie Prostate Cancer Metastatic Colonization—Role of MKK4 PA-99-081 CA89569

Rosenfeld,

Michael G Repressors in Prostate Cancer PA-99-081 CA97134

Roy-Burman,

Pradip Pathogenesis of Human Prostate Carcinomas CA59705

Sehgal, Inder Neuropeptide Regulation of Prostate Cancer Metastasis PA-98-022 CA82139

Sheng, Shijie A Role of Maspin in Prostate Cancer CA84176

Shuman, Marc Proteases in Cancer—Biology and Drug Development CA72006

Simons, Jonathon Project 5: Cellular and Molecular Basis of Prostate Metastasis to Bone CA-94-031 CA58236-Sub-05

Skelton, Timothy Decoding Cancer Signature Glycoforms of Serum Tumor Mark PAR-00-025 CA89730

Slamon, Dennis J Signal Transduction in Oncogenesis CA32737

Soff, Gerald Project 3: Generation of, and Angiostatin Levels in, Prostate Cancer PAR-99-167 CA90386-Sub-03

Stampfer, Meir J Growth Factors and Prostate Cancer Risk CA90598

Table B-2 (cont.)
NATIONAL CANCER INSTITUTE

B-8

Appendix B NCI-Supported Research Projects Relevant to Prostate Cancer That Were Active in 2002

Principal

Investigator Title RFA or PA Project ID

Stanford, Jean Molecular Predictors of Prostate Cancer Progression and Mortality PAR-00-087 CA97186-Sub-01

Stearns, Mark IL-10 and IGF1 Receptor Axis in Prostate Cancer CA90397

Stearns, Mark TIMP-1 Regulatory Factors in Human Prostate Cancer CA76639

Strom, Sara Project 5: Clinical, Epidemiological, and Molecular Markers of

Prostate Cancer Progression PAR-99-167 CA90270-Sub-05

Sun, Zijie Androgen Receptor Associated Proteins in Prostate Cancer CA70297

Sytkowski, Arthur J Chemopreventive Action of Human Selenium Binding Protein PAR-00-025 CA96047

Theodorescu, Dan Endothelial Growth Factor in Prostate Cancer Metastasis PA-99-081 CA85329

Thompson, Timothy Mechanisms of Metastasis in Experimental Prostate Cancer PA-99-081 CA68814

Thompson, Timothy Progression Mechanisms—Oncogene Induced Prostate Cancer PA-99-081 CA50588

Wang, Bing-Cheng Eph Kinase Signaling in Prostate Cancer DK-01-008 CA96533

Wang, Bing-Cheng EphA2 Agonists as Novel Inhibitors of Tumor Progression PA-99-081 CA92259

Wang, Zhou Project 2: Suppressive Role of Androgen-Response Gene

Calreticulin in Prostate Cancer PAR-99-167 CA90386-Sub-02

Wheeler, Thomas Project 1: Markers of Progression and Metastasis PAR-00-087 CA58204-Sub-01

Wu, Guan Neuroendocrine Differentiation in Prostate Cancer CA72872

Yamamoto, Keith Project 1: Mechanisms of Hormone Resistance in Prostate Cancer PAR-99-167 CA89520-Sub-01

Yang, Catherine Proteolyic Activity of Prostate Specific Antigen CA89162

Young, Charles Human Kallikreins as Novel Markers of Prostate Cancer PAR-99-167 CA91956-Sub-02

Zetter, Bruce Cell Motility in Tumor Metastasis CA37393

Zhau, Haiyen Characterization of an Invasive Human Prostate Cancer CA82739

Table B-2 (cont.)
B-9

Appendix B NCI-Supported Research Projects Relevant to Prostate Cancer That Were Active in 2002

NATIONAL CANCER INSTITUTE

Principal

Investigator Title RFA or PA Project ID

Abate-Shen, Cory Nkx3.1 and Prostate Development and Cancer CA76501

Chang, David D Expression and Function of Eplin CA90498

Couch, Fergus p21 Induction by BRCA2 CA78878

Hixson, Douglas Molecular Determinants of Multicellular Organization CA42714

Jarrard, David F Modulation of IGF-II Imprinting in the Aging Prostate CA97131

Kakar, Sham Molecular Characterization of GnRH Receptors CA60871

Milbrandt, Jeffrey Nkx3.1 and Prostate Development and Cancer CA81564

Miller, Gary Role of Homeodomain Genes in Human Prostate Cancer CA84269

Mueller, Elisabetta PPAR as a Target of Therapy for Prostate Cancer PAR-99-167 CA90381-Sub-02

Slamon, Dennis J Signal Transduction in Oncogenesis CA32737

Table B-3

NCI Projects Supported in 2002 Addressing the PRG Priority:

What are the biochemical and molecular events that govern the continuation of

prostate development from early embryogenesis to the onset of adulthood,

through maturation, aging, and death?
NATIONAL CANCER INSTITUTE

B-10

Appendix B NCI-Supported Research Projects Relevant to Prostate Cancer That Were Active in 2002

Principal

Investigator Title RFA or PA Project ID

Celis, Esteban Immune-Based Therapeutic Approach for Prostate Cancer CA82677

Celis, Esteban An Immune-Based Therapeutic Approach for Prostate Cancer PAR-99-167 CA91956-Sub-04

Chung, Leland Extracellular Matrix Integrin Signaling in Prostate Cancer CA76620

Couch, Fergus p21 Induction by BRCA2 CA78878

Cunha, Gerald Cell–Cell Interactions in Prostate Cancer CA59831

Demarzo, Angelo Inflammation and Atrophy in Prostate Carcinogenesis PA-99-005 CA84997

Emmert-Buck,

Michael R Genetic Progression of Cancer SC10437

Fisher, Paul Novel Prostate Cancer Gene and Monoclonal Antibody CA74468

Frelinger, John Targeted CTL Mediated Immunity for Prostate Cancer CA70218

Kwon, Eugene CTLA-4 Blockade Immunotherapy for Prostate Cancer CA82185

Languino, Lucia Molecular Analysis of B1 Integrins CA71870

Lin, Sue-Hwa Function of C-CAM in Prostate Cancer CA64856

Morton, Ronald E-Cadherin—Marker of Prostate Cancer Progression CA74290

Parsons, Sarah Neuroendocrine Cell Signaling in Prostate Cancer CA76649

Pasqualini, Renata Project 2: Targeting Prostate Cancer Bone Metastasis PAR-99-167 CA90270-Sub-02

Ratliff, Timothy Host/Tumor Interactions in Immunotherapy of Prostate Cancer PA-99-081 CA89062

Sherman, Simon Immunogenic Tumor Associated Mucin Peptides CA84106

Tlsty, Thea Fibroblast Regulation of Human Prostatic Carcinogenesis CA83812

Tsai, Ming-Jer Project 7: Endocrinology and the Role of Stroma Genes in

Prostate Cancer PAR-00-087 CA58204-Sub-07

Wang, Zhou Project 2: Suppressive Role of Androgen-Response Gene 

Calreticulin in Prostate Cancer PAR-99-167 CA90386-Sub-02

Wu, Guan Neuroendocrine Differentiation in Prostate Cancer CA72872

Table B-4

NCI Projects Supported in 2002 Addressing the PRG Priority:

What are the specific cell–cell interactions between and among developing epithelial

cells, stromal cells, endothelial cells, neuroepithelial cells, and inflammatory cells?
B-11

Appendix B NCI-Supported Research Projects Relevant to Prostate Cancer That Were Active in 2002

NATIONAL CANCER INSTITUTE

Principal

Investigator Title RFA or PA Project ID

Boynton, Alton Mediators of Platelet Derived Growth Factor Action CA57064

Bushman, Wade A Shh Signaling as a Therapeutic Target in Prostate Cancer PAR-01-045 CA95386

Chang, David D Expression and Function of Eplin CA90498

Cunha, Gerald Smooth Muscle–Epithelial Interactions in Prostate Cancer CA64872

Cuttitta, Frank Identification of Peptide Growth Factors That Regulate Human

Tumor Proliferation SC00173

Cuttitta, Frank Growth of Human Tumor Cell Lines in Protein-Free/Hormone-Free

Media SC00192

Day, Mark Project 4: Rb as a Regulator of Prostate Tumorigenesis CA-94-031 CA69568-Sub-04

Fidler, Isiah Project 1: The Biology of Human Prostate Cancer Metastasis PAR-99-167 CA90270-Sub-01

Greenberg, Norman KGF in Prostate Cancer—A Transgenic Animal Model CA64851

Hixson, Douglas Molecular Determinants of Multicellular Organization CA42714

Lange, Paul H Mechanisms and Markers of Prostate Cancer Metastases CA85859

Lin, Ming-Fong Steroid Regulation of Human Prostate Cancer Cells CA72274

Lin, Sue-Hwa Function of C-CAM in Prostate Cancer CA64856

Lin, Sue-Hwa Regulation of Angiogenesis by C-CAM1 CA86342

Lokeshwar,

Balakrishna Control of Metastatic Progression of Prostate Cancer CA61038

Lynch, Kevin Lysophosphatidic Acid and the Progression of Prostate Cancer CA88994

Moscatelli, David A Angiopoietins in Prostate Biology and Disease PA-99-081 CA90593

Mulder, Kathleen Mechanisms of TGF-Beta Production in Human Cancer Cells CA90765

Muschel, Ruth Molecular Mechanisms of Metastasis CA46830

Parsons, Sarah Neuroendocrine Cell Signaling in Prostate Cancer CA76649

Rowley, David Mesenchymal Derived Growth Factors in Prostatic Cancer CA58093

Shah, Girish Calcitonin in Prostate Growth and Neoplasia DK-01-008 CA96534

Simons, Jonathon Project 5: Cellular and Molecular Basis of Prostate Metastasis to Bone CA-94-031 CA58236-Sub-05

Smith, Gary Age and Microenvironment Effect on Prostate Cancer CA64865

Sun, Luzhe Z Targeting Transforming Growth Factor Beta for Cancer Treatment CA75253

Theodorescu, Dan Endothelial Growth Factor in Prostate Cancer Metastasis PA-99-081 CA85329

Wang, Zhou Project 2: Suppressive Role of Androgen-Response Gene 

Calreticulin in Prostate Cancer PAR-99-167 CA90386-Sub-02

Weber, Michael Cell Signaling in Prostate Cancer Progression CA76465

Table B-5

NCI Projects Supported in 2002 Addressing the PRG Priority:

What are the regulatory effector molecules that control reciprocal interactions

between epithelial and stromal cells, among clonal cancer epithelial cells, and

between cancer cells and most immune-reactive cells?
NATIONAL CANCER INSTITUTE

B-12

Appendix B NCI-Supported Research Projects Relevant to Prostate Cancer That Were Active in 2002

Principal

Investigator Title RFA or PA Project ID

Cavalieri, Ercole Molecular Origin Cancer—Catechol Estrogen-3,4-Quinones CA49210

Dent, Paul Carcinoma Cell Radiosensitization by MAPK Inhibition CA88906

DeWeese, Theodore Project 14: Determinants of Radiosensitivity in Prostate Cancer CA-94-031 CA58236-Sub-14

El-Zein, Randa Molecular Biomarkers for Prostate Cancer Susceptibility CA88301

Gelmann, Edward Apoptosis in Prostate Cancer CA79912

Green, Jeffrey E Transgenic Models for Prostate and Breast Cancer BC05740

Griffith, Jeffrey Prognostic Value of Telomere DNA in Prostate Biopsy PAR-99-102 CA86136

Harper, J Wade Project 2: The Role of CDK Inhibitors in Prostate Cancer PAR-00-087 CA58204-Sub-02

Hay, Nissim PI3K/PTEN/Akt (PKB), Signaling, and Genesis of Cancer CA90764

Holt, Jeffrey Mechanisms of Carcinogenesis in BRCA2 Mutant Cells CA85269

Jenkins, Robert Biologic and Clinical Studies of Overrepresented 8q24 Region

Associated with Prostate Cancer Progression PAR-99-167 CA91956-Sub-03

Kim, Seong Jin Molecular Mechanisms of Resistance to TGF-Beta-Mediated Apoptosis BC10050

Loda, Massimo Isopeptidases, Ubiquitin-Degradation, and Prostate Cancer CA81755

Malins, Donald DNA Damage in Mouse Tumors Evaluated by IR Spectroscopy CA79479

Malins, Donald FT-IR/GC-MS Models for Predicting Prostate Cancer CA79690

McDonnell, Timothy Project 3: Therapeutic Modulation of Apoptosis in Prostate Cancer

Patients PAR-99-167 CA90270-Sub-03

Nelson, William Project 12: Rational Prostate Cancer Prevention Studies CA-94-031 CA58236-Sub-12

Rauscher, Frank Role of the BRCA1 Associated Protein BAP1 in DNA Repair CA92088

Rosen, Eliot Role of BRCA1 as a Human Prostate Suppressor Gene CA80000

Sellers, William Single Nucleotide Repeat Polymorphism Analysis of Recurrent

Prostate Cancer after Radiation Therapy PAR-99-167 CA90381-Sub-03

Uhr, Jonathan Early Detection/Characterization of Tumor Cells in Blood CA78303

Wahl, Geoffrey Anticancer Agent Sensitivity and Cell Cycle Control CA61449

Yeh, Grace Chao Dietary Regulation of Biochemical/Molecular Changes in

Carcinogen Resistant Cells BC00189

Zimbrick, John Radiation Biochemistry of Clustered Damage Sites in DNA CA80211

Table B-6

NCI Projects Supported in 2002 Addressing the PRG Priority:

Are there features of DNA damage, DNA repair, or cell-cycle

progression that are novel in prostate cancer cells?
B-13

Appendix B NCI-Supported Research Projects Relevant to Prostate Cancer That Were Active in 2002

NATIONAL CANCER INSTITUTE

Principal

Investigator Title RFA or PA Project ID

Abate-Shen, Cory Nkx3.1 and Prostate Development and Cancer CA76501

Abato, Paul Validation of Prostate Cancer Oncogenes CA96276

Aebersold, Ruedi Novel Quantitative, Comprehensive Proteomic Technology CA-01-011 CA93302

Altieri, Dario Control of Apoptosis in Cancer by Survivin CA78810

Arap, Wadih Project 4: Exploring the Molecular Diversity of Blood Vessels

for Diagnostic and Therapeutic Targeting in Prostate Cancer PAR-99-167 CA90270-Sub-04

Balk, Steven The Androgen Receptor in Hormone Refractory Disease PAR-99-167 CA90381-Sub-05

Barrett, J Carl A Metastasis Suppressor Gene for Prostatic Cancer BC10431

Baserga, Renato L Biology of the p53 Protein CA89640

Bova, G Modes of Prostate Cancer Progression—Role of p53 Pathway PA-99-081 CA92234

Brothman, Arthur Molecular and Cytogenetic Analysis of Prostate Carcinoma CA46269

Chakrabarti, Ratna Molecular Markers for Prostate Cancer PA-98-022 CA81329

Cho-Chung, Yoon S Mechanism of cAMP-Growth Regulatory Function BC08281

Coffey, Donald Project 4: Human Prostate Cancer Nuclei: Abnormalities in

Structure and the Development of New Molecular Markers CA-94-031 CA58236-Sub-04

Cohen, Pinchas Interactions between IGFBPs and Nuclear Receptors in Prostate

Cancer PAR-99-167 CA92131-Sub-03

Collins, Colin Project 2: Genomics of Prostate Cancer PAR-99-167 CA89520-Sub-02

Couch, Fergus p21 Induction by BRCA2 CA78878

Danielpour, David Function and Regulation of Trespin, a Novel Serpin CA83069

Dong, Jin-Tang Molecular Dissection of 13q14 in Prostate Cancer PA-99-081 CA85560

Dong, Jin-Tang Tumor Suppressor Gene at 13q21 in Prostate Cancer PA-99-081 CA87921

Ellis, William Genomic and Gene Expression Profiling of Disseminated Prostate

Cancer PAR-00-087 CA97186-Sub-02

Emmert-Buck,

Michael R Genetic Progression of Cancer SC10437

Everson, Richard Receptor Gene Polymorphisms in Prostate Cancer CA81240

Felton, James S Carcinogenic Significance of Heterocyclic Amines CA55861

Figg, William D Development of Angiogenesis Inhibitors Using Prostate Cancer

as a Tumor Model SC06538

Garcia-Blanco,

Mariano A Imaging Alternative Splicing during Tumor Progression PAR-01-106 CA97502

Gerald, William Molecular Classification of Prostate Cancer CA-98-027 CA84999

Giovannucci, Genetic and Serologic Determinants of Prostate Cancer

Edward Risk and Progression PAR-99-167 CA90381-Sub-01

Table B-7

NCI Projects Supported in 2002 Addressing the PRG Priority:

What are the genetic and epigenetic determinants that affect progression of

prostate cancer from the localized to disseminated state?

What molecular markers are associated with such progression?
NATIONAL CANCER INSTITUTE

B-14

Appendix B NCI-Supported Research Projects Relevant to Prostate Cancer That Were Active in 2002

Principal

Investigator Title RFA or PA Project ID

Gleave, Martin Characterization of Anti-Apoptotic Genes Induced during

Androgen Independent Progression and Chemotherapy PAR-00-087 CA97186-Sub-03

Glinsky, Gennadi Transcriptome of Metastatic Prostate Cancer CA89827

Golub, Todd Genomic Expression Analysis of Tumors after Radical Prostatectomy PAR-99-167 CA90381-Sub-04

Green, Jeffrey E Transgenic Models for Prostate and Breast Cancer BC05740

Hendrix, Mary Prostatic Vasculogenic Mimicry: A New Metastatic Pathway PA-99-081 CA88043

Project 8: Down Regulation of Metastasis Suppressor Genes as 

Isaacs, John T Diagnostic Methods for Predicting the Biologic Behavior of CA-94-031 CA58236-Sub-08

Histologically Detectable Prostate Cancer

Issa, Jean-Pierre J Neoplasia and Methylated CpG Islands Amplification PAR-99-100 CA89837

Jarrard, David F Modulation of IGF-II Imprinting in the Aging Prostate CA97131

Jenkins, Robert Biologic and Clinical Studies of Overrepresented 8q24 Region

Associated with Prostate Cancer Progression PAR-99-167 CA91956-Sub-03

Kelly, Kathleen ERK-Dependent Growth and Differentiation Pathways SC09358

Languino, Lucia Integrin Signaling Pathways in Prostate Cancer PA-99-081 CA89720

Lee, Byungkook Molecular Modeling and Bioinformatics BC08759

Liao, Shutsung Molecular Mechanisms of Growth Control—Prostate Cancer CA58073

Lin, Ming-Fong Signaling in Androgen Refractory Prostate Cancer PA-99-055 CA88184

Linehan, W Marston Molecular Genetics of Prostate Cancer SC10095

Liotta, Lance Laser Capture Microdissection Applied to Human Pathophysiology SC09185

Malins, Donald FT-IR/GC-MS Models for Predicting Prostate Cancer CA79690

Mc Keehan, Wallace Growth Factors in Prostate Cancer CA59971

Mikovits, Judy A Development of DNA Methyltransferase Inhibitors as Anti* PA-01-091 CA92828

Milbrandt, Jeffrey Nkx3.1 and Prostate Development and Cancer CA81564

Mueller, Elisabetta PPAR as a Target of Therapy for Prostate Cancer PAR-99-167 CA90381-Sub-02

Nelson, Peter Serine Proteases in Prostate Cancer Metastasis PA-99-081 CA85286

Nelson, William Project 12: Rational Prostate Cancer Prevention Studies CA-94-031 CA58236-Sub-12

Ornstein, David K Proteomic Study of Androgen Independent Prostate Cancer PA-01-010 CA93759

Pandolfi, Pier Paolo Molecular Analysis of Carcinogenesis in the Mouse and Human

Prostate PAR-99-167 CA92629-Sub-02

Parkos, Charles Phage Display and Prostate Neoplasia Progression PAR-99-102 CA91435

Pasqualini, Renata Project 2: Targeting Prostate Cancer Bone Metastasis PAR-99-167 CA90270-Sub-02

Petros, John A Mitochondrial DNA in Mutations in Prostate Cancer CA96994

Pretlow, Thomas Cytogenetics and Biochemistry of Prostate Cancer CA57179

Rangnekar, Vivek Mechanism of Apoptosis by Par4 CA60872

Table B-7 (cont.)
B-15

Appendix B NCI-Supported Research Projects Relevant to Prostate Cancer That Were Active in 2002

NATIONAL CANCER INSTITUTE

Principal

Investigator Title RFA or PA Project ID

Reiter, Robert Prostate Stem Cell Antigen (PSCA) in the Biology and Therapy

of Prostate Cancer PAR-99-167 CA92131-Sub-01

Sawyers, Charles Targeted Therapy of PTEN Null Prostate Cancer PAR-99-167 CA92131-Sub-02

Scher, Howard Mechanism Based Therapy for Prostate Cancer PAR-99-167 CA92629-Sub-04

Sellers, William Functional Analysis of the PTEN Tumor Suppressor Protein PA-99-081 CA85912

Sellers, William Single Nucleotide Repeat Polymorphism Analysis of Recurrent

Prostate Cancer after Radiation Therapy PAR-99-167 CA90381-Sub-03

Sheikh, M Death Receptors in Prostate Cancer Biology and Apoptosis PA-99-081 CA89043

Singal, Rakesh GSTP1 Gene Repression in Prostate Cancer PA-99-081 CA89348

Skelton, Timothy Decoding Cancer Signature Glycoforms of Serum Tumor Mark PAR-00-025 CA89730

Spencer, David FGFR Signaling in Prostate Development and Cancer PA-99-081 CA87569

Stanford, Janet Molecular Predictors of Prostate Cancer Progression and Mortality PAR-00-087 CA97186-Sub-01

Strom, Sara Project 5: Clinical, Epidemiological, and Molecular Markers of 

Prostate Cancer Progression PAR-99-167 CA90270-Sub-05

Veltri, Robert Methylation Specific PCR for Cancer Diagnosis/Prognosis CA90007

Waalkes, Michael P Mechanisms of Inorganic Carcinogenesis BC05488

Wang, Zhou Project 2: Suppressive Role of Androgen-Response Gene 

Calreticulin in Prostate Cancer PAR-99-167 CA90386-Sub-02

Weber, Michael Cell Signaling in Prostate Cancer Progression CA76465

Wheeler, Thomas Project 1: Markers of Progression and Metastasis PAR-00-087 CA58204-Sub-01

Wu, Guan Neuroendocrine Differentiation in Prostate Cancer CA72872

Yamamoto,

Fumiichiro Technology to Detect Genome Wide DNA Methylation Changes PAR-99-100 CA84704

Yamamoto, Keith Project 1: Mechanisms of Hormone Resistance in Prostate Cancer PAR-99-167 CA89520-Sub-01

Ying, Shao-Yao Novel Molecular Profiling of Prostate Cancer Signatures CA85722

Zhao, Yingming Identification of Prostate and Ovarian Cancer Markers CA-98-028 CA85146

Table B-7 (cont.)
NATIONAL CANCER INSTITUTE

B-16

Appendix B NCI-Supported Research Projects Relevant to Prostate Cancer That Were Active in 2002

Principal

Investigator Title RFA or PA Project ID

Abdulkadir, Sarki A Modeling Prostate Cancer by Conditional Gene Targeting CA94858

Aebersold, Ruedi Novel Quantitative, Comprehensive Proteomic Technology CA-01-011 CA93302

Agus, David The Role of the Her-Kinase Axis in Emergence of Androgen

Independence in Human Prostate Cancer PAR-99-167 CA92131-Sub-04

Ahmed, Mansoor EGR-1 and Apoptosis in Prostate Cancer CA78471

Ambs, Stefan Identification of Allele Variant Genes That Are Risk Factors for

Human Breast and Prostate Cancer BC10439

Arap, Wadih Project 4: Exploring the Molecular Diversity of Blood Vessels for

Diagnostic and Therapeutic Targeting in Prostate Cancer PAR-99-167 CA90270-Sub-4

Barrack, Evelyn R Project 3: Androgen Receptor Gene Structure and Function in

Human Prostate Cancer CA-94-031 CA58236-Sub-3

Bova, G Modes of Prostate Cancer Progression—Role of p53 Pathway PA-99-081 CA92234

Cheng, Jin AKT1 Oncogene in Carcinogenesis CA89242

Chinnaiyan, Arul M The Role of Polycomb Group Proteins in Prostate Cancer CA97063

Coffey, Donald Project 4: Human Prostate Cancer Nuclei: Abnormalities in

Structure and the Development of New Molecular Markers CA-94-031 CA58236-Sub-04

Cohen, Pinchas Interactions between IGFBPs and Nuclear Receptors in Prostate

Cancer PAR-99-167 CA92131-Sub-3

Day, Mark Project 4: Rb as a Regulator of Prostate Tumorigenesis CA-94-031 CA69568-Sub-04

De Vere White,

Ralph hAR Alterations and Androgen Independent Prostate Cancer CA92069

Ellis, William Genomic and Gene Expression Profiling of Disseminated Prostate

Cancer PAR-00-087 CA97186-Sub-2

Everson, Richard Receptor Gene Polymorphisms in Prostate Cancer CA81240

Fidler, Isiah Project 1: The Biology of Human Prostate Cancer Metastasis PAR-99-167 CA90270-Sub-01

Figg, William D Development of Angiogenesis Inhibitors Using Prostate Cancer

as a Tumor Model SC06538

Gelmann, Edward Apoptosis in Prostate Cancer CA79912

Gerald, William Molecular Classification of Prostate Cancer CA-98-027 CA84999

Giovannucci, Genetic and Serologic Determinants of Prostate Cancer Risk and

Edward Progression PAR-99-167 CA90381-Sub-01

Gleave, Martin Characterization of Anti-Apoptotic Genes Induced during Androgen

Independent Progression and Chemotherapy PAR-00-087 CA97186-Sub-03

Golub, Todd Genomic Expression Analysis of Tumors after Radical Prostatectomy PAR-99-167 CA90381-Sub-4

Hay, Nissim PI3K/PTEN/Akt (PKB), Signaling, and Genesis of Cancer CA90764

Heeb, Mary Forms of Prostate Specific Antigen and hK2 in Cancer CA59979

Hixson, Douglas Molecular Determinants of Multicellular Organization CA42714

Holt, Jeffrey Mechanisms of Carcinogenesis in BRCA2 Mutant Cells CA85269

Table B-8

NCI Projects Supported in 2002 Addressing the PRG Priority:

Are there hereditary markers, angiogenesis switches, and/or

biochemical and molecular determinants that predict progression?
B-17

Appendix B NCI-Supported Research Projects Relevant to Prostate Cancer That Were Active in 2002

NATIONAL CANCER INSTITUTE

Principal

Investigator Title RFA or PA Project ID

Hood, Leroy Transcriptome and Proteome Stratification of Prostate 

Adenocarcinoma Phenotypes PAR-00-087 CA97186-Sub-4

Project 8: Down Regulation of Metastasis Suppressor Genes as 

Isaacs, John T Diagnostic Methods for Predicting the Biologic Behavior of CA-94-031 CA58236-Sub-8

Histologically Detectable Prostate Cancer

Isaacs, William B Project 2: Search for Hereditary Prostate Cancer Genes Using

Linkage Analysis and Positional Cloning Approaches CA-94-031 CA58236-Sub-2

Languino, Lucia Integrin Signaling Pathways in Prostate Cancer PA-99-081 CA89720

Lawrence, Daniel Regulation of Angiogenesis by PAI1 CA83090

Lee, Chung Project 1: Clusterin as a Negative Prognostic Indicator in Prostate

Cancer PAR-99-167 CA90386-Sub-01

Livingston, David Gene Expression Analysis of Prostate and Lung Cancer CA-98-027 CA84995

Loda, Massimo Isopeptidases, Ubiquitin-Degradation, and Prostate Cancer CA81755

Lynch, Kevin Lysophosphatidic Acid and the Progression of Prostate Cancer CA88994

McDonnell, Timothy Project 3: Therapeutic Modulation of Apoptosis in Prostate

Cancer Patients PAR-99-167 CA90270-Sub-03

Pandolfi, Pier Paolo Molecular Analysis of Carcinogenesis in the Mouse and Human

Prostate PAR-99-167 CA92629

Parkos, Charles Phage Display and Prostate Neoplasia Progression PAR-99-102 CA91435

Parsons, Ramon PTEN Tumor Suppressor and Signal Transduction CA82783

Rauscher, Frank Role of the BRCA1 Associated Protein BAP1 in DNA Repair CA92088

Ross, Jeffrey Human RNA Binding Protein as a Cancer Marker PA-01-010 CA94082

Sellers, William Single Nucleotide Repeat Polymorphism Analysis of Recurrent

Prostate Cancer after Radiation Therapy PAR-99-167 CA90381-Sub-3

Shreve, Paul C11 Acetate PET Imaging of Prostate and Renal Cancer CA89448

Simons, Jonathon Project 5: Cellular and Molecular Basis of Prostate Metastasis to Bone CA-94-031 CA58236-Sub-05

Skelton, Timothy Decoding Cancer Signature Glycoforms of Serum Tumor Mark PAR-00-025 CA89730

Smith, Steven DNA Methylation in Early Detection of Prostate Cancer PAR-00-025 CA91234

Soff, Gerald Project 3: Generation of, and Angiostatin Levels in, Prostate Cancer PAR-99-167 CA90386-Sub-03

Stampfer, Meir J Growth Factors and Prostate Cancer Risk CA90598

Stanford, Janet Molecular Predictors of Prostate Cancer Progression and Mortality PAR-00-087 CA97186-Sub-01

Wang, Bing-Cheng EphA2 Agonists as Novel Inhibitors of Tumor Progression PA-99-081 CA92259

Wang, Zhou Project 2: Suppressive Role of Androgen-Response Gene 

Calreticulin in Prostate Cancer PAR-99-167 CA90386-Sub-02

Wheeler, Thomas Project 1: Markers of Progression and Metastasis PAR-00-087 CA58204-Sub-01

Yamamoto, Keith Project 1: Mechanisms of Hormone Resistance in Prostate Cancer PAR-99-167 CA89520-Sub-01

Yang, Catherine Proteolytic Activity of Prostate Specific Antigen CA89162

Table B-8 (cont.)
NATIONAL CANCER INSTITUTE

B-18

Appendix B NCI-Supported Research Projects Relevant to Prostate Cancer That Were Active in 2002

Principal

Investigator Title RFA or PA Project ID

Agus, David The Role of the Her-Kinase Axis in Emergence of Androgen

Independence in Human Prostate Cancer PAR-99-167 CA92131-Sub-04

Ahmed, Khalil Normal and Neoplastic Prostate CA15062

Aoki, Masahiro Nuclear Targets of AKT Oncoproteins CA93837

Bai, Wenlong AR-PTEN Antagonism in Prostate Cell Growth and Apoptosis CA93666

Baldwin, Albert Antiapoptotic Mechanisms in Prostate Cancer CA75080

Baldwin, Albert Regulation of BCL2 by Ras and Tumor Suppressors CA72771

Balmain, Allan Project 5: Identification of Prostate Tumor Susceptibility Genes

Using Mouse Models for Prostate Cancer PAR-99-167 CA89520-Sub-05

Barrett, J Carl A Metastasis Suppressor Gene for Prostatic Cancer BC10431

Baserga, Renato L Biology of the p53 Protein CA89640

Boss, Gerry R Analysis of Ras and Rho Activation in Prostate Cancer PA-00-080 CA90932

Bova, G Modes of Prostate Cancer Progression—Role of p53 Pathway PA-99-081 CA92234

Bova, Steven G Project 1: Molecular Genetics of Human Prostate Cancer CA-94-031 CA58236-Sub-01

Boynton, Alton Mediators of Platelet Derived Growth Factor Action CA57064

Cantley, Lewis The Role of PTEN and the PI3K Pathway in Prostate Cancer CA89021

Caprioli, Richard M Molecular Analysis of Cancer—Imaging Mass Spectrometry PAR-99-102 CA86243

Chakrabarti, Ratna Molecular Markers for Prostate Cancer PA-98-022 CA81329

Chen, Ching-Shih Apoptosis Regulation by Lipid Signals in Prostate Cancer PA-99-081 CA94829

Cheng, Jin AKT1 Oncogene in Carcinogenesis CA89242

Chinault, Craig Project 3: Physical and Functional Analysis of Prostate Cancer Genes PAR-00-087 CA58204-Sub-03

Cho-Chung, Yoon S Mechanism of cAMP-Growth Regulatory Function BC08281

Cho-Chung, Yoon S The Role of cAMP-Dependent Protein Kinase in Growth Control BC05216

Cohen, Michael Fas-Mediated Apoptosis in Prostate Cancer CA76673

Cohen, Michael TNF Alpha Mediated Apoptosis in Prostate Cancer PA-99-081 CA87617

Cohen, Michael B Trail Mediated Apoptosis in Prostate Cancer CA93870

Collins, Colin Project 2: Genomics of Prostate Cancer PAR-99-167 CA89520-Sub-02

Couch, Fergus p21 Induction by BRCA2 CA78878

Croce, Carlo 8p22 Alterations, in Prostate, Breast, and Esophageal Cancer CA83698

Cuttitta, Frank Identification of Peptide Growth Factors the Regulate Human

Tumor Proliferation SC00173

Dang, Chi c-Myc Targets in the Pathogenesis of Human Cancers CA57341

Day, Mark Project 4: Rb as a Regulator of Prostate Tumorigenesis CA-94-031 CA69568-Sub-04

De Vere White,

Ralph hAR Alterations and Androgen Independent Prostate Cancer CA92069

Table B-9

NCI Projects Supported in 2002 Addressing the PRG Priority:

What are the critical housekeeping and regulatory genes that may be

associated with human prostate cancer development and progression?
B-19

Appendix B NCI-Supported Research Projects Relevant to Prostate Cancer That Were Active in 2002

NATIONAL CANCER INSTITUTE

Principal

Investigator Title RFA or PA Project ID

Deluca, L Retinoids in Differentiation and Neoplasia BC04798

Fisher, Paul Novel Prostate Cancer Gene and Monoclonal Antibody CA74468

Franklin, Renty Zinc Transport Relationships in Prostate Cancer Cells CA79903

Gao, Allen STAT3 in Androgen Receptor Signaling in Prostate Cancer CA90271

Garcia-Blanco,

Mariano A Imaging Alternative Splicing during Tumor Progression PAR-01-106 CA97502

Gelman, Irwin H PKC/PKA Regulation in Prostate Cancer by SSeCKS/Gravin CA94108

Gelmann, Edward Apoptosis in Prostate Cancer CA79912

Gelmann, Edward Beta Catenin in Prostate Cancer PA-99-081 CA87855

Gerald, William Molecular Classification of Prostate Cancer CA-98-027 CA84999

Giovannucci, Genetic and Serologic Determinants of Prostate Cancer

Edward Risk and Progression PAR-99-167 CA90381-Sub-01

Gleave, Martin Characterization of Anti-Apoptotic Genes Induced during

Androgen Independent Progression and Chemotherapy PAR-00-087 CA97186-Sub-03

Golub, Todd Genomic Expression Analysis of Tumors after Radical Prostatectomy PAR-99-167 CA90381-Sub-04

Green, Jeffrey E Transgenic Models for Prostate and Breast Cancer BC05740

Greenberg, Norman IGF Axis in Prostate Cancer—Transgenic Study CA82807

Greenberg, Norman Project 6: Prostate-Specific Gene Expression in Transgenic Animals PAR-00-087 CA58204-Sub-06

Hann, Stephen B-Myc Regulation and Function CA78888

Hayward, Simon Hormonal Carcinogenesis in Rb-Knockout Mouse Prostate CA96403

Ho, Shuk-Mei Metallothionein and Cadmium Carcinogenesis in Rat Prostate CA62269

Holt, Jeffrey Mechanisms of Carcinogenesis in BRCA2 Mutant Cells CA85269

Hood, Leroy Transcriptome and Proteome Stratification of Prostate

Adenocarcinoma Phenotypes PAR-00-087 CA97186-Sub-04

Hoosein, Naseema Neuroendocrine Factors in Prostate Cancer CA63225

Project 8: Down Regulation of Metastasis Suppressor Genes as

Isaacs, John T Diagnostic Methods for Predicting the Biologic Behavior of CA-94-031 CA58236-Sub-08

Histologically Detectable Prostate Cancer

Jarrard, David F Modulation of IGF-II Imprinting in the Aging Prostate CA97131

Jay, Gilbert Large Scale Gene Discovery—Human Prostate Cancer CA81900

Jenkins, Robert Biologic and Clinical Studies of Overrepresented 8q24 Region

Associated with Prostate Cancer Progression PAR-99-167 CA91956-Sub-03

Kazanietz, Marcelo Prostate Carcinogenesis and PKC Signaling PA-99-081 CA89202

Kelly, Kathleen ERK-Dependent Growth and Differentiation Pathways SC09358

Kim, Seong Jin Molecular Mechanisms of Resistance to TGF-Beta-Mediated Apoptosis BC10050

Koff, Andrew p27Kip1 Expression, a Prognostic Indicator—But Why? CA89563

Table B-9 (cont.)
NATIONAL CANCER INSTITUTE

B-20

Appendix B NCI-Supported Research Projects Relevant to Prostate Cancer That Were Active in 2002

Principal

Investigator Title RFA or PA Project ID

Kraft, Andrew Regulation of Prostate Cancer Programmed Cell Death CA78631

Kung, Hsing-Jien ErbB Kinase Activation and Transformation CA39207

Lange, Paul H Mechanisms and Markers of Prostate Cancer Metastases CA85859

Lee, Byungkook Molecular Modeling and Bioinformatics BC08759

Lee, Chung Clusterin—An Anti-Apoptotic Mediator in Prostate Cancer CA80953

Lee, Chung Project 1: Clusterin as a Negative Prognostic Indicator in Prostate

Cancer PAR-99-167 CA90386-Sub-01

Libermann, Towia Role of a New Ets Factor, PDEF, in Prostate Cancer PA-99-081 CA85467

Lin, Ming-Fong Steroid Regulation of Human Prostate Cancer Cells CA72274

Linehan, W Marston Molecular Genetics of Prostate Cancer SC10095

Loda, Massimo Isopeptidases, Ubiquitin-Degradation, and Prostate Cancer CA81755

Lynch, Kevin Lysophosphatidic Acid and the Progression of Prostate Cancer CA88994

McKeon, Frank Murine p73 in Tumorigenesis CA75340

Mercola, Dan Oncogenic Role of Jun Kinase in Human Prostate Cancer CA84107

Mercola, Daniel Jun Kinase and Human Tumors CA63783

Morton, Ronald E-Cadherin—Marker of Prostate Cancer Progression CA74290

Mulder, Kathleen Mechanisms of TGF-Beta Production in Human Cancer Cells CA90765

Nanus, David Neutral Endopeptidase Inactivation in Advanced Prostate PA-99-081 CA80240

Nelson, William GSTPI Promoter Hypermethylation in Human Prostate Cancer CA70196

Nelson, William Project 12: Rational Prostate Cancer Prevention Studies CA-94-031 CA58236-Sub-12

Pandolfi, Pier Paolo Molecular Analysis of Carcinogenesis in the Mouse and Human

Prostate PAR-99-167 CA92629-Sub-02

Parsons, Ramon PTEN Tumor Suppressor and Signal Transduction CA82783

Parsons, Ramon E PI-3 Kinase Therapy in Mouse Tumor Models PAR-02-051 CA99523

Pasqualini, Renata A Receptor for Tumor Homing Peptides in Vasculature CA78512

Pestell, Richard Cyclin D1 Function in Prostate Cancer PA-99-081 CA86072

Pincus, Matthew Protein Structure and Oncogenesis CA42500

Pretlow, Thomas Cytogenetics and Biochemistry of Prostate Cancer CA57179

Qiu, Yun IL-6 and Neuroendocrine Differentiation of Prostate Cancer CA85380

Rangnekar, Vivek Mechanism of Apoptosis by Par4 PA-99-081 CA60872

Rauscher, Frank Role of the BRCA1 Associated Protein BAP1 in DNA Repair CA92088

Rosenfeld, Ron Insulin-Like Growth Factors and Prostate Carcinogenesis CA58110

Ross, Jeffrey Human RNA Binding Protein as a Cancer Marker PA-01-010 CA94082

Roy-Burman, Pradip Pathogenesis of Human Prostate Carcinomas CA59705

Table B-9 (cont.)
B-21

Appendix B NCI-Supported Research Projects Relevant to Prostate Cancer That Were Active in 2002

NATIONAL CANCER INSTITUTE

Principal

Investigator Title RFA or PA Project ID

Rui, Hallgeir Targeting of Tyrosine Kinase Pathways in Prostate Cancer CA83813

Sawyers, Charles Regulation of the PTEN Gene in Prostate Cancer CA87079

Sellers, William Single Nucleotide Repeat Polymorphism Analysis of Recurrent

Prostate Cancer after Radiation Therapy PAR-99-167 CA90381-Sub-03

Shah, Girish Calcitonin in Prostate Growth and Neoplasia DK-01-008 CA96534

Singal, Rakesh GSTP1 Gene Repression in Prostate Cancer PA-99-081 CA89348

Slamon, Dennis J Signal Transduction in Oncogenesis CA32737

Smith, Steven DNA Methylation in Early Detection of Prostate Cancer PAR-00-025 CA91234

Soff, Gerald Project 3: Generation of, and Angiostatin Levels in, Prostate Cancer PAR-99-167 CA90386-Sub-03

Srivastava, Shiv Characterization of Novel Prostate Specific Gene, PCGEM1 CA85596

Stampfer, Meir J Growth Factors and Prostate Cancer Risk CA90598

Stearns, Mark IL-10 and IGF1 Receptor Axis in Prostate Cancer CA90397

Stein, Cy A Orthogonal Strategies for Specific Knockout Production CA91058

Sun, Zijie TGF-Beta/Smads and Androgen Signaling in Prostate Cancer PA-99-081 CA87767

Sytkowski, Arthur J Chemopreventive Action of Human Selenium Binding Protein PAR-00-025 CA96047

Tang, Dean Mitochondria Signaled Apoptosis in Prostate Cancer Cells CA90297

Thibodeau, Stephen Genetic Susceptibility in Prostate Cancer PAR-99-167 CA91956-Sub-01

Tsai, Ming-Jer Project 7: Endocrinology and the Role of Stroma Genes in Prostate 

Cancer PAR-00-087 CA58204-Sub-07

Veltri, Robert Methylation Specific PCR for Cancer Diagnosis/Prognosis CA90007

Wakefield, Lalage M Epithelial Homeostasis and Tumorigenesis in TGF-Compromised

Mouse Models BC05785

Walden, Paul BTG2 Antiproliferative Gene and Prostate Cancer CA84441

Wang, Bing-Cheng EphA2 Agonists as Novel Inhibitors of Tumor Progression PA-99-081 CA92259

Wang, Jean Nuclear Function of the cABL Protooncoprotein CA43054

Wang, Zhou Project 2: Suppressive Role of Androgen-Response 

Gene Calreticulin in Prostate Cancer PAR-99-167 CA90386-Sub-02

Watabe, Kounosuke Tumor Metastasis Suppressor Gene on Human Chromosome 16 CA79473

Waterman, Marian Activities of Beta Catenin and LEF/TCF Complexes CA83982

Weber, Michael Cell Signaling in Prostate Cancer Progression CA76465

Wheeler, Thomas Project 1: Markers of Progression and Metastasis PAR-00-087 CA58204-Sub-01

Yamamoto,

Fumiichiro Technology to Detect Genome Wide DNA Methylation Changes PAR-99-100 CA84704

Yamamoto, Keith Project 1: Mechanisms of Hormone Resistance in Prostate Cancer PAR-99-167 CA89520-Sub-01

Yung, Wai-Kwan 10q Tumor Suppressor Gene CA56041

Zhou, Ming-Ming Structure/Function of the MAPK Phosphatase—PAC1 CA80938

Table B-9 (cont.)
NATIONAL CANCER INSTITUTE

B-22

Appendix B NCI-Supported Research Projects Relevant to Prostate Cancer That Were Active in 2002

Principal

Investigator Title RFA or PA Project ID

Ambs, Stefan Identification of Allele Variant Genes That Are Risk Factors for

Human Breast and Prostate Cancer BC10439

Barany, Francis Identifying Genome Changes in Cancer Development CA81467

Cooney, Kathleen Project 3: Hereditary Prostate Cancer in African American Families CA-94-031 CA69568-Sub-03

Couch, Fergus p21 Induction by BRCA2 CA78878

Everson, Richard Receptor Gene Polymorphisms in Prostate Cancer CA81240

Giusti, Ruthann Israeli Prostate Cancer CP10144-Sub-08185

Green, Jeffrey E Transgenic Models for Prostate and Breast Cancer BC05740

Isaacs, William B Project 2: Search for Hereditary Prostate Cancer Genes Using

Linkage Analysis and Positional Cloning Approaches CA-94-031 CA58236-Sub-02

Isaacs, William B Prostate Cancer Susceptibility: The ICPCQ Study CA89600

Linehan, W Marston Molecular Genetics of Prostate Cancer SC10095

Mandal, Diptasri M Genetics of Prostate Cancer in an African American Population PA-01-021 CA97778

O’Brien, Stephen J Approaches to Gene Mapping Development and Applications BC05681

Smith, Michael W Prostate and Breast Cancer Susceptibility Genes in African

Americans and Hispanics BC05800

Stanford, Janet Molecular Predictors of Prostate Cancer Progression and Mortality PAR-00-087 CA97186-Sub-01

Thibodeau, Stephen Genetic Susceptibility in Prostate Cancer PAR-99-167 CA91956-Sub-01

Weber, Barbara University of Pennsylvania Cancer Genetics Network CA-97-004 CA78156

Table B-10

NCI Projects Supported in 2002 Addressing the PRG Priority:

How do we define genetic susceptibility of individuals to prostate cancer, and

how is such susceptibility associated with other forms of malignancies or diseases?
B-23

Appendix B NCI-Supported Research Projects Relevant to Prostate Cancer That Were Active in 2002

NATIONAL CANCER INSTITUTE

Principal

Investigator Title RFA or PA Project ID

Gann, Peter Project 5: Clinical Trial on Lycopene PAR-99-167 CA90386-Sub-05

Glazer, Robert I Structure Based Discovery of Akt Inhibitors PAR-01-045 CA95378

Gupta, Smiti NF-kB: A Marker for Cellular Oxidative Stress CA91658

Hu, Ming Absorption and Metabolism of Isoflavones CA87779

Ma, Jianjie Calcium Signaling and Cytochrome C Release in Apoptosis CA95739

McVary, Kevin Project 4: Molecular Mechanisms of Neuropathic

Erectile Dysfunction PAR-99-167 CA90386-Sub-04

Piwnica-Worms,

David R Washington University Molecular Imaging Center CA-01-014 CA94056

Woods, Catherine Novel Prostate Homing Peptides as Potential Diagnostics CA92933

Table B-11

Additional Prostate Cancer Biology Projects

B-25

Appendix B NCI-Supported Research Projects Relevant to Prostate Cancer That Were Active in 2002

NATIONAL CANCER INSTITUTE

Principal

Investigator Title RFA or PA Project ID

Validation of Family History of Cancer Questionnaire PC95039

Ambs, Stefan Identification of Allele Variant Genes That Are Risk Factors for 

Human Breast and Prostate Cancer BC10439

Balmain, Allan Project 5: Identification of Prostate Tumor Susceptibility Genes

Using Mouse Models for Prostate Cancer PAR-99-167 CA89520-Sub-05

Barany, Francis Identifying Genome Changes in Cancer Development CA81467

Barrack, Evelyn Androgen Receptor Variants and Prostate Cancer Etiology CA-94-028 CA68645

Bova, Steven G Project 1: Molecular Genetics of Human Prostate Cancer CA-94-031 CA58236-Sub-01

Buetow, Kenneth Molecular Genetic Epidemiology of Leading U.S. Cancers CP10140

Bunker, Clareann Molecular Epidemiology of Prostate Cancer In Tobagonians PA-99-055 CA84950

Cannon-Albright,

Lisa Mapping and Cloning Prostate Cancer Predisposition Loci PA-00-080 CA90752

Chen, Chu Endogenous Sex Hormones, Genetics, and Prostate Cancer PA-95-084 CA78812

Chinault, Craig Project 3: Physical and Functional Analysis of Prostate Cancer Genes PAR-00-087 CA58204-Sub-03

Church, Timothy Molecular Epidemiology of Prostate Carcinogenesis PA-95-084 CA74103

Coetzee, Gerhard Androgen Receptor and Prostate Cancer Risk in Chinese PA-99-055 CA84890

Cooney, Kathleen Genetic Analysis of Hereditary Prostate Cancer Families CA79596

Cooney, Kathleen Project 3: Hereditary Prostate Cancer in African American Families CA-94-031 CA69568-Sub-03

Demarzo, Angelo Inflammation and Atrophy in Prostate Carcinogenesis PA-99-055 CA84997

Everson, Richard Polymorphisms in Prostate Cancer Carcinogenesis PA-99-055 CA84989

Figg, William D Development of Angiogenesis Inhibitors Using Prostate Cancer 

as a Tumor Model SC06538

Figg, William D Identify SNPs and Polymorphisms That Are Important in the 

Development of Prostate Cancer BC10453

Geliebter, Jan Gene Expression in Diet Induced Prostate Cancer PA-99-081 CA88982

Giovannucci,

Edward Diet and Genetic Interactions in Prostate Cancer CA76622

Giovannucci,

Edward Nutritional and Hormonal Biomarkers in Prostate Cancer CA72036

Giusti, Ruthann BRCA Prostate Cancer Intervention Study CP10144-Sub-07035

Giusti, Ruthann Israeli Prostate Cancer CP10144-Sub-08185

Golub, Todd Genomic Expression Analysis of Tumors after Radical Prostatectomy PAR-99-167 CA90381-Sub-04

Greene, Mark H Clinical and Genetic Studies of Familial and Hereditary Cancer 

Syndromes CP10144

FY 2002 Etiology and Prevention Projects

Table B-12

NCI Projects Supported in 2002 Addressing the PRG Priority:

What genes are important in the etiology of prostate cancer?

What fraction of familial prostate cancer is monogenic with Mendelian

inheritance of susceptibility alleles? What is the function of such genes?
NATIONAL CANCER INSTITUTE

B-26

Appendix B NCI-Supported Research Projects Relevant to Prostate Cancer That Were Active in 2002

Principal

Investigator Title RFA or PA Project ID

Harris, C Molecular Epidemiology of Human Cancer BC05480

Hayes, Richard Prostate Cancer in the PLCO Trial CP10152-Sub-10003

Hein, David Pharmacogenetics of Drug and Carcinogen Metabolism PA-95-084 CA34627

Helzlsouer, Kathy Epidemiology of Prostate Cancer—ODC and AR Genotypes CA88180

Ho, Shuk-Mei Metallothionein and Cadmium Carcinogenesis in Rat Prostate CA62269

Project 8: Down Regulation of Metastasis Suppressor Genes as 

Isaacs, John T Diagnostic Methods for Predicting the Biologic Behavior of CA-94-031 CA58236-Sub-08

Histologically Detectable Prostate Cancer

Isaacs, William B Project 2: Search for Hereditary Prostate Cancer Genes

Using Linkage Analysis and Positional Cloning Approaches CA-94-031 CA58236-Sub-02

Isaacs, William B Prostate Cancer Susceptibility: The ICPCQ Study CA89600

Jay, Gilbert Large Scale Gene Discovery—Human Prostate Cancer CA81900

Koff, Andrew p27Kip1 Expression, a Prognostic Indicator—But Why? CA89563

Lee, Byungkook Molecular Modeling and Bioinformatics BC08759

Mandal, Diptasri M Genetics of Prostate Cancer in an African American Population PA-01-021 CA97778

McDonnell, Timothy Project 3: Therapeutic Modulation of Apoptosis in Prostate

Cancer Patients PAR-99-167 CA90270-Sub-03

Meyskens, Frank Chemoprevention of Familial Prostate Cancer CA-98-012 CA81886

Montie, James Project 2: Epidemiology of Prostate Cancer in African Americans CA-94-031 CA69568-Sub-02

Nelson, William Project 12: Rational Prostate Cancer Prevention Studies CA-94-031 CA58236-Sub-12

O’Brien, Stephen J Approaches to Gene Mapping Development and Applications BC05681

Ostrander, Elaine Genetics of Prostate Cancer Susceptibility CA78836

Pandolfi, Pier Paolo Molecular Analysis of Carcinogenesis in the Mouse and 

Human Prostate PAR-99-167 CA92629-Sub-02

Rangnekar, Vivek Mechanism of Apoptosis by Par4 PA-99-081 CA60872

Rebbeck, Timothy Molecular Epidemiology of Prostate Cancer PA-99-055 CA85074

Reichardt, Juergen 5 Alpha Reductase Genotype, Race Prostate Cancer Risk PA-95-084 CA68581

Rosen, Eliot Role of BRCA1 as a Human Prostate Suppressor Gene CA80000

Sellers, William Single Nucleotide Repeat Polymorphism Analysis of Recurrent

Prostate Cancer after Radiation Therapy PAR-99-167 CA90381-Sub-03

Smith, Michael W High-Throughput Genotyping for Genetic Analysis BC10270

Stampfer, Meir Dietary and Biochemical Markers of Prostate Cancer Risk CA58684

Stanford, Janet Genetic Epidemiology of Prostate Cancer CA80122

Stanford, Janet Genetic Polymorphisms and Prostate Cancer Risk CA82664

Stanford, Janet Molecular Predictors of Prostate Cancer Progression and Mortality PAR-00-087 CA97186-Sub-01

Table B-12 (cont.)
B-27

Appendix B NCI-Supported Research Projects Relevant to Prostate Cancer That Were Active in 2002

NATIONAL CANCER INSTITUTE

Principal

Investigator Title RFA or PA Project ID

Strom, Sara Project 5: Clinical, Epidemiological, and Molecular Markers of 

Prostate Cancer Progression PAR-99-167 CA90270-Sub-05

Strom, Sara Prostate Cancer in Mexican Americans and African American PA-99-055 CA84964

Thibodeau, Stephen Genetic Susceptibility in Prostate Cancer PAR-99-167 CA91956-Sub-01

Thibodeau, Stephen Localization of Susceptibility Loci in Prostate Cancer CA72818

Thompson, Patricia Beta 2 Adrenergic Receptors and Prostate Cancer Risk PAR-98-023 CA88299

Ware, Joy Mechanisms of Prostate Epithelial Cell Transformation CA58126

Weber, Barbara University of Pennsylvania Cancer Genetics Network CA-97-004 CA78156

Weiss, Noel Androgen Pathway and Genetic Risk of Prostate Cancer PAR-98-023 CA92706

Weiss, Noel IGF-I Levels, IGF-I Genotype, and Prostate Cancer PA-99-055 CA85064

White, Raymond Rocky Mountain Cancer Genetics Coalition CA-97-004 CA78174

Whittemore, Alice Genetic Epidemiology of Prostate Cancer CA67044

Willett, Walter Prospective Studies of Diet and Cancer in Men and Women CA55075

Witte, John Genetic Epidemiology of Prostate Cancer Aggressiveness PA-99-055 CA88164

Witte, John S Androgen Pathway Factors and Prostate Cancer PA-00-080 CA94211

Zhao, Yingming Identification of Prostate and Ovarian Cancer Markers CA-98-028 CA85146

Table B-12 (cont.)
NATIONAL CANCER INSTITUTE

B-28

Appendix B NCI-Supported Research Projects Relevant to Prostate Cancer That Were Active in 2002

Principal

Investigator Title RFA or PA Project ID

Albanes, D Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study

and Cohort Follow-Up SC00100

Albanes, Demetrius ATBC Study CP10127-Sub-03031

Aronson, William The Role of Quantity and Composition of Dietary Fat in the

Prevention of Prostate Cancer PAR-99-167 CA92131-Sub-05

Bergan, Raymond C Molecular Correlates of Soy in Humans PA-00-047 CA99263

Bosland, Maarten Preclinical Prostate Cancer Chemoprevention Studies CA76426

Brown, Linda Morris PHS Black/White Study CP10113-Sub-00430

Church, Timothy Molecular Epidemiology of Prostate Carcinogenesis PA-95-084 CA74103

Coltman, Charles Selenium Based Chemoprevention CA-98-001 CA77178

Deluca, L Retinoids in Differentiation and Neoplasia BC04798

Demark-Wahnefried,

Wendy Prostate Cancer: Impact of Fat and Flaxseed Modified Diet CA85740

Felton, James S Carcinogenic Significance of Heterocyclic Amines CA55861

Fraser, Gary Cancer Epidemiology in Adventists—A Low Risk Group CA94594

Gann, Peter Project 5: Clinical Trial on Lycopene PAR-99-167 CA90386-Sub-05

Gann, Peter H Effects of Lycopene on High-Risk Prostatic Tissue PA-00-080 CA90759

Gapstur, Susan Determinants of Steroid Hormones in Black and White Men CA77704

Gaziano, Michael J Physicians Health Study II: Prevention Trial of Vitamins CA97193

Geliebter, Jan Gene Expression in Diet Induced Prostate Cancer PA-99-081 CA88982

Giovannucci,

Edward Diet and Genetic Interactions in Prostate Cancer CA76622

Giovannucci,

Edward Nutritional and Hormonal Biomarkers in Prostate Cancer CA72036

Gladyshev, Vadim Selenoprotein as a Target for Cancer Prevention CA80946

Gupta, Sanjay Inhibition of Prostate Carcinogenesis by Apigenin PAR-00-025 CA99049

Gupta, Sanjay Prostate Cancer Chemoprevention by Apigenin PAR-00-025 CA94248

Guttenplan, Joseph Antimutagenesis by Lycopene and Selenium in Lac Rodents CA76281

Hatfield, Dolph L Role of Selenium in Cancer and Human Health BC05317

Ho, Shuk-Mei Metallothionein and Cadmium Carcinogenesis in Rat Prostate CA62269

Hsing, Ann Pilot Study of Prostate Cancer in Africa CP10180-Sub-01130

Hsing, Ann Shanghai Prostate Cancer Study CP10180-Sub-01140

Hu, Ming Absorption and Metabolism of Isoflavones CA87779

Ingles, Sue Risk Factors for Advanced Prostate Cancer PA-99-055 CA84979

Table B-13

NCI Projects Supported in 2002 Addressing the PRG Priority:

Which dietary nutrients affect risk of prostate cancer

(e.g., fat, phytoestrogens, and micronutrients)?

What are the mechanisms by which these nutrients alter risk?
B-29

Appendix B NCI-Supported Research Projects Relevant to Prostate Cancer That Were Active in 2002

NATIONAL CANCER INSTITUTE

Principal

Investigator Title RFA or PA Project ID

Kim, Jeri A Feasibility Study of L-Selenomethionine and Alpha-Tocopherol PA-99-070 CA88761

Kolonel, Laurence Multiethnic/Minority Cohort Study of Diet and Cancer CA54281

Lewis, Kevin C Systems-Based Modeling of Retinoid—Drug Interactions BC00162

Liao, Shutsung Molecular Mechanisms of Growth Control—Prostate Cancer CA58073

Lin, Young C Chemopreventive Effects of Dietary Cottonseed Oil PAR-00-025 CA95915

Marshall, James Nutritional Prevention of Cancer CA49764

Marshall, James Phase II Chemoprevention Trial of SE and Prostate Cancer CA79080

Marshall, James Phase III Trial of Selenium for Prostate Cancer Prevention CA77789

Mukhtar, Hasan Cancer Chemopreventive Mechanisms of Green Tea CA78809

Nomura, Abraham Cancer Sero Epidemiology among the Japanese in Hawaii CA33644

Pinto, John T Allium Compounds in Control of Human Prostate Cancer CA89815

Rice, Lori Dietary Isoflavone Regulated Genes in Prostate Cancer PAR-00-025 CA91231

Sinha, Rashmi Genetic, Dietary, and Hormonal Risk Factors in Breast and

Prostate Cancer (GEM) CP10127-Sub-03060

Sporn, Michael New Triterpenoids for Chemoprevention of Cancer PAR-01-046 CA78814

Stampfer, Meir Dietary and Biochemical Markers of Prostate Cancer Risk CA58684

Stampfer, Meir Nutritional and Biochemical/Genetic Markers of Cancer CA42182

Sytkowski, Arthur J Chemopreventive Action of Human Selenium Binding Protein PAR-00-025 CA96047

Van Breemen,

Richard Prevention of DNA Oxidation by Tocopherol and Carotenoids CA70771

Weigel, Nancy Inhibition of Prostate Cancer Cell Growth by Vitamin D CA75337

White, Emily Cohort Study of Dietary Supplements and Cancer Risk CA74846

Whittemore, Alice Cancer Epidemiology and Biostatistics CA47448

Willett, Walter Prospective Studies of Diet and Cancer in Men and Women CA55075

Witte, John S Androgen Pathway Factors and Prostate Cancer PA-00-080 CA94211

Young, Charles Y Growth Control of Prostate Cancer Cells by Plant Phenols PA-99-081 CA88900

Zhou, Jin-Rong Dietary Soybean Components’ Effect on Prostate Cancer Progression CA78521

Ziegler, Regina G Blood Micronutrients, Fatty Acids, and Prostate Cancer 

(U.S. Black/White Study) CP10169-Sub-03033

Ziegler, Regina G Nutritional and Metabolic Determinants of Cancer CP10169

Ziegler, Regina G NHANES Follow-Up Study CP10169-Sub-03210

Table B-13 (cont.)
NATIONAL CANCER INSTITUTE

B-30

Appendix B NCI-Supported Research Projects Relevant to Prostate Cancer That Were Active in 2002

Principal

Investigator Title RFA or PA Project ID

Ahmad, Nihal Chemoprevention of Prostate Cancer by Sanguinarine PAR-00-025 CA89723

Alavanja, Michael Prospective Study of Farmers and Their Families (Agricultural Health Study) CP10119-Sub-02020

Blair, Aaron Selected Cancers, Serum Organochlorines in the Norwegian JANUS Cohort CP10120-Sub-02135

Blair, Aaron Occupation and Cancer Risk in Sweden: The Cancer Environment Registry CP10120-Sub-44-95-03

Chen, Chu Endogenous Sex Hormones, Genetics, and Prostate Cancer PA-95-084 CA78812

Church, Timothy Molecular Epidemiology of Prostate Carcinogenesis PA-95-084 CA74103

Deluca, L Retinoids in Differentiation and Neoplasia BC04798

DeWeese, Theodore Project 14: Determinants of Radiosensitivity in Prostate Cancer CA-94-031 CA58236-Sub-14

Dosemeci, Mustafa Occupational Exposures and Cancer Risk in Turkey CP10120-Sub-02366

Eisen, Ellen A Prostate Cancer Morbidity and Metal Working Fluids PA-01-021 CA99514

Gail, Mitchell Record-Linkage Studies of Cancer CP10105

Gapstur, Susan Determinants of Steroid Hormones in Black and White Men CA77704

Goedert, James Epidemiology and Natural History of Cancer-Associated Viruses CP10176

Goedert, James PCA—Prostate Cancer Study CP10176-Sub-05624

Haase, Ashley Trans and Pathog of KS-Associated Herpesvirus Infection CA75172

Hayes, Richard Prostate Cancer in the PLCO Trial CP10152-Sub-10003

Hoover, Robert Early Life Exposures and Subsequent Cancer Risk CP10168

Hsing, Ann Pilot Study of Prostate Cancer in Africa CP10180-Sub-01130

Hsing, Ann Shanghai Prostate Cancer Study CP10180-Sub-01140

Kash, Kathryn Behavioral Aspects of Familial Risk for Prostate Cancer PA-97-055 CA86826

Land, Charles Cancer Risk among Japanese A-Bomb Survivors CP10134-Sub-04016

Lubin, Jay H Studies of Environmental and Occupational Exposures CP10113

Mukhtar, Hasan Prostate Cancer Chemoprevention by Cox 2 Inhibition PAR-00-025 CA89739

Ron, Elaine Studies of Medical Radiation and Other Therapeutic Agents CP10131

Ron, Elaine Studies of Populations Exposed to Occupational Sources of Radiation CP10133

Sinha, Rashmi Genetic, Dietary, and Hormonal Risk Factors in Breast and 

Prostate Cancer (GEM) CP10127-Sub-03060

Skelton, Timothy Decoding Cancer Signature Glycoforms of Serum Tumor Mark PAR-00-025 CA89730

Stanford, Janet NSAIDs and Other Medications in Prostate Cancer Etiology PA-00-080 CA92579

Stanford, Janet L Oncogenic Human Papillomaviruses and Prostate Cancer Risk PAR-98-023 CA92777

Tarone, Robert Consulting and Collaboration on Epidemiologic Studies CP10118

Waalkes, Michael P Mechanisms of Inorganic Carcinogenesis BC05488

Whittemore, Alice Cancer Epidemiology and Biostatistics CA47448

Yeh, Grace Chao Dietary Regulation of Biochemical/Molecular Changes in

Carcinogen Resistant Cells BC00189

Table B-14

NCI Projects Supported in 2002 Addressing the PRG Priority:

What other exogenous risk factors are involved in prostate cancer

(e.g., viral, exercise, vasectomy, and sexual factors)?
B-31

Appendix B NCI-Supported Research Projects Relevant to Prostate Cancer That Were Active in 2002

NATIONAL CANCER INSTITUTE

Principal

Investigator Title RFA or PA Project ID

Barrack, Evelyn R Project 3: Androgen Receptor Gene Structure and Function in 

Human Prostate Cancer CA-94-031 CA58236-Sub-03

Bova, G Modes of Prostate Cancer Progression—Role of p53 Pathway PA-99-081 CA92234

Brown, Linda Morris PHS Black/White Study CP10113-Sub-00430

Chen, Chu Endogenous Sex Hormones, Genetics, and Prostate Cancer PA-95-084 CA78812

Cooney, Kathleen Project 3: Hereditary Prostate Cancer in African American Families CA-94-031 CA69568-Sub-03

Demarzo, Angelo Inflammation and Atrophy in Prostate Carcinogenesis PA-99-055 CA84997

Eisen, Ellen A Prostate Cancer Morbidity and Metal Working Fluids PA-01-021 CA99514

Erwin, Deborah Arkansas Special Populations Access Network (A-Span) CA-99-003 CA86081

Etzioni, Ruth PSA Screening and U.S. Prostate Cancer Trends CA-99-013 CA88160

Everson, Richard Polymorphisms in Prostate Cancer Carcinogenesis PA-99-055 CA84989

Everson, Richard Receptor Gene Polymorphisms in Prostate Cancer CA81240

Figg, William D Development of Angiogenesis Inhibitors Using Prostate Cancer as

a Tumor Model SC06538

Fraser, Gary Cancer Epidemiology in Adventists—A Low Risk Group CA94594

Gany, Francesca Cancer Awareness Network for Immigrant Minority Populations CA86286

Giovannucci, Genetic and Serologic Determinants of Prostate Cancer Risk 

Edward and Progression PAR-99-167 CA90381-Sub-01

Hayes, Richard South Carolina Older Men’s Health Project CP10136-Sub-02317

Hsing, Ann Pilot Study of Prostate Cancer in Africa CP10180-Sub-01130

Hsing, Ann Shanghai Prostate Cancer Study CP10180-Sub-01140

Jensen, Ronald Feasibility of New Prostate Cancer Molecular Genetic Techniques CA81625

Kash, Kathryn Behavioral Aspects of Familial Risk for Prostate Cancer PA-97-055 CA86826

Kolonel, Laurence Multiethnic/Minority Cohort Study of Diet and Cancer CA54281

Mandal, Diptasri M Genetics of Prostate Cancer in an African American Population PA-01-021 CA97778

Mohler, James Prostate Cancer: Transition to Androgen-Independence CA77739

Montie, James Project 2: Epidemiology of Prostate Cancer in African Americans CA-94-031 CA69568-Sub-02

Myers, Ronald Increasing Access to Clinical and Educational Studies CA-99-003 CA86084

Ramirez, Amelie Redes En Accion—Cancer Awareness, Training, and Research CA-99-003 CA86117

Rebbeck, Timothy Molecular Epidemiology of Prostate Cancer PA-99-055 CA85074

Reichardt, Juergen 5 Alpha Reductase Genotype, Race Prostate Cancer Risk PA-95-084 CA68581

Rice, Lori Dietary Isoflavone Regulated Genes in Prostate Cancer PAR-00-025 CA91231

Smith, Michael W High-Throughput Genotyping for Genetic Analysis BC10270

Table B-15

NCI Projects Supported in 2002 Addressing the PRG Priority:

Which genetic and exogenous risk factors account for differences

in incidence and mortality among African American, Caucasian,

Hispanic, and Asian American populations?
NATIONAL CANCER INSTITUTE

B-32

Appendix B NCI-Supported Research Projects Relevant to Prostate Cancer That Were Active in 2002

Principal

Investigator Title RFA or PA Project ID

Smith, Michael W Prostate and Breast Cancer Susceptibility Genes in African 

Americans and Hispanics BC05800

Strom, Sara Project 5: Clinical, Epidemiological, and Molecular Markers of 

Prostate Cancer Progression PAR-99-167 CA90270-Sub-05

Strom, Sara Prostate Cancer in Mexican Americans and African Americans PA-99-055 CA84964

Sullivan, Louis National Black Leadership Cancer Control Research and Training 

Network CA-99-003 CA86274

Thompson, Ian San Antonio Center of Biomarkers of Risk for Prostate Cancer CA-99-007 CA86402

Whittemore, Alice Genetic Epidemiology of Prostate Cancer CA67044

Young, Charles Human Kallikreins as Novel Markers of Prostate Cancer PAR-99-167 CA91956-Sub-02

Table B-15 (cont.)
B-33

Appendix B NCI-Supported Research Projects Relevant to Prostate Cancer That Were Active in 2002

NATIONAL CANCER INSTITUTE

Principal

Investigator Title RFA or PA Project ID

Ambs, Stefan Identification of Allele Variant Genes That Are Risk Factors for

Human Breast and Prostate Cancer BC10439

Balk, Steven The Androgen Receptor in Hormone Refractory Disease PAR-99-167 CA90381-Sub-05

Bova, Steven G Project 1: Molecular Genetics of Human Prostate Cancer CA-94-031 CA58236-Sub-01

Bunker, Clareann Molecular Epidemiology of Prostate Cancer in Tobagonians PA-99-055 CA84950

Chen, Chu Endogenous Sex Hormones, Genetics, and Prostate Cancer PA-95-084 CA78812

Day, Mark Project 4: Rb as a Regulator of Prostate Tumorigenesis CA-94-031 CA69568-Sub-04

Demark-Wahnefried,

Wendy Prostate Cancer: Impact of Fat and Flaxseed Modified Diet CA85740

Ellis, William Genomic and Gene Expression Profiling of Disseminated 

Prostate Cancer PAR-00-087 CA97186-Sub-02

Emmert-Buck,

Michael R Genetic Progression of Cancer SC10437

Etzioni, Ruth PSA Screening and U.S. Prostate Cancer Trends CA-99-013 CA88160

Figg, William D Development of Angiogenesis Inhibitors Using Prostate Cancer

as a Tumor Model SC06538

Figg, William D Identify SNPs and Polymorphisms That Are Important in the 

Development of Prostate Cancer BC10453

Gann, Peter Project 5: Clinical Trial on Lycopene PAR-99-167 CA90386-Sub-05

Giovannucci, Edward Genetic and Serologic Determinants of Prostate Cancer

Risk and Progression PAR-99-167 CA90381-Sub-01

Gleave, Martin Characterization of Anti-Apoptotic Genes Induced during

Androgen Independent Progression and Chemotherapy PAR-00-087 CA97186-Sub-03

Golub, Todd Genomic Expression Analysis of Tumors after Radical Prostatectomy PAR-99-167 CA90381-Sub-04

Hood, Leroy Transcriptome and Proteome Stratification of Prostate

Adenocarcinoma Phenotypes PAR-00-087 CA97186-Sub-04

Hsing, Ann GW Prostate Tissue Study CP10180-Sub-01072

Ingles, Sue Risk Factors for Advanced Prostate Cancer PA-99-055 CA84979

Jenkins, Robert Biologic and Clinical Studies of Overrepresented 8q24 Region

Associated with Prostate Cancer Progression PAR-99-167 CA91956-Sub-03

Jensen, Ronald Feasibility of New Prostate Cancer Molecular Genetic Techniques CA81625

Katten, Michael Natural History of Prostate Cancer, Prognostic Models, and

Decision Making PAR-99-167 CA92629-Sub-01

Loeb, Lawrence Oxygen Induced DNA Damage, Mutations, and Cancer CA80993

Marshall, James Phase II Chemoprevention Trial of SE and Prostate Cancer CA79080

Marshall, James Phase III Trial of Selenium for Prostate Cancer Prevention CA77789

McDonnell, Timothy Project 3: Therapeutic Modulation of Apoptosis in Prostate

Cancer Patients PAR-99-167 CA90270-Sub-03

Table B-16

NCI Projects Supported in 2002 Addressing the PRG Priority:

Are there genetic or exogenous factors associated with prostate

cancer progression, as opposed to its incidence?
NATIONAL CANCER INSTITUTE

B-34

Appendix B NCI-Supported Research Projects Relevant to Prostate Cancer That Were Active in 2002

Principal

Investigator Title RFA or PA Project ID

Reichardt, Juergen 5 Alpha Reductase Genotype, Race Prostate Cancer Risk PA-95-084 CA68581

Reiter, Robert Prostate Stem Cell Antigen (PSCA) in the Biology and

Therapy of Prostate Cancer PAR-99-167 CA92131-Sub-01

Sellers, William Single Nucleotide Repeat Polymorphism Analysis of Recurrent

Prostate Cancer after Radiation Therapy PAR-99-167 CA90381-Sub-03

Skelton, Timothy Decoding Cancer Signature Glycoforms of Serum Tumor Mark PAR-00-025 CA89730

Stanford, Jean Molecular Predictors of Prostate Cancer Progression and Mortality PAR-00-087 CA97186-Sub-01

Strom, Sara Project 5: Clinical, Epidemiological, and Molecular Markers of

Prostate Cancer Progression PAR-99-167 CA90270-Sub-05

Thibodeau, Stephen Localization of Susceptibility Loci in Prostate Cancer CA72818

Witte, John Genetic Epidemiology of Prostate Cancer Aggressiveness PA-99-055 CA88164

Woodson, Karen Gene Methylation in Prostate Cancer BC10459

Ying, Shao-Yao Novel Molecular Profiling of Prostate Cancer Signatures CA85722

Young, Charles Human Kallikreins as Novel Markers of Prostate Cancer PAR-99-167 CA91956-Sub-02

Table B-16 (cont.)
B-35

Appendix B NCI-Supported Research Projects Relevant to Prostate Cancer That Were Active in 2002

NATIONAL CANCER INSTITUTE

Principal

Investigator Title RFA or PA Project ID

Alavanja, Michael Prospective Study of Farmers and Their Families (Agricultural

Health Study) CP10119-Sub-02020

Albanes, D Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study and

Cohort Follow-Up SC00100

Balmain, Allan Project 5: Identification of Prostate Tumor Susceptibility Genes

Using Mouse Models for Prostate Cancer PAR-99-167 CA89520-Sub-05

Buetow, Kenneth Molecular Genetic Epidemiology of Leading U.S. Cancers CP10140

Bunker, Clareann Molecular Epidemiology of Prostate Cancer in Tobagonians PA-99-055 CA84950

Church, Timothy Molecular Epidemiology of Prostate Carcinogenesis PA-95-084 CA74103

Gapstur, Susan Determinants of Steroid Hormones in Black and White Men CA77704

Geliebter, Jan Gene Expression in Diet Induced Prostate Cancer PA-99-081 CA88982

Giovannucci,

Edward Diet and Genetic Interactions in Prostate Cancer CA76622

Giovannucci,

Edward Nutritional and Hormonal Biomarkers in Prostate Cancer CA72036

Hayes, Richard Prostate Cancer in the PLCO Trial CP10152-Sub-10003

Hein, David Pharmacogenetics of Drug and Carcinogen Metabolism PA-95-084 CA34627

Hsing, Ann Shanghai Prostate Cancer Study CP10180-Sub-01140

Meyskens, Frank Chemoprevention of Familial Prostate Cancer CA-98-012 CA81886

Sinha, Rashmi Genetic, Dietary, and Hormonal Risk Factors in Breast and

Prostate Cancer (GEM) CP10127-Sub-03060

Stampfer, Meir Nutritional and Biochemical/Genetic Markers of Cancer CA42182

Stanford, Janet Molecular Predictors of Prostate Cancer Progression and Mortality PAR-00-087 CA97186-Sub-01

Strom, Sara Prostate Cancer in Mexican Americans and African Americans PA-99-055 CA84964

Whittemore, Alice Cancer Epidemiology and Biostatistics CA47448

Willett, Walter Prospective Studies of Diet and Cancer in Men and Women CA55075

Witte, John S Androgen Pathway Factors and Prostate Cancer PA-00-080 CA94211

Table B-17

NCI Projects Supported in 2002 Addressing the PRG Priority:

Are there interactions between genetic predisposition and exogenous exposures?
NATIONAL CANCER INSTITUTE

B-36

Appendix B NCI-Supported Research Projects Relevant to Prostate Cancer That Were Active in 2002

Principal

Investigator Title RFA or PA Project ID

Agarwal, Rajesh Receptor Signaling, Phytic Acid, and Prostate Cancer CA83741

Ahmad, Nihal Chemoprevention of Prostate Cancer by Sanguinarine PAR-00-025 CA89723

Albanes, D Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study

and Cohort Follow-Up SC00100

Aronson, William The Role of Quantity and Composition of Dietary Fat in the

Prevention of Prostate Cancer PAR-99-167 CA92131-Sub-05

Bergan, Raymond C Molecular Correlates of Soy in Humans PA-00-047 CA99263

Bosland, Maarten Preclinical Prostate Cancer Chemoprevention Studies CA76426

Bosland, Maarten Prostate Cancer Chemoprevention Clinical Trials CA-96-001 CA72290

Coltman, Charles Selenium Based Chemoprevention CA-98-001 CA77178

Cunha, Gerald Preclinical Evaluations of Intermediate Endpoints and Their

Modulation of Chemoprevention CN15114

Demark-Wahnefried,

Wendy Prostate Cancer: Impact of Fat and Flaxseed Modified Diet CA85740

Demarzo, Angelo Inflammation and Atrophy in Prostate Carcinogenesis PA-99-055 CA84997

Ensley, Burt Selenium Enriched Plant Material for Chemoprevention CA80444

Foster, Barbara A Vitamin D Analogs for Chemoprevention of Prostate Cancer CA95367

Gann, Peter Project 5: Clinical Trial on Lycopene PAR-99-167 CA90386-Sub-05

Gann, Peter H Effects of Lycopene on High-Risk Prostatic Tissue PA-00-080 CA90759

Gaziano, Michael J Physicians Health Study II: Prevention Trial of Vitamins CA97193

Gupta, Sanjay Inhibition of Prostate Carcinogenesis by Apigenin PAR-00-025 CA99049

Gupta, Sanjay Prostate Cancer Chemoprevention by Apigenin PAR-00-025 CA94248

Gupta, Smiti NF-kB: A Marker for Cellular Oxidative Stress CA91658

Henning, Susanne Bioavailability of Tea Polyphenols in Prostate Cancer PAR-00-025 CA91163

Kennedy, Ann Screening of Chemopreventive Agents by Molecular Profiling

Using Stable Clones of CN15134

Kim, Jeri A Feasibility Study of L-Selenomethionine and Alpha-Tocopherol PA-99-070 CA88761

Lee, Chung Project 1: Clusterin as a Negative Prognostic Indicator in Prostate

Cancer PAR-99-167 CA90386-Sub-01

Lewis, Kevin C Systems-Based Modeling of Retinoid-Drug Interactions BC00162

Lin, Young C Chemopreventive Effects of Dietary Cottonseed Oil PAR-00-025 CA95915

Marshall, James Phase II Chemoprevention Trial of SE and Prostate Cancer CA79080

Marshall, James Phase III Trial of Selenium for Prostate Cancer Prevention CA77789

McCormick, David Efficacy Studies of Chemopreventive Agents in Animal Models,

WS 90 CN15110

McCormick, David Efficacy Studies of Chemopreventive Agents in Animal Models,

WS 97 CN25113

Table B-18

NCI Projects Supported in 2002 Addressing the PRG Priority:

What interventions can alter the underlying etiology of prostate cancer?

What are the most promising potential preventive agents and activities?
B-37

Appendix B NCI-Supported Research Projects Relevant to Prostate Cancer That Were Active in 2002

NATIONAL CANCER INSTITUTE

Principal

Investigator Title RFA or PA Project ID

Meyskens, Frank Chemoprevention of Familial Prostate Cancer CA-98-012 CA81886

Mueller, Elisabetta PPAR as a Target of Therapy for Prostate Cancer PAR-99-167 CA90381-Sub-02

Mukhtar, Hasan Prostate Cancer Chemoprevention by Cox 2 Inhibition PAR-00-025 CA89739

Nelson, William Project 12: Rational Prostate Cancer Prevention Studies CA-94-031 CA58236-Sub-12

Sarkar, Fazlul Molecular Mechanism of Genistein in Prostate Cancer CA83695

Sheikh, M Death Receptors in Prostate Cancer Biology and Apoptosis PA-99-081 CA89043

Weigel, Nancy Inhibition of Prostate Cancer Cell Growth by Vitamin D CA75337

Table B-18 (cont.)
NATIONAL CANCER INSTITUTE

B-38

Appendix B NCI-Supported Research Projects Relevant to Prostate Cancer That Were Active in 2002

Principal

Investigator Title RFA or PA Project ID

Bosland, Maarten Preclinical Prostate Cancer Chemoprevention Studies CA76426

Cunha, Gerald Preclinical Evaluations of Intermediate Endpoints and Their

Modulation of Chemoprevention CN15114

Gupta, Sanjay Inhibition of Prostate Carcinogenesis by Apigenin PAR-00-025 CA99049

Guttenplan, Joseph Antimutagenesis by Lycopene and Selenium in Lac Rodents CA76281

Lee, Eva Mouse Cancer Models by Regulated Inactivation of Tumor

Suppressor Genes CA-98-013 CA84241

McCormick, David Efficacy Studies of Chemopreventive Agents in Animal Models,

WS 90 CN15110

McCormick, David Efficacy Studies of Chemopreventive Agents in Animal Models,

WS 94 CN25017

McCormick, David Efficacy Studies of Chemopreventive Agents in Animal Models,

WS 97 CN25113

Mukhtar, Hasan Efficacy Testing of Selected Chemopreventive Agents in the TRAMP CN15147

Mukhtar, Hasan Prostate Cancer Chemoprevention by Cox 2 Inhibition PAR-00-025 CA89739

Nelson, William Project 12: Rational Prostate Cancer Prevention Studies CA-94-031 CA58236-Sub-12

Schwartz, Gary Calcidiol Therapy for Prostate Cancer PAR-98-023 CA85750

Young, Charles Y Growth Control of Prostate Cancer Cells by Plant Phenols PA-99-081 CA88900

Table B-19

NCI Projects Supported in 2002 Addressing the PRG Priority:

What is the potential of new animal models for testing of

potential chemopreventive agents?
B-39

Appendix B NCI-Supported Research Projects Relevant to Prostate Cancer That Were Active in 2002

NATIONAL CANCER INSTITUTE

Principal

Investigator Title RFA or PA Project ID

Devesa, Susan General Descriptive Studies CP10108

Ross, Richardus Isoflavone-Rich Pasta—Clinical and Commercial Potential CA69878

Table B-20

Additional NCI Etiology and Prevention Projects Supported in 2002

B-41

Appendix B NCI-Supported Research Projects Relevant to Prostate Cancer That Were Active in 2002

NATIONAL CANCER INSTITUTE

FY 2002 Early Detection, Diagnosis, and Prognosis Projects

Principal

Investigator Title RFA or PA Project ID

Abato, Paul Validation of Prostate Cancer Oncogenes CA96276

Aebersold, Ruedi Novel Quantitative, Comprehensive Proteomic Technology CA-01-011 CA93302

Agus, David The Role of the Her-Kinase Axis in Emergence of Androgen

Independence in Human Prostate Cancer PAR-99-167 CA92131-Sub-04

Arap, Wadih Project 4: Exploring the Molecular Diversity of Blood Vessels for

Diagnostic and Therapeutic Targeting in Prostate Cancer PAR-99-167 CA90270-Sub-04

Balk, Steven The Androgen Receptor in Hormone Refractory Disease PAR-99-167 CA90381-Sub-05

Balmain, Allan Project 5: Identification of Prostate Tumor Susceptibility Genes

Using Mouse Models for Prostate Cancer PAR-99-167 CA89520-Sub-05

Beach, Kirk Tissue Pulsatility Imaging for Cancer Detection CO07118

Beranova-Giorgianni,

Sarka Cancer Relevant Proteins in the Human Prostate Proteome PAR-00-025 CA91254

Bernardi, Richard Real-Time Ultrasonic Tissue Imaging for Prostate Cancer CA78097

Bhujwalla, Zaver Functional Imaging of the Metastatic Phenotype CA73850

Blasberg, Ronald MSKCC Center for In Vivo Molecular Imaging in Cancer CA-99-004 CA86438

Bova, Steven G Project 1: Molecular Genetics of Human Prostate Cancer CA-94-031 CA58236-Sub-01

Brothman, Arthur Molecular and Cytogenetic Analysis of Prostate Carcinoma CA46269

Brown, Patrick A Cancer Taxonomy Based on Gene Expression Patterns CA-98-027 CA85129

Carter, H Ballentine Project 6: Longitudinal Studies of Men with and without Prostate

Cancer CA-94-031 CA58236-Sub-06

Chakrabarti, Ratna Molecular Markers for Prostate Cancer PA-98-022 CA81329

Cheng, Leo Characterization of Prostate Cancer with HRMAS 1HMRS PA-98-022 CA80901

Christens-Barry, Project 13: New Methods to Determine Tissue Architecture

William and Chromatin Structure CA-94-031 CA58236-Sub-13

Clinthorne, Neal Compton Imaging Probe for the Prostate CA-99-015 CA88179

Coffey, Donald Project 4: Human Prostate Cancer Nuclei: Abnormalities in

Structure and the Development of New Molecular Markers CA-94-031 CA58236-Sub-04

Cohen, Pinchas Interactions between IGFBPs and Nuclear Receptors in Prostate

Cancer PAR-99-167 CA92131-Sub-03

Collins, Colin Project 2: Genomics of Prostate Cancer PAR-99-167 CA89520-Sub-02

Cuttitta, Frank Identification of Peptide Growth Factors That Regulate Human

Tumor Proliferation SC00173

Delikatny, Edward NMR Detection of Prostate Tumor Differentiation PA-98-008 CA79718

Diamandis,

Eleftherios P Human Kallikrein 4 (HK4): A New Prostatic Biomarker? PA-01-010 CA93492

Table B-21

NCI Projects Supported in 2002 Addressing the PRG Priority:

What biologic determinants, independent of stage, can provide a better

definition of the malignant phenotype, natural history, and prognosis

with various therapeutic interventions?
NATIONAL CANCER INSTITUTE

B-42

Appendix B NCI-Supported Research Projects Relevant to Prostate Cancer That Were Active in 2002

Principal

Investigator Title RFA or PA Project ID

Duerk, Jeffrey IMRI/SPECT Guided Prostate Cancer Biopsy and Therapy CA-99-015 CA88144

Ellis, William Genomic and Gene Expression Profiling of Disseminated Prostate

Cancer PAR-00-087 CA97186-Sub-02

Emmert-Buck,

Michael R Genetic Progression of Cancer SC10437

Everson, Richard Receptor Gene Polymorphisms in Prostate Cancer CA81240

Feleppa, Ernest Clinical Ultrasonic Characterization of the Prostate CA53561

Ferrari, Anna Molecular Staging of Lymph Nodes—Outcome of Prostate Cancer CA79918

Fisher, Paul Novel Prostate Cancer Gene and Monoclonal Antibody CA74468

Frangioni, John Low-Molecular Weight Ligands for Prostate Cancer CA-99-015 CA88245

Gann, Peter Project 5: Clinical Trial on Lycopene PAR-99-167 CA90386-Sub-05

Garg, Pradeep Androgen Receptor Mediated Detection of Prostate Cancer CA-99-015 CA88146

Gerald, William Molecular Classification of Prostate Cancer CA-98-027 CA84999

Giovannucci, Genetic and Serologic Determinants of Prostate Cancer

Edward Risk and Progression PAR-99-167 CA90381-Sub-01

Gleave, Martin Characterization of Anti-Apoptotic Genes Induced during

Androgen Independent Progression and Chemotherapy PAR-00-087 CA97186-Sub-03

Glinsky, Gennadi Transcriptome of Metastatic Prostate Cancer CA89827

Glode, L Molecular Markers for Prostate Cancer Detection CA81073

Golub, Todd Genomic Expression Analysis of Tumors after Radical Prostatectomy PAR-99-167 CA90381-Sub-04

Griffith, Jeffrey Prognostic Value of Telomere DNA in Prostate Biopsy PAR-99-102 CA86136

Herschman, Harvey The UCLA Center for In Vivo Imaging in Cancer Biology CA-99-004 CA86306

Hood, Leroy Transcriptome and Proteome Stratification of Prostate

Adenocarcinoma Phenotypes PAR-00-087 CA97186-Sub-04

Hricak, Hedvig Imaging in Risk Assessment of Prostate Cancer Patients CA76423

Huang, Tim High Throughput Methylation Analysis in Cancer PAR-98-067 CA84701

Project 8: Down Regulation of Metastasis Suppressor Genes as

Isaacs, John T Diagnostic Methods for Predicting the Biologic Behavior of CA-94-031 CA58236-Sub-08

Histologically Detectable Prostate Cancer

Jenkins, Robert Biologic and Clinical Studies of Overrepresented 8q24 Region

Associated with Prostate Cancer Progression PAR-99-167 CA91956-Sub-03

Jiang, Yulei Neural Network Prediction of Prostate Cancer Progression PA-01-010 CA97308

Jones, Alun Technetium and Rhenium in Nuclear Medicine CA34970

Kattan, Michael Natural History of Prostate Cancer, Prognostic Models,

and Decision Making PAR-99-167 CA92629-Sub-01

Lee, Chung Project 1: Clusterin as a Negative Prognostic Indicator in Prostate

Cancer PAR-99-167 CA90386-Sub-01

Table B-21 (cont.)
B-43

Appendix B NCI-Supported Research Projects Relevant to Prostate Cancer That Were Active in 2002

NATIONAL CANCER INSTITUTE

Principal

Investigator Title RFA or PA Project ID

Lemkin, Peter F Computer Aided Two-Dimensional Electrophoretic Gel Analysis

(GELLAB) BC08381

Linehan, W Marston Molecular Genetics of Prostate Cancer SC10095

Liotta, Lance Laser Capture Microdissection Applied to Human Pathophysiology SC09185

Livingston, David Gene Expression Analysis of Prostate and Lung Cancer CA-98-027 CA84995

Lizardi, Paul Messenger RNA Profiling by Single Molecule Counting PAR-98-067 CA81671

Ma, Haiching Prostate Cancer Chip CA97844

Malins, Donald FT-IR/GC-MS Models for Predicting Prostate Cancer CA79690

Marks, James Project 4: Antibody Gene Diversity Libraries and Phage Display to

Generate Recombinant Human Antibodies for Prostate Cancer Therapy PAR-99-167 CA89520-Sub-04

Mason, Ralph MR Measurement of Tumor pH, pO2, and Vascularity In Vivo CA79515

McDonnell, Timothy Project 3: Therapeutic Modulation of Apoptosis in Prostate Cancer

Patients PAR-99-167 CA90270-Sub-03

Mercola, Dan Characterization of Early Stage Prostate Cancer CA-98-027 CA84998

Michalopoulos,

George Molecular Reclassification of Prostatic Cancer CA-98-027 CA88110

Morton, Ronald E-Cadherin—Marker of Prostate Cancer Progression CA74290

Mueller, Elisabetta PPAR as a Target of Therapy for Prostate Cancer PAR-99-167 CA90381-Sub-02

Ophir, Jonathan Elastography: Clinical and Basic Science CA64597

Ornstein, David K Proteomic Study of Androgen Independent Prostate Cancer PA-01-010 CA93759

Pandolfi, Pier Paolo Molecular Analysis of Carcinogenesis in the Mouse and Human

Prostate PAR-99-167 CA92629-Sub-02

Parkos, Charles Phage Display and Prostate Neoplasia Progression PAR-99-102 CA91435

Pasqualini, Renata Project 2: Targeting Prostate Cancer Bone Metastasis PAR-99-167 CA90270-Sub-02

Piwnica-Worms,

David Molecular Imaging Center Planning Grant CA86251

Rao, Chandra Analysis of Circulating Cancer Cells Early in Disease PAR-99-101 CA83598

Reiter, Robert Prostate Stem Cell Antigen (PSCA) in the Biology and Therapy of

Prostate Cancer PAR-99-167 CA92131-Sub-01

Ross, Jeffrey Human RNA Binding Protein as a Cancer Marker PA-01-010 CA94082

Roy-Burman, Pradip Pathogenesis of Human Prostate Carcinomas CA59705

Sanghvi, Narendra Quantitative Imaging and Treatment with Focused Ultrasound CA83244

Sawyers, Charles Targeted Therapy of PTEN Null Prostate Cancer PAR-99-167 CA92131-Sub-02

Sellers, William Single Nucleotide Repeat Polymorphism Analysis of Recurrent

Prostate Cancer after Radiation Therapy PAR-99-167 CA90381-Sub-03

Table B-21 (cont.)
NATIONAL CANCER INSTITUTE

B-44

Appendix B NCI-Supported Research Projects Relevant to Prostate Cancer That Were Active in 2002

Principal

Investigator Title RFA or PA Project ID

Shreve, Paul C11 Acetate PET Imaging of Prostate and Renal Cancer CA89448

Skelton, Timothy Decoding Cancer Signature Glycoforms of Serum Tumor Mark PAR-00-025 CA89730

Smith, Steven DNA Methylation in Early Detection of Prostate Cancer PAR-00-025 CA91234

Soff, Gerald Project 3: Generation of, and Angiostatin Levels in, Prostate Cancer PAR-99-167 CA90386-Sub-03

Stampfer, Meir J Growth Factors and Prostate Cancer Risk CA90598

Strom, Sara Project 5: Clinical, Epidemiological, and Molecular Markers of

Prostate Cancer Progression PAR-99-167 CA90270-Sub-05

Thomas, Richard Flow Cytometry of Nuclear Volume/Tumor Marker Expression CA88530

Uhr, Jonathan Early Detection/Characterization of Tumor Cells in Blood CA78303

Van Dort, Marcian Novel Radiotracers for Androgen Receptor Imaging CA77287

Vigneron, Daniel Metabolic Imaging of the Prostate Using 3D MRSI CA59897

Volkert, Wynn Center for Single Photo Emitting Cancer Imaging Agents CA-99-002 CA86290

Wang, Zhou Project 2: Suppressive Role of Androgen-Response Gene

Calreticulin in Prostate Cancer PAR-99-167 CA90386-Sub-02

Welch, Michael Research Resource in Radionuclide Research CA86307

Wheeler, Thomas Project 1: Markers of Progression and Metastasis PAR-00-087 CA58204-Sub-01

Windle, Bradford hTERT Expression as a Marker for Early Cancer Detection PA-98-022 CA90240

Xu, Jiangchun Novel Markers for Prostate Cancer Diagnosis/Prognosis CA80518

Yamamoto, Keith Project 1: Mechanisms of Hormone Resistance in Prostate Cancer PAR-99-167 CA89520-Sub-01

Yang, Catherine Proteolytic Activity of Prostate Specific Antigen CA89162

Ying, Shao-Yao Novel Molecular Profiling of Prostate Cancer Signatures CA85722

Young, Charles Human Kallikreins as Novel Markers of Prostate Cancer PAR-99-167 CA91956-Sub-02

Young, Charles Novel Markers for Prostate Cancer CA70892

Zagzebski, James Accurate In Vivo Ultrasonic Scattering Assessments CA39224

Zhao, Yingming Identification of Prostate and Ovarian Cancer Markers CA-98-028 CA85146

Table B-21 (cont.)
B-45

Appendix B NCI-Supported Research Projects Relevant to Prostate Cancer That Were Active in 2002

NATIONAL CANCER INSTITUTE

Principal

Investigator Title RFA or PA Project ID

Aronson, William The Role of Quantity and Composition of Dietary Fat in the

Prevention of Prostate Cancer PAR-99-167 CA92131-Sub-05

Balk, Steven The Androgen Receptor in Hormone Refractory Disease PAR-99-167 CA90381-Sub-05

Beach, Kirk Tissue Pulsatility Imaging for Cancer Detection CO07118

Brown, Patrick A Cancer Taxonomy Based on Gene Expression Patterns CA-98-027 CA85129

Carter, H Ballentine Project 6: Longitudinal Studies of Men with and without Prostate Cancer CA-94-031 CA58236-Sub-06

Ellis, William Genomic and Gene Expression Profiling of Disseminated Prostate Cancer PAR-00-087 CA97186-Sub-02

El-Zein, Randa Molecular Biomarkers for Prostate Cancer Susceptibility CA88301

Etzioni, Ruth Statistical Methods for Prostate Cancer Research CA70227

Gann, Peter Project 5: Clinical Trial on Lycopene PAR-99-167 CA90386-Sub-05

Giovannucci, Genetic and Serologic Determinants of Prostate Cancer Risk and

Edward Progression PAR-99-167 CA90381-Sub-01

Golub, Todd Genomic Expression Analysis of Tumors after Radical Prostatectomy PAR-99-167 CA90381-Sub-04

Griffith, Jeffrey Prognostic Value of Telomere DNA in Prostate Biopsy PAR-99-102 CA86136

Hood, Leroy Transcriptome and Proteome Stratification of Prostate

Adenocarcinoma Phenotypes PAR-00-087 CA97186-Sub-04

Jenkins, Robert Biologic and Clinical Studies of Overrepresented 8q24 Region

Associated with Prostate Cancer Progression PAR-99-167 CA91956-Sub-03

Kattan, Michael Natural History of Prostate Cancer, Prognostic Models, and

Decision Making PAR-99-167 CA92629-Sub-01

Kung, Hsing-Jien ErbB Kinase Activation and Transformation CA39207

Lee, Chung Project 1: Clusterin as a Negative Prognostic Indicator in Prostate Cancer PAR-99-167 CA90386-Sub-01

McDonnell, Timothy Project 3: Therapeutic Modulation of Apoptosis in Prostate Cancer

Patients PAR-99-167 CA90270-Sub-03

Mercola, Dan Characterization of Early Stage Prostate Cancer CA-98-027 CA84998

Michalopoulos,

George Molecular Reclassification of Prostatic Cancer CA-98-027 CA88110

Mueller, Elisabetta PPAR as a Target of Therapy for Prostate Cancer PAR-99-167 CA90381-Sub-02

Pandolfi, Pier Paolo Molecular Analysis of Carcinogenesis in the Mouse and Human

Prostate PAR-99-167 CA92629-Sub-02

Sawyers, Charles Targeted Therapy of PTEN Null Prostate Cancer PAR-99-167 CA92131-Sub-02

Sellers, William Single Nucleotide Repeat Polymorphism Analysis of Recurrent

Prostate Cancer after Radiation Therapy PAR-99-167 CA90381-Sub-03

Soff, Gerald Project 3: Generation of, and Angiostatin Levels in, Prostate Cancer PAR-99-167 CA90386-Sub-03

Stanford, Jean Molecular Predictors of Prostate Cancer Progression and Mortality PAR-00-087 CA97186-Sub-01

Stein, Cy A Orthogonal Strategies for Specific Knockout Production CA91058

Young, Charles Human Kallikreins as Novel Markers of Prostate Cancer PAR-99-167 CA91956-Sub-02

Young, Charles Novel Markers for Prostate Cancer CA70892

Table B-22

NCI Projects Supported in 2002 Addressing the PRG Priority:

How should prognostic markers be validated?
NATIONAL CANCER INSTITUTE

B-46

Appendix B NCI-Supported Research Projects Relevant to Prostate Cancer That Were Active in 2002

Principal

Investigator Title RFA or PA Project ID

Beach, Kirk Tissue Pulsatility Imaging for Cancer Detection CO07118

Brown, Patrick A Cancer Taxonomy Based on Gene Expression Patterns CA-98-027 CA85129

Chakrabarti, Ratna Molecular Markers for Prostate Cancer PA-98-022 CA81329

Cheng, Leo Characterization of Prostate Cancer with HRMAS 1HMRS PA-98-022 CA80901

Fisher, Paul Novel Prostate Cancer Gene and Monoclonal Antibody CA74468

Giovannucci, Genetic and Serologic Determinants of Prostate Cancer Risk

Edward and Progression PAR-99-167 CA90381-Sub-01

Glode, L Molecular Markers for Prostate Cancer Detection CA81073

Heeb, Mary Forms of Prostate Specific Antigen and HK2 in Cancer CA59979

Jenkins, Robert Biologic and Clinical Studies of Overrepresented 8q24 Region 

Associated with Prostate Cancer Progression PAR-99-167 CA91956-Sub-03

Kung, Hsing-Jien ErbB Kinase Activation and Transformation CA39207

Mason, Ralph MR Measurement of Tumor pH, pO2, and Vascularity In Vivo CA79515

McDonnell, Timothy Project 3: Therapeutic Modulation of Apoptosis in Prostate

Cancer Patients PAR-99-167 CA90270-Sub-03

Mercola, Dan Characterization of Early Stage Prostate Cancer CA-98-027 CA84998

Michalopoulos,

George Molecular Reclassification of Prostatic Cancer CA-98-027 CA88110

Morton, Ronald E-Cadherin—Marker of Prostate Cancer Progression CA74290

Pretlow, Thomas Cytogenetics and Biochemistry of Prostate Cancer CA57179

Thomas, Richard Flow Cytometry of Nuclear Volume/Tumor Marker Expression CA88530

Uhr, Jonathan Early Detection/Characterization of Tumor Cells in Blood CA78303

Windle, Bradford hTERT Expression as a Marker for Early Cancer Detection PA-98-022 CA90240

Table B-23

NCI Projects Supported in 2002 Addressing the PRG Priority:

What biologic determinants characterize the growth rate and/or

tumor-doubling time during the progression of prostate cancer?
B-47

Appendix B NCI-Supported Research Projects Relevant to Prostate Cancer That Were Active in 2002

NATIONAL CANCER INSTITUTE

Principal

Investigator Title RFA or PA Project ID

Beach, Kirk Tissue Pulsatility Imaging for Cancer Detection CO07118

Etzioni, Ruth PSA Screening and U.S. Prostate Cancer Trends CA-99-013 CA88160

Griffith, Jeffrey Prognostic Value of Telomere DNA in Prostate Biopsy PAR-99-102 CA86136

Kattan, Michael Natural History of Prostate Cancer, Prognostic Models, and

Decision Making PAR-99-167 CA92629-Sub-01

Morton, Ronald E-Cadherin—Marker of Prostate Cancer Progression CA74290

Rhoads, George PSA Screening and Prostate Cancer Mortality CA71734

Tsodikov, Alexander Survival Effects of Prostate Cancer Surveillance CA-02-010 CA97414

Young, Charles Novel Markers for Prostate Cancer CA70892

Table B-24

NCI Projects Supported in 2002 Addressing the PRG Priority:

Does early detection change mortality from prostate cancer?
NATIONAL CANCER INSTITUTE

B-48

Appendix B NCI-Supported Research Projects Relevant to Prostate Cancer That Were Active in 2002

Principal

Investigator Title RFA or PA Project ID

Etzioni, Ruth PSA Screening and U.S. Prostate Cancer Trends CA-99-013 CA88160

Rhoads, George PSA Screening and Prostate Cancer Mortality CA71734

Table B-25

NCI Projects Supported in 2002 Addressing the PRG Priority:

What are the effects of early detection on morbidity and quality of life?
B-49

Appendix B NCI-Supported Research Projects Relevant to Prostate Cancer That Were Active in 2002

NATIONAL CANCER INSTITUTE

Principal

Investigator Title RFA or PA Project ID

Alam, Sheikh Diagnostic Freehand Elastographic Imaging of Cancer PA-98-008 CA84274

Chance, Britton 2 and 3D Imaging of Contrast Agents in Animal Models CA72895

Degrado, Timothy R Automated Synthesis of F-18 Fluorocholine PAR-00-090 CA94387

Difilippo, Frank Improved Medium-Energy and High-Energy SPECT CA88373

Frederickson,

Christopher J Zinc-Based Diagnostic for Prostate Cancer CA96354

Gambhir, Sanjiv UCLA Imaging Resource for Mouse Cancer Models CA-01-012 CA92865

Giusti, Ruthann Israeli Prostate Cancer CP10144-Sub-08185

Gmitro, Arthur F Confocal Microendoscope for In Vivo Molecular Imaging PAR-00-089 CA94287

Gunter, Donald Prostate Gamma Probe CA90149

Haas, Gabriel P Postmortem PSA: Role in Epidemiology of Prostate Cancer PA-01-021 CA97751

Hainfeld, James F Improved MRI Contrast Agents CA94495

Henrichs, P Mark Optoacoustic Rectal Probe for Prostate Cancer Imaging CA96153

Kurhanewicz, John Improved MRI/MRSI for Biopsy Guidance of Prostate Cancer CA-99-015 CA88214

Mourant, Judith Light Scattering and Normal Tissue Models CA71898

Piwnica-Worms,

David R Washington University Molecular Imaging Center CA-01-014 CA94056

Sommer, F Precise MRI Directed Sonic Ablation of Prostate Cancer CA-99-015 CA88205

Stoianovici, Dan Multi-Imager Compatible Robot for Prostate Access PAR-00-089 CA88232

Taylor,

John-Stephen Nucleic Acid Triggered Prodrug and Probe Activation CA92477

Watabe, Kounosuke Tumor Metastasis Suppressor Gene on Human Chromosome 16 CA79473

Zipfel, Warren R Nonlinear Intrinsic Microspectroscopy of Cancer PAR-00-089 CA94311

Table B-26

Additional NCI Projects Supported in 2002 in Early Detection,

Diagnosis, and Prognosis

B-51

Appendix B NCI-Supported Research Projects Relevant to Prostate Cancer That Were Active in 2002

NATIONAL CANCER INSTITUTE

FY 2002 Scientific Model Systems Projects

Principal

Investigator Title RFA or PA Project ID

Abate-Shen, Cory A Mouse Model for Prostate Cancer CA-98-013 CA84294

Abdulkadir, Sarki A Modeling Prostate Cancer by Conditional Gene Targeting CA94858

Agus, David The Role of the Her-Kinase Axis in Emergence of Androgen

Independence in Human Prostate Cancer PAR-99-167 CA92131-Sub-04

Balk, Steven The Androgen Receptor in Hormone Refractory Disease PAR-99-167 CA90381-Sub-05

Balmain, Allan Project 5: Identification of Prostate Tumor Susceptibility Genes

Using Mouse Models for Prostate Cancer PAR-99-167 CA89520-Sub-05

Borgstrom, Per VEGF and Prostate Cancer Angiogenesis CA79004

Chen, Ching-Shih Testing of Novel Apoptotic Agents in Prostate Cancer PA-99-081 CA92307

Clohisy, Denis Bone Cancer and Skeletal Pain CA90434

Cohen, Pinchas Interactions between IGFBPs and Nuclear Receptors in Prostate

Cancer PAR-99-167 CA92131-Sub-03

Gleave, Martin Characterization of Anti-Apoptotic Genes Induced during Androgen

Independent Progression and Chemotherapy PAR-00-087 CA97186-Sub-03

Glinsky, Gennadi Transcriptome of Metastatic Prostate Cancer CA89827

Greenberg, Norman Androgen Independent Prostate Cancer—A Transgenic Model CA73747

Greenberg, Norman KGF in Prostate Cancer—A Transgenic Animal Model CA64851

Greenberg, Norman Project 6: Prostate-Specific Gene Expression in Transgenic Animals PAR-00-087 CA58204-Sub-06

Hay, Nissim PI3K/PTEN/Akt (PKB), Signaling, and Genesis of Cancer CA90764

Hayward, Simon Hormonal Carcinogenesis in Rb-Knockout Mouse Prostate CA96403

Kraft, Andrew Regulation of Prostate Cancer Programmed Cell Death CA78631

Languino, Lucia Integrin Signaling Pathways in Prostate Cancer PA-99-081 CA89720

Matusik, Robert Transgenic Mouse Model for Prostate Cancer CA76142

McKeon, Frank Murine p73 in Tumorigenesis CA75340

Mundy, Gregory Tumors’ Effects on the Skeleton CA40035

Muschel, Ruth Molecular Mechanisms of Metastasis CA46830

Norris, James Induction and Analysis of Prostate Cancer CA69598

Pandolfi, Pier Paolo Molecular Analysis of Carcinogenesis in the Mouse and Human

Prostate PAR-99-167 CA92629-Sub-02

Parsons, Ramon PTEN Tumor Suppressor and Signal Transduction CA82783

Petros, John A Mitochondrial DNA in Mutations in Prostate Cancer CA96994

Pienta, Kenneth Project 5: Inhibition of Human Prostate Cancer Metastasis CA-94-031 CA69568-Sub-05

Table B-27

NCI Projects Supported in 2002 Addressing the PRG Priority:

Can models be designed to display the carcinogenic characteristics of

human prostate cancer (i.e., genetics, host–tumor interactions,

microenvironment, angiogenesis, and progression)? Importantly,

can models that mimic bone marrow metastases be developed?
NATIONAL CANCER INSTITUTE

B-52

Appendix B NCI-Supported Research Projects Relevant to Prostate Cancer That Were Active in 2002

Principal

Investigator Title RFA or PA Project ID

Abate-Shen, Cory A Mouse Model for Prostate Cancer CA-98-013 CA84294

Balk, Steven The Androgen Receptor in Hormone Refractory Disease PAR-99-167 CA90381-Sub-05

Bosland, Maarten Hormonal Induction Animal Model of Prostate Cancer CA75293

Brodie, Angela Androgen Synthesis Inhibitors for Prostate Cancer CA27440

Gleave, Martin Characterization of Anti-Apoptotic Genes Induced during Androgen

Independent Progression and Chemotherapy PAR-00-087 CA97186-Sub-03

Hayward, Simon Hormonal Carcinogenesis in Rb-Knockout Mouse Prostate CA96403

Ho, Shuk-Mei Prostatic Differentiation and Sex Hormone Metabolism CA15776

Hochberg, Richard Biologically Active Steroid Analogs CA37799

Sanda, Martin Modulating Tolerance for Prostate Cancer Antigen Vaccine CA82419

Wang, Zhou Project 2: Suppressive Role of Androgen-Response Gene

Calreticulin in Prostate Cancer PAR-99-167 CA90386-Sub-02

Table B-28

NCI Projects Supported in 2002 Addressing the PRG Priority:

Can models be designed to display the hormone responsiveness of

human prostate cancer and its progression to hormone independence?
B-53

Appendix B NCI-Supported Research Projects Relevant to Prostate Cancer That Were Active in 2002

NATIONAL CANCER INSTITUTE

Principal

Investigator Title RFA or PA Project ID

Agus, David The Role of the Her-Kinase Axis in Emergence of Androgen

Independence in Human Prostate Cancer PAR-99-167 CA92131-Sub-04

Brodie, Angela Androgen Synthesis Inhibitors for Prostate Cancer CA27440

Chang, Esther H Targeting Stealth Liposome for Cancer Gene Therapy CA91660

Cohen, Pinchas Interactions between IGFBPs and Nuclear Receptors in Prostate

Cancer PAR-99-167 CA92131-Sub-03

Davidson, Bradley New Antimicrotubule Agents from Marine Organisms CA81388

Day, Billy Validation and Optimization of Tubulin Targeted Drugs CA88833

Figg, William D Development of Pharmacokinetic Models to Characterize the

Disposition of New Anticancer Agents SC06537

Gleave, Martin Characterization of Anti-Apoptotic Genes Induced during Androgen

Independent Progression and Chemotherapy PAR-00-087 CA97186-Sub-03

Jones, Terence Peptide Antagonists of Urokinase Plasminogen Activator CA-98-022 CA86150

Kadmon, Dov Project 4: Biological Therapy for Prostate Cancer PAR-00-087 CA58204-Sub-04

Lazo, John Combinatorial Approaches for Novel Anticancer Agents CA-97-006 CA78039

Lee, Yue-Wei SAR of Novel Topo I Inhibitor against Prostate Cancer CA81002

McCormick, David L Efficacy Studies of Chemopreventive Agents CN95113

McCormick, David Efficacy Studies of Chemopreventive Agents in Animal Models, CN25017 WS 94

McDonnell, Timothy Project 3: Therapeutic Modulation of Apoptosis in Prostate Cancer

Patients PAR-99-167 CA90270-Sub-03

Mueller, Elisabetta PPAR as a Target of Therapy for Prostate Cancer PAR-99-167 CA90381-Sub-02

Needham, David Thermally Sensitive Drug Delivery System for Tumors CA87630

Nelson, William Project 9: Mechanisms of Sensitivity and Drug Resistance in

Prostate Cancer CA-94-031 CA58236-Sub-09

Ratliff, Timothy Host/Tumor Interactions in Immunotherapy of Prostate Cancer PA-99-081 CA89062

Sherman, David Combinatorial Creation of New Anticancer Agents CA-98-009 CA83155

Thompson, Timothy Project 5: Gene Therapy for Prostate Cancer PAR-00-087 CA58204-Sub-05

Von Hoff, Daniel Novel A Ring and E Ring Modified Camptothecin Analogs CA76563

Wientjes, M Intraprostatic Doxorubicin Therapy PA-92-27 CA74179

Yang, Meng GFP Imaging for In Vivo High-Throughput Drug Screening PAR-00-030 CA89779

Table B-29

NCI Projects Supported in 2002 Addressing the PRG Priority:

Can laboratory models be used to screen potential chemotherapeutic agents,

clarify dose/response relationships, and understand chemotherapy

resistance and mechanisms of therapeutic response?
NATIONAL CANCER INSTITUTE

B-54

Appendix B NCI-Supported Research Projects Relevant to Prostate Cancer That Were Active in 2002

Principal

Investigator Title RFA or PA Project ID

Abrams, Scott Host Immune Responses to Human Carcinoma Antigens

Induced by Peptide Vaccines BC09029

Beer, Tomasz Pulse Calcitriol for Prostate Cancer Prevention PA-98-042 CA82504

Borgstrom, Per VEGF and Prostate Cancer Angiogenesis CA79004

Chatta, Gurkamal Immunologic Therapy of Prostate Cancer CA76033

Chung, Leland Ad-OC-TK/Val Gene Therapy Clinical Correlates CA85555

Dahut, William L The Evaluation of Novel Therapeutics for Genitourinary

Malignancies SC10098

Denardo, Gerald Synergistic Multimodality Antibody Therapy CA47829

Donovan, Gerald P Development of PSMA-Based Vaccines for Prostate Cancer CA91746

Feldman, David Androgen-Independent Prostate Cancer: Mechanisms and Treatment PA-99-081 CA92238

Frelinger, John Targeted CTL Mediated Immunity for Prostate Cancer CA70218

Gardner, Jason P Alphavirus Prime-Boost Vaccines for Prostate Cancer PA-01-091 CA95928

Green, Jeffrey E Transgenic Models for Prostate and Breast Cancer BC05740

Houghton, Alan The Development of DNA Vaccines against Prostate Cancer with

PSMA as a Target PAR-99-167 CA92629-Sub-03

Kasahara, Noriyuki Cellular Transduction by Retrotransposon-Adenovirus Hybrid Vector CA93709

Lee, Chung Clusterin—An Anti-Apoptotic Mediator in Prostate Cancer CA80953

Margalit, Ruth Development of Novel Adenovirus-Lentivirus Hybrid Vector CA96410

McCormick, Frank Project 3: Viral Therapy for Prostate Cancer PAR-99-167 CA89520-Sub-03

McDonnell, Timothy Project 3: Therapeutic Modulation of Apoptosis in Prostate

Cancer Patients PAR-99-167 CA90270-Sub-03

Morris, John Gene Therapy of Prostate Cancer Using Radioiodine PAR-99-167 CA91956-Sub-06

Pardoll, Drew Project 10: Transgenic Models of Prostatic Cancer and Autoimmunity CA-94-031 CA58236-Sub-10

Pastan, Ira Immunotoxin Therapy of Solid and Hematopoietic Tumors:

Preclinical Studies BC08753

Peace, David A Pilot Phase Ib Trial of a PSA Peptide Vaccine PA-99-070 CA88062

Pretlow, Thomas Cytogenetics and Biochemistry of Prostate Cancer CA57179

Ratliff, Timothy L Enhancement of Gene Transfer and Prostate Cancer Immunity CA96691

Reiter, Robert Prostate Stem Cell Antigen (PSCA) in the Biology and Therapy of

Prostate Cancer PAR-99-167 CA92131-Sub-01

Sanda, Martin Modulating Tolerance for Prostate Cancer Antigen Vaccine CA82419

Schlom, Jeffrey Cytokines as Biologic Adjuvants BC10428

Schlom, Jeffrey Design and Development of Novel Immunotherapeutics and

Strategies for Cancer Immunotherapy BC05190

Table B-30

NCI Projects Supported in 2002 Addressing the PRG Priority:

Can models be used to test novel therapeutic approaches

(e.g., cancer vaccines, gene therapy, and immunological therapies)?
B-55

Appendix B NCI-Supported Research Projects Relevant to Prostate Cancer That Were Active in 2002

NATIONAL CANCER INSTITUTE

Principal

Investigator Title RFA or PA Project ID

Schlom, Jeffrey Development of Vaccines and Vaccine Strategies for Human Cancer BC10425

Schlom, Jeffrey Mechanism of Human T-Cell Activation BC10427

Schlom, Jeffrey Novel Recombinant Immunoglobulin Forms for Cancer

Therapy and Diagnosis BC10429

Schlom, Jeffrey T-Cell Costimulation in the Design of Cancer Vaccines BC10426

Small, Eric Project 6: Anti-CTLA4 Antibody Immunologic Therapy for

Prostate Cancer PAR-99-167 CA89520-Sub-06

Thompson, Timothy Project 5: Gene Therapy for Prostate Cancer PAR-00-087 CA58204-Sub-05

Uhr, Jonathan Early Detection/Characterization of Tumor Cells in Blood CA78303

Vile, Richard Use of Fusogenic Membrane Glycoproteins for Gene Therapy of

Prostate Cancer PAR-99-167 CA91956-Sub-05

Zanetti, Maurizio Targeted Therapeutic Vaccination in Prostate Cancer CA84062

Table B-30 (cont.)
NATIONAL CANCER INSTITUTE

B-56

Appendix B NCI-Supported Research Projects Relevant to Prostate Cancer That Were Active in 2002

Principal

Investigator Title RFA or PA Project ID

Felton, James S Carcinogenic Significance of Heterocyclic Amines CA55861

Gambhir, Sanjiv UCLA Imaging Resource for Mouse Cancer Models CA-01-012 CA92865

Greenberg, Norman Transgenic Mouse Models of Prostate Cancer CA-98-013 CA84296

Table B-31

Additional NCI Scientific Models Research Projects Supported in 2002
B-57

Appendix B NCI-Supported Research Projects Relevant to Prostate Cancer That Were Active in 2002

NATIONAL CANCER INSTITUTE

FY 2002 Treatment Projects

Principal

Investigator Title RFA or PA Project ID

Beitz, Alvin J In Vivo Analysis of Tumor Peptide Secretion PAR-01-106 CA86330

Cheng, Leo Characterization of Prostate Cancer with HRMAS 1HMRS PA-98-022 CA80901

Dahl, Thomas Automated Microscopy for Rare Cancer Cell Detection CA94454

Ellis, William Genomic and Gene Expression Profiling of Disseminated Prostate

Cancer PAR-00-087 CA97186-Sub-02

Gallagher, Robert Arsenic Trioxide in Advanced Prostate Cancer PA-99-070 CA86794

Ganju-Krishan,

Awtar T Flow Cytometry to Detect Human Tumor Cells in Body Fluid CA97335

Gerald, William Molecular Classification of Prostate Cancer CA-98-027 CA84999

Karczmar, Gregory S High Spectral and Spatial Resolution MRI of Rodent Tumors PA-01-030 CA89408

Kattan, Michael Natural History of Prostate Cancer, Prognostic Models, and

Decision Making PAR-99-167 CA92629-Sub-01

Livingston, David Gene Expression Analysis of Prostate and Lung Cancer CA-98-027 CA84995

Mason, Ralph MR Measurement of Tumor pH, pO2, and Vascularity In Vivo CA79515

Morton, Ronald E-Cadherin—Marker of Prostate Cancer Progression CA74290

Pretlow, Thomas Cytogenetics and Biochemistry of Prostate Cancer CA57179

Rao, Chandra Analysis of Circulating Cancer Cells Early in Disease PAR-99-101 CA83598

Uhr, Jonathan Early Detection/Characterization of Tumor Cells in Blood CA78303

Windle, Bradford hTERT Expression as a Marker for Early Cancer Detection PA-98-022 CA90240

Woodson, Karen Gene Methylation in Prostate Cancer BC10459

Young, Charles Novel Markers for Prostate Cancer CA70892

Table B-32

NCI Projects Supported in 2002 Addressing the PRG Priority:

What new technologies can detect clinically significant metastases prior to

treatment? What is the clinical significance of circulating prostate cells detected by

molecular techniques and their relationship to treatment failure and metastases?
NATIONAL CANCER INSTITUTE

B-58

Appendix B NCI-Supported Research Projects Relevant to Prostate Cancer That Were Active in 2002

Principal

Investigator Title RFA or PA Project ID

Ahmed, Mansoor EGR-1 and Apoptosis in Prostate Cancer CA78471

Bischof, John Establishment of Mechanisms of Cryodestruction CA75284

Blasberg, Ronald MSKCC Center for In Vivo Molecular Imaging in Cancer CA-99-004 CA86438

Burdette, Everette Real-Time Robotic Image-Guided Prostate Brachytherapy PAR-99-149 CA88139

Camphausen, Kevin The Synergy between Radiotherapy and Angiogenesis Inhibitors SC10373

Cetas, Thomas Dosimetric Markers for Image Guided Radiation Therapy CA91039

Cho, Paul Seed Localizer for Image Guided Prostate Brachytherapy PA-98-008 CA89061

Dahut, William L The Evaluation of Novel Therapeutics for Genitourinary Malignancies SC10098

Deasy, Joseph Intensity Modulated Radiotherapy—Computational Studies CA85181

Denardo, Gerald Synergistic Multimodality Antibody Therapy CA47829

Dent, Paul Carcinoma Cell Radiosensitization by MAPK Inhibition CA88906

DeWeese, Theodore Project 14: Determinants of Radiosensitivity in Prostate Cancer CA-94-031 CA58236-Sub-14

Duerk, Jeffrey IMRI/SPECT Guided Prostate Cancer Biopsy and Therapy CA-99-015 CA88144

Dumoulin, Charles MR Guided Focused Ultrasound Ablation of Prostate Cancer CA-99-015 CA88102

Duncan, James Automatic Image Registration for Prostate Radiotherapy PAR-99-009 CA80894

Epstein, Alan TNT Imaging to Monitor the Efficacy of Cancer Therapy CA-98-024 CA83001

Ettinger, Gil Dynamic Dosimetry Planning for Ultrasound Brachytherapy CA88378

Feleppa, Ernest Novel Ultrasonic Imaging of Brachytherapy Seeds CA88231

Fidler, Isiah Project 1: The Biology of Human Prostate Cancer Metastasis PAR-99-167 CA90270-Sub-01

Freytag, Svend Combined Suicide Gene Therapy/Radiotherapy for Cancer CA75456

Gudkov, Andrei Stress Induced Bystander Effect in Cancer Treatment CA88071

Hahn, Stephen Phase I Trial of PDT in Patients with Prostate Carcinoma PA-99-070 CA88064

Hasan, Tayyaba Physical and Biological Determinants for Optimal PDT CA84203

Hasegawa, Bruce Improved Prostate Cancer Staging with Dual Mode Imaging PA-98-008 CA86893

Jankun, Jerzy Computer Directed Photodynamic Therapy of Prostate Cancer CA90524

King, Ivan Bacterial Gene Delivery Vectors for Cancer Therapy CA77963

Koch, Tad New Drugs Targeted to Metastatic Cancer and Angiogenesis CA92107

Kurhanewicz, John Improved MRI/MRSI for Biopsy Guidance of Prostate Cancer CA-99-015 CA88214

Kurhanewicz, John Metabolic Studies of Response to Prostate Cancer Therapy CA64667

Kurhanewicz, John Monitoring Radiation Therapy of Prostate Cancer by MRSI CA79980

Lasser, Marvin E Speckle-Free Attenuation Ultrasound Prostate Imaging CA96149

Lattanzi, Joseph Ultrasound Image Guided Stereotactic Navigational System CA-99-015 CA88337

Table B-33

NCI Projects Supported in 2002 Addressing the PRG Priority:

What technologies (e.g., new, irradiation therapy and localization techniques)

can be developed to decrease morbidity and enhance efficacy of

therapy for the primary tumor?
B-59

Appendix B NCI-Supported Research Projects Relevant to Prostate Cancer That Were Active in 2002

NATIONAL CANCER INSTITUTE

Principal

Investigator Title RFA or PA Project ID

Lee, Chung Project 1: Clusterin as a Negative Prognostic Indicator in Prostate

Cancer PAR-99-167 CA90386-Sub-01

Line, Bruce Diagnostic Imaging and Guide Therapy in Prostate Cancer CA-99-015 CA91770

Ling, Clifton 3D Conformal Radiation Therapy CA59017

Lizzi, Frederic Integrated Ultrasonic Systems for Noninvasive Therapy PAS-00-006 CA84588

Mason, Ralph MR Measurement of Tumor pH, pO2 and Vascularity In Vivo CA79515

McCormick, Frank Project 3: Viral Therapy for Prostate Cancer PAR-99-167 CA89520-Sub-03

McDonnell, Timothy Project 3: Therapeutic Modulation of Apoptosis in Prostate Cancer

Patients PAR-99-167 CA90270-Sub-03

McNichols, Roger Interactive Image Guided Closed Loop Thermal Therapy CA79282

McVary, Kevin Project 4: Molecular Mechanisms of Neuropathic Erectile Dysfunction PAR-99-167 CA90386-Sub-04

Mehta, Minesh Improving Cancer Outcome—Adaptive Helical Tomotherapy CA88960

Mitchell, James B Modulation of Therapeutic Response SC06321

Nakaar, Valerian Potentiating the Anti-Tumor Activity of Salmonella CA94699

Needham, David Thermally Sensitive Drug Delivery System for Tumors CA87630

Oleinick, Nancy Phototherapy of Prostate Cancer—Pro and Anti Apoptosis CA83917

Peng, Yongren Production of Y-90 Microspheres for Radiation Therapy CA79225

Peng, Yongren Timed-Bioresorbable Radioseeds for Prostate Cancer CA86567

Piwnica-Worms,

David R Washington University Molecular Imaging Center CA-01-014 CA94056

Pizer, Stephen M Medical Image Presentation: Structural Image Analysis CA47982

Pogue, Brian Oxygen Dosimetry in Photodynamic Therapy CA78734

Samant, Sanjiv KCD Based System for Megavoltage Portal Imaging CA76061

Sanghvi, Narendra High Intensity Ultrasound for Prostate Treatment CA81340

Sanghvi, Narendra Quantitative Imaging and Treatment with Focused Ultrasound CA83244

Sawyers, Charles Targeted Therapy of PTEN Null Prostate Cancer PAR-99-167 CA92131-Sub-02

Saxena, Indu Fiber Temperature Sensor for Hyperthermia Treatment CA78114

Schneiderman,

Martin Tumor-Targeted Radiosensitizers in Cancer Therapy CA72411

Schultheiss, Timothy Normal Tissue Dose Volume Response in Radiation Therapy CA73766

Sioshansi, Piran Linear PD Sources for Prostate Brachytherapy CA78005

Sommer, F Precise MRI Directed Sonic Ablation of Prostate Cancer CA-99-015 CA88205

Sommer, F Prostate Cancer and BPH Ablation Using HIFU Waveguide PA-98-008 CA79931

Sterzer, Fred Microwave Treatment of Localized Prostate Cancer CA86656

Thompson, Timothy Project 5: Gene Therapy for Prostate Cancer PAR-00-087 CA58204-Sub-05

Thornton, Kenneth Dynamic Prostate Brachytherapy CA88150

Table B-33 (cont.)
NATIONAL CANCER INSTITUTE

B-60

Appendix B NCI-Supported Research Projects Relevant to Prostate Cancer That Were Active in 2002

Principal

Investigator Title RFA or PA Project ID

Vaughn, James Improving ErbB2 Antisense Efficacy for Cancer Therapy CA83953

Vigneron, Daniel Metabolic Imaging of the Prostate Using 3D MRSI CA59897

Welch, Michael Research Resource in Radionuclide Research CA86307

Wientjes, M Intraprostatic Doxorubicin Therapy PA92-27 CA74179

Williamson, Jeffrey Brachytherapy Dosimetry Using Plastic Scintillator CA57222

Williamson, Jeffrey Heterogeneity Corrections in Brachytherapy Dosimetry CA46640

Woynarowska,

Barbara DNA Damaging Agents and Apoptosis in Prostate Cancer CA78706

Wu, Ed Sodium MRI for Assessing Early Chemotherapy Response PA-98-008 CA85594

Yan, Di Adaptive Radiation Therapy CA71785

Yu, Cedric Treatment Uncertainty—Implication on Conformal Therapy CA66075

Yu, Yan Piper: Prostate Implant Planning Engine for Radiotherapy CA78115

Zakian, Kristen Monitoring Chemotherapy in Prostate Cancer by Proton NMR PA-98-042 CA84258

Zheng, Gang Photodynamic Therapy for Prostate Cancer PAR-01-045 CA95330

Zipfel, Warren R Nonlinear Intrinsic Microspectroscopy of Cancer PAR-00-089 CA94311

Table B-33 (cont.)
B-61

Appendix B NCI-Supported Research Projects Relevant to Prostate Cancer That Were Active in 2002

NATIONAL CANCER INSTITUTE

Principal

Investigator Title RFA or PA Project ID

Agus, David The Role of the Her-Kinase Axis in Emergence of Androgen

Independence in Human Prostate Cancer PAR-99-167 CA92131-Sub-04

Camphausen, Kevin Molecular Imaging of the Proliferating Endothelium SC10372

Ellis, William Genomic and Gene Expression Profiling of Disseminated Prostate

Cancer PAR-00-087 CA97186-Sub-02

Emmert-Buck,

Michael R Genetic Progression of Cancer SC10437

Etzioni, Ruth PSA Screening and U.S. Prostate Cancer Trends CA-99-013 CA88160

Etzioni, Ruth Statistical Methods for Prostate Cancer Research CA70227

Fidler, Isiah Project 1: The Biology of Human Prostate Cancer Metastasis PAR-99-167 CA90270-Sub-01

Gelmann, Edward Apoptosis in Prostate Cancer CA79912

Ghosh, Malay Bayesian Neural Networks for Prostate Cancer Study CA85414

Golub, Todd Genomic Expression Analysis of Tumors after Radical Prostatectomy PAR-99-167 CA90381-Sub-04

Hood, Leroy Transcriptome and Proteome Stratification of Prostate 

Adenocarcinoma Phenotypes PAR-00-087 CA97186-Sub-04

Jiang, Yulei Neural Network Prediction of Prostate Cancer Progression PA-01-010 CA97308

Karczmar, Gregory S High Spectral and Spatial Resolution MRI of Rodent Tumors PA-01-030 CA89408

Kattan, Michael Natural History of Prostate Cancer, Prognostic Models, and

Decision Making PAR-99-167 CA92629-Sub-01

King, Jean A NMR Imaging of Prostate Cancer Using Ligands PAR-01-101 CA95876

Lee, Chung Project 1: Clusterin as a Negative Prognostic Indicator in Prostate

Cancer PAR-99-167 CA90386-Sub-01

McDonnell, Timothy Project 3: Therapeutic Modulation of Apoptosis in Prostate Cancer

Patients PAR-99-167 CA90270-Sub-03

Pandolfi, Pier Paolo Molecular Analysis of Carcinogenesis in the Mouse and Human

Prostate PAR-99-167 CA92629-Sub-02

Pretlow, Thomas Cytogenetics and Biochemistry of Prostate Cancer CA57179

Sawyers, Charles Targeted Therapy of PTEN Null Prostate Cancer PAR-99-167 CA92131-Sub-02

Scher, Howard Mechanism Based Therapy for Prostate Cancer PAR-99-167 CA92629-Sub-04

Sellers, William Single Nucleotide Repeat Polymorphism Analysis of Recurrent

Prostate Cancer after Radiation Therapy PAR-99-167 CA90381-Sub-03

Simons, Jonathon Project 5: Cellular and Molecular Basis of Prostate Metastasis to Bone CA-94-031 CA58236-Sub-05

Spielman, Daniel Magnetic Resonance Spectroscopic Neoplasm Imaging CA48269

Stanford, Janet NSAIDs and Other Medications in Prostate Cancer Etiology PA-00-080 CA92579

Wheeler, Thomas Project 1: Markers of Progression and Metastasis PAR-00-087 CA58204-Sub-01

Wilson, Michael S Antibody Microarray for Detection of Tumor Markers CA96250

Table B-34

NCI Projects Supported in 2002 Addressing the PRG Priority:

What critical features of the primary tumor determine treatment success?

What clinical, pathological, and molecular determinants can be used as

markers of aggressiveness and “indolent” prostate cancer?

How can multiple test results be combined using informatics?
NATIONAL CANCER INSTITUTE

B-62

Appendix B NCI-Supported Research Projects Relevant to Prostate Cancer That Were Active in 2002

Principal

Investigator Title RFA or PA Project ID

Abrams, Scott Host Immune Responses to Human Carcinoma Antigens

Induced by Peptide Vaccines BC09029

Allison, James T Cell Costimulation in Antitumor Responses CA57986

Banchereau,

Jacques Dendritic Cell Vaccine in Metastatic Prostate Cancer PA-00-047 CA91556

Celis, Esteban Immune Based Therapeutic Approach for Prostate Cancer CA82677

Celis, Esteban An Immune-Based Therapeutic Approach for Prostate Cancer PAR-99-167 CA91956-Sub-04

Chang, Esther Immunoliposome Mediated Gene Therapy for Prostate Cancer CA80449

Chang, Esther H Targeting Stealth Liposome for Cancer Gene Therapy CA91660

Chatterjee, Malaya HER-2/Neu—A Target for Cancer Immunotherapy CA91878

Chung, Leland Ad-OC-TK/Val Gene Therapy Clinical Correlates CA85555

Dahut, William L The Evaluation of Novel Therapeutics for Genitourinary Malignancies SC10098

Disis, Mary HER2 Vaccination for the Treatment of Cancer CA85374

Donovan, Gerald P Development of Anti-PSMA Antibodies for Prostate Cancer CA92927

Donovan, Gerald P Development of PSMA-Based Vaccines for Prostate Cancer CA91746

Donovan, Gerald P Human Anti-PSMA Antibodies for Prostate Cancer Therapy PA-01-091 CA96075

Freytag, Svend Combined Suicide Gene Therapy/Radiotherapy for Cancer CA75456

Gardner, Jason P Alphavirus Prime-Boost Vaccines for Prostate Cancer PA-01-091 CA95928

Gilboa, Eli Tumor RNA Transfected Dendritic Cell Vaccines CA85307

Greenberg, Norman Project 6: Prostate-Specific Gene Expression in Transgenic Animals PAR-00-087 CA58204-Sub-06

Houghton, Alan The Development of DNA Vaccines against Prostate Cancer with

PSMA as a Target PAR-99-167 CA92629-Sub-03

Humphreys, Robert Prostate Cancer Vaccine by Suppressing II Protein CA85100

Kasahara, Noriyuki Cellular Transduction by Retrotransposon-Adenovirus Hybrid Vector CA93709

Lee, Byungkook Molecular Modeling and Bioinformatics BC08759

Margalit, Ruth Development of Novel Adenovirus-Lentivirus Hybrid Vector CA96410

Margalit, Ruth Retroviral Vectors for Cancer Gene Therapy CA91659

McCready, Victor Radionuclide Therapy of Skeletal Metastases from Cancer PA-99-070 CA86784

Morris, John Gene Therapy of Prostate Cancer Using Radioiodine PAR-99-167 CA91956-Sub-06

Norris, James Viral Vector CORE Facility PAR-99-127 CA88163

Pastan, Ira Immunotoxin Therapy of Solid and Hematopoietic Tumors:

Preclinical Studies BC08753

Peace, David A Pilot Phase Ib Trial of a PSA Peptide Vaccine PA-99-070 CA88062

Ratliff, Timothy L Enhancement of Gene Transfer and Prostate Cancer Immunity CA96691

Table B-35

NCI Projects Supported in 2002 Addressing the PRG Priority:

Which gene therapies, including immunotherapeutic approaches, appear

most suitable for localized and systemic prostate cancer treatment?
B-63

Appendix B NCI-Supported Research Projects Relevant to Prostate Cancer That Were Active in 2002

NATIONAL CANCER INSTITUTE

Principal

Investigator Title RFA or PA Project ID

Reiter, Robert Prostate Stem Cell Antigen (PSCA) in the Biology and Therapy

of Prostate Cancer PAR-99-167 CA92131-Sub-01

Sanda, Martin Project 6: Vaccinia PSA for Androgen-Modulated, Post-Surgical

Recurrence of Prostate Cancer CA-94-031 CA69568-Sub-06

Schlom, Jeffrey Cytokines as Biologic Adjuvants BC10428

Schlom, Jeffrey Design and Development of Novel Immunotherapeutics and

Strategies for Cancer Immunotherapy BC05190

Schlom, Jeffrey Development of Vaccines and Vaccine Strategies for Human Cancer BC10425

Schlom, Jeffrey Mechanism of Human T-Cell Activation BC10427

Schlom, Jeffrey Novel Recombinant Immunoglobulin Forms for Cancer Therapy

and Diagnosis BC10429

Schlom, Jeffrey T-Cell Costimulation in the Design of Cancer Vaccines BC10426

Simons, Jonathon Project 11: Gene Therapy for Human Prostate Cancer CA-94-031 CA58236-Sub-11

Small, Eric Project 6: Anti-CTLA4 Antibody Immunologic Therapy for Prostate

Cancer PAR-99-167 CA89520-Sub-06

Thompson, Timothy Project 5: Gene Therapy for Prostate Cancer PAR-00-087 CA58204-Sub-05

Topalian, Suzanne L Specific Immune Recognition of Tumor-Associated Antigens by

Human T Cells SC06664

Vaughn, James Improving ErbB2 Antisense Efficacy for Cancer Therapy CA83953

Vieweg, Johannes W Telomerase RNA Transfected Dendritic Cell Vaccines PA-99-046 CA93910

Vile, Richard Use of Fusogenic Membrane Glycoproteins for Gene Therapy of

Prostate Cancer PAR-99-167 CA91956-Sub-05

Zanetti, Maurizio Targeted Therapeutic Vaccination in Prostate Cancer CA84062

Table B-35 (cont.)
NATIONAL CANCER INSTITUTE

B-64

Appendix B NCI-Supported Research Projects Relevant to Prostate Cancer That Were Active in 2002

Principal

Investigator Title RFA or PA Project ID

Agus, David The Role of the Her-Kinase Axis in Emergence of Androgen

Independence in Human Prostate Cancer PAR-99-167 CA92131-Sub-04

Balk, Steven The Androgen Receptor in Hormone Refractory Disease PAR-99-167 CA90381-Sub-05

Cheng, Yung-Chi Nucleoside Analogs as Anticancer Compounds CA63477

Chinnadurai,

Govindaswamy Oncogenesis and Chemoresistance by Bcl-2 CA73803

Dalton, James Nonsteroidal Affinity Ligands for the Androgen Receptor CA68096

Frelinger, John Targeted CTL Mediated Immunity for Prostate Cancer CA70218

Gleave, Martin Characterization of Anti-Apoptotic Genes Induced during

Androgen Independent Progression and Chemotherapy PAR-00-087 CA97186-Sub-03

Golde, David Memorial Sloan-Kettering Cancer Gene Therapy Program CA59350

Liao, Shutsung Molecular Mechanisms of Growth Control—Prostate Cancer CA58073

Lu, Michael L Molecular Regulation of Androgen Receptor Activation PA-99-081 CA87997

Nelson, William Project 9: Mechanisms of Sensitivity and Drug Resistance in

Prostate Cancer CA-94-031 CA58236-Sub-09

Schor, Nina Targeted Therapy for Chemoresistant Tumors CA74289

Tew, Kenneth Determinants of Estramustine Resistance and Response CA83778

Yamamoto, Keith Project 1: Mechanisms of Hormone Resistance in Prostate Cancer PAR-99-167 CA89520-Sub-01

Table B-36

NCI Projects Supported in 2002 Addressing the PRG Priority:

What are the mechanisms associated with resistance to hormone

therapy, immunotherapy, radiation, and chemotherapy?
B-65

Appendix B NCI-Supported Research Projects Relevant to Prostate Cancer That Were Active in 2002

NATIONAL CANCER INSTITUTE

Principal

Investigator Title RFA or PA Project ID

Abrams, Scott Host Immune Responses to Human Carcinoma Antigens

Induced by Peptide Vaccines BC09029

Baldwin, Albert Antiapoptotic Mechanisms in Prostate Cancer CA75080

Banchereau,

Jacques Dendritic Cell Vaccine in Metastatic Prostate Cancer PA-00-047 CA91556

Beer, Tomasz Calcitriol in Recurrent Prostate Cancer CA85585

Beer, Tomasz Pulse Calcitriol for Prostate Cancer Prevention PA-98-042 CA82504

Bystryn,

Jean-Claude Polypeptide Vaccine in Il-2 Liposomes for Prostate Cancer CA90562

Celis, Esteban An Immune-Based Therapeutic Approach for Prostate Cancer PAR-99-167 CA91956-Sub-04

Chang, Esther Immunoliposome Mediated Gene Therapy for Prostate Cancer CA80449

Chang, Esther H Targeting Stealth Liposome for Cancer Gene Therapy CA91660

Chatta, Gurkamal Immunologic Therapy of Prostate Cancer CA76033

Chung, Leland Ad-OC-TK/Val Gene Therapy Clinical Correlates CA85555

Curiel, David Replicative Adenoviruses with Enhanced Infectivity CA83821

Donovan, Gerald P Development of Anti-PSMA Antibodies for Prostate Cancer CA92927

Donovan, Gerald P Development of PSMA-Based Vaccines for Prostate Cancer CA91746

Donovan, Gerald P Human Anti-PSMA Antibodies for Prostate Cancer Therapy PA-01-091 CA96075

Freytag, Svend Combined Suicide Gene Therapy/Radiotherapy for Cancer CA75456

Gardner, Jason P Alphavirus Prime-Boost Vaccines for Prostate Cancer PA-01-091 CA95928

Gilboa, Eli Tumor RNA Transfected Dendritic Cell Vaccines CA85307

Golde, David Memorial Sloan-Kettering Cancer Gene Therapy Program CA59350

Houghton, Alan The Development of DNA Vaccines against Prostate Cancer

with PSMA as a Target PAR-99-167 CA92629-Sub-03

Humphreys, Robert Prostate Cancer Vaccine by Suppressing II Protein CA85100

Kao, Chinghai Tissue Specific Gene Therapy for Human Prostate Cancer CA74042

Kasahara, Noriyuki Cellular Transduction by Retrotransposon-Adenovirus Hybrid Vector CA93709

Kasahara, Noriyuki Transcriptional Targeting of Retroviral Replication CA85908

King, Ivan Bacterial Gene Delivery Vectors for Cancer Therapy CA77963

Margalit, Ruth Development of Novel Adenovirus-Lentivirus Hybrid Vector CA96410

Margalit, Ruth Retroviral Vectors for Cancer Gene Therapy CA91659

Morris, John Gene Therapy of Prostate Cancer Using Radioiodine PAR-99-167 CA91956-Sub-06

Norris, James Viral Vector CORE Facility PAR-99-127 CA88163

Pasqualini, Renata Targeted Delivery of Genes to Angiogenic Vasculature PAR-98-096 CA88106

Pastan, Ira Immunotoxin Therapy of Solid and Hematopoietic Tumors:

Preclinical Studies BC08753

Table B-37

NCI Projects Supported in 2002 Addressing the PRG Priority:

What is the role of gene and cellular therapy for prostate cancer?
NATIONAL CANCER INSTITUTE

B-66

Appendix B NCI-Supported Research Projects Relevant to Prostate Cancer That Were Active in 2002

Principal

Investigator Title RFA or PA Project ID

Peace, David A Pilot Phase Ib Trial of a PSA Peptide Vaccine PA-99-070 CA88062

Ratliff, Timothy Host/Tumor Interactions in Immunotherapy of Prostate Cancer PA-99-081 CA89062

Ratliff, Timothy L Enhancement of Gene Transfer & Prostate Cancer Immunity CA96691

Sanda, Martin Project 6: Vaccinia PSA for Androgen-Modulated, Post-Surgical

Recurrence of Prostate Cancer CA-94-031 CA69568-Sub-06

Schlom, Jeffrey Cytokines as Biologic Adjuvants BC10428

Schlom, Jeffrey Design and Development of Novel Immunotherapeutics and

Strategies for Cancer Immunotherapy BC05190

Schlom, Jeffrey Development of Vaccines and Vaccine Strategies for Human Cancer BC10425

Schlom, Jeffrey Mechanism of Human T-Cell Activation BC10427

Schlom, Jeffrey Novel Recombinant Immunoglobulin Forms for Cancer Therapy

and Diagnosis BC10429

Schlom, Jeffrey T-Cell Costimulation in the Design of Cancer Vaccines BC10426

Schor, Nina Targeted Therapy for Chemoresistant Tumors CA74289

Simons, Jonathon Project 11: Gene Therapy for Human Prostate Cancer CA-94-031 CA58236-Sub-11

Spencer, David Regulated Apoptosis in the Treatment of Prostate Cancer CA77266

Tempero, Margaret Mechanism Based Evaluations of ErbB Targeted Agents CA-00-001 CA90788

Thompson, Timothy Project 5: Gene Therapy for Prostate Cancer PAR-00-087 CA58204-Sub-05

Vaughn, James Improving ErbB2 Antisense Efficacy for Cancer Therapy CA83953

Vieweg,

Johannes W Telomerase RNA Transfected Dendritic Cell Vaccines PA-99-046 CA93910

Vile, Richard Use of Fusogenic Membrane Glycoproteins for Gene Therapy of 

Prostate Cancer PAR-99-167 CA91956-Sub-05

Zhang, Wei-Wei Complementary Adenoviral Vectors for Treatment of Cancer CA-98-022 CA83156

Table B-37 (cont.)
B-67

Appendix B NCI-Supported Research Projects Relevant to Prostate Cancer That Were Active in 2002

NATIONAL CANCER INSTITUTE

Principal

Investigator Title RFA or PA Project ID

Beer, Tomasz Calcitriol in Recurrent Prostate Cancer CA85585

Carducci, Michael Phenylbutyrate Bioactivity Assessment in Prostate Cancer CA75525

Cohen, Pinchas Interactions between IGFBPs and Nuclear Receptors in Prostate

Cancer PAR-99-167 CA92131-Sub-03

Etzioni, Ruth PSA Screening and U.S. Prostate Cancer Trends CA-99-013 CA88160

Fidler, Isiah Project 1: The Biology of Human Prostate Cancer Metastasis PAR-99-167 CA90270-Sub-01

Gallagher, Robert Arsenic Trioxide in Advanced Prostate Cancer PA-99-070 CA86794

Hood, Leroy Transcriptome and Proteome Stratification of Prostate

Adenocarcinoma Phenotypes PAR-00-087 CA97186-Sub-04

Kufe, Donald Phase I Trials of New Anticancer Agents CA62490

Sanda, Martin Project 6: Vaccinia PSA for Androgen-Modulated, Post-Surgical

Recurrence of Prostate Cancer CA-94-031 CA69568-Sub-06

Smith, David Phase II Trial of Tetrathiomolybdate in Prostate Cancer PA-00-047 CA94510

Tempero, Margaret Mechanism Based Evaluations of ErbB Targeted Agents CA-00-001 CA90788

Table B-38

NCI Projects Supported in 2002 Addressing the PRG Priority:

What are the relevant endpoints for clinical trials of systemic therapies

(e.g., PSA levels, time to progression, quality of life, and survival)?

How can endpoints be validated? What is the impact of treatment on survival?
NATIONAL CANCER INSTITUTE

B-68

Appendix B NCI-Supported Research Projects Relevant to Prostate Cancer That Were Active in 2002

Principal

Investigator Title RFA or PA Project ID

Agus, David The Role of the Her-Kinase Axis in Emergence of Androgen

Independence in Human Prostate Cancer PAR-99-167 CA92131-Sub-04

Aoki, Masahiro Nuclear Targets of Akt Oncoproteins CA93837

Arap, Wadih Project 4: Exploring the Molecular Diversity of Blood Vessels for

Diagnostic and Therapeutic Targeting in Prostate Cancer PAR-99-167 CA90270-Sub-04

Balk, Steven The Androgen Receptor in Hormone Refractory Disease PAR-99-167 CA90381-Sub-05

Beranova-Giorgianni,

Sarka Cancer Relevant Proteins in the Human Prostate Proteome PAR-00-025 CA91254

Bojanowski,

Krzysztof Development of a New Antiangiogenic Tumor Blocker SBD.1 PA-01-091 CA96058

Boothman, David Exploiting IR Inducible NQ01 Levels Using Beta Lapachone CA92250

Borgstrom, Per VEGF and Prostate Cancer Angiogenesis CA79004

Borrello, Melinda New Target Antigens for Prostate Cancer Vaccines CA82948

Cantley, Lewis The Role of PTEN and the PI3K Pathway in Prostate Cancer CA89021

Caprioli, Richard M Molecular Analysis of Cancer—Imaging Mass Spectrometry PAR-99-102 CA86243

Celis, Esteban An Immune-Based Therapeutic Approach for Prostate Cancer PAR-99-167 CA91956-Sub-04

Chang, Esther Immunoliposome Mediated Gene Therapy for Prostate Cancer CA80449

Chatta, Gurkamal Immunologic Therapy of Prostate Cancer CA76033

Chatterjee, Malaya HER-2/Neu—A Target for Cancer Immunotherapy CA91878

Chen, Ching-Shih Apoptosis Regulation by Lipid Signals in Prostate Cancer PA-99-081 CA94829

Chen, Ching-Shih Testing of Novel Apoptotic Agents in Prostate Cancer PA-99-081 CA92307

Cheng, Jin Akt1 Oncogene in Carcinogenesis CA89242

Cheng, Yung-Chi Nucleoside Analogs as Anticancer Compounds CA63477

Christman, Judith De Novo DNA Methyltransferases as Anticancer Drug Targets PAR-00-060 CA91315

Chung, Leland Extracellular Matrix Integrin Signaling in Prostate Cancer CA76620

Cohen, Pinchas Interactions between IGFBPs and Nuclear Receptors in Prostate

Cancer PAR-99-167 CA92131-Sub-03

Corey, David Consequences of Inhibition of Cellular Telomerase CA85363

Counter,

Christopher M Targeting Functional Domains in Telomerase PAR-01-045 CA95155

Davar, Gudarz Endothelin 1 Induced Pain and Metastatic Prostate Cancer CA80153

Denardo, Gerald Synergistic Multimodality Antibody Therapy CA47829

Disis, Mary HER2 Vaccination for the Treatment of Cancer CA85374

Dou, Q Tea Targeting Proteasome—A Role in Cancer Prevention PAR-00-025 CA91282

Ellis, William Genomic and Gene Expression Profiling of Disseminated

Prostate Cancer PAR-00-087 CA97186-Sub-02

Table B-39

NCI Projects Supported in 2002 Addressing the PRG Priority:

How can new targets be identified and what is the role of

novel therapeutic agents directed at these targets?
B-69

Appendix B NCI-Supported Research Projects Relevant to Prostate Cancer That Were Active in 2002

NATIONAL CANCER INSTITUTE

Principal

Investigator Title RFA or PA Project ID

Fidler, Isiah Project 1: The Biology of Human Prostate Cancer Metastasis PAR-99-167 CA90270-Sub-01

Figg, William D Development of Angiogenesis Inhibitors Using Prostate Cancer

as a Tumor Model SC06538

Finstad, Connie LHRH Synthetic Peptide Vaccine for Prostate Cancer CA83450

Fletterick, Robert J Inhibition of Androgen Receptor Activation PAR-01-045 CA95324

Foster, Barbara A Vitamin D Analogs for Chemoprevention of Prostate Cancer CA95367

Glazer, Robert I Structure Based Discovery of Akt Inhibitors PAR-01-045 CA95378

Gleave, Martin Characterization of Anti-Apoptotic Genes Induced during Androgen

Independent Progression and Chemotherapy PAR-00-087 CA97186-Sub-03

Glode, L M Cytotoxic Gonadotropin Releasing Hormone Derivatives PA-01-091 CA96049

Glode, L GnRH Analog Toxins for Targeted Gonadotroph Ablation CA75662

Gudkov, Andrei Stress Induced Bystander Effect in Cancer Treatment CA88071

Hainfeld, James F Improved MRI Contrast Agents CA94495

Honn, Kenneth V Formulation and Evaluation of a Prostate Cancer Drug CA97863

Hood, Leroy Transcriptome and Proteome Stratification of Prostate

Adenocarcinoma Phenotypes PAR-00-087 CA97186-Sub-04

Houghton, Alan The Development of DNA Vaccines against Prostate Cancer with

PSMA as a Target PAR-99-167 CA92629-Sub-03

Jenkins, Robert Biologic and Clinical Studies of Overrepresented 8q24 Region

Associated with Prostate Cancer Progression PAR-99-167 CA91956-Sub-03

Johnson, Candace Antitumor Mechanisms and Therapeutic Effects of Vitamin D CA67267

Jones, Alun Technetium and Rhenium in Nuclear Medicine CA34970

Jones, Peter De Novo DNA Methylation in Bladder Cancer CA83867

Jones, Terence Peptide Antagonists of Urokinase Plasminogen Activator CA-98-022 CA86150

Kadmon, Dov Project 4: Biological Therapy for Prostate Cancer PAR-00-087 CA58204-Sub-04

King, Jean A NMR Imaging of Prostate Cancer Using Ligands PAR-01-101 CA95876

Koch, Tad New Drugs Targeted to Metastatic Cancer and Angiogenesis CA92107

Kwon, Eugene CTLA-4 Blockade Immunotherapy for Prostate Cancer CA82185

Lazo, John Combinatorial Approaches for Novel Anticancer Agents CA-97-006 CA78039

Lee, Byungkook Molecular Modeling and Bioinformatics BC08759

Lee, Yue-Wei SAR of Novel Topo I Inhibitor against Prostate Cancer CA81002

Lemkin, Peter F Computer Aided Two-Dimensional Electrophoretic Gel Analysis

(GELLAB) BC08381

Lewis, Kevin C Systems-Based Modeling of Retinoid—Drug Interactions BC00162

Lin, Sue-Hwa Regulation of Angiogenesis by C-CAM1 CA86342

Table B-39 (cont.)
NATIONAL CANCER INSTITUTE

B-70

Appendix B NCI-Supported Research Projects Relevant to Prostate Cancer That Were Active in 2002

Principal

Investigator Title RFA or PA Project ID

Lokeshwar,

Balakrishna Control of Metastatic Progression of Prostate Cancer CA61038

Project 4: Antibody Gene Diversity Libraries and Phage Display

Marks, James to Generate Recombinant Human Antibodies for Prostate Cancer PAR-99-167 CA89520-Sub-04

Therapy

Maslak, Peter Inhibition of Histone Deacetylase as Anti Cancer Therapy CA82740

McDonnell, Timothy Project 3: Therapeutic Modulation of Apoptosis in Prostate Cancer

Patients PAR-99-167 CA90270-Sub-03

Merajver, Sofia Prevention of Mammary Cancer in HER-2/Neu Transgenic Mice CA77612

Meyn, Raymond Anticancer Drug Resistance by Bcl-2 Oncogene Expression CA69003

Mikovits, Judy Development of Inhibitors of the DNA Methylation Process CA90013

Mikovits, Judy A Development of DNA Methyltransferase Inhibitors as Anti* PA-01-091 CA92828

Mitchell, James B Nitroxides as Protectors against Oxidative Stress SC06387

Molinski, Tadeusz F Natural Product Antitumor Inducers of Apoptosis CA85602

Morris, John Gene Therapy of Prostate Cancer Using Radioiodine PAR-99-167 CA91956-Sub-06

Moses, Marsha Novel Angiogenesis Inhibitor from Cartilage PAR-98-096 CA83106

Mueller, Elisabetta PPAR as a Target of Therapy for Prostate Cancer PAR-99-167 CA90381-Sub-02

Mulder, Kathleen Mechanisms of TGF-Beta Production in Human Cancer Cells CA90765

Mundy, Gregory Tumors’ Effects on the Skeleton CA40035

Nakaar, Valerian Potentiating the Anti-Tumor Activity of Salmonella CA94699

Ornstein, David K Proteomic Study of Androgen Independent Prostate Cancer PA-01-010 CA93759

Pan, Xing Folate Conjugates for Prostate Cancer Imaging PAR-00-090 CA81975

Parchment, Ralph Stable Stereoisomer Analogs of Topo II-Beta Inhibitors CA90088

Pasqualini, Renata Project 2: Targeting Prostate Cancer Bone Metastasis PAR-99-167 CA90270-Sub-02

Pasqualini, Renata A Receptor for Tumor Homing Peptides in Vasculature CA78512

Pastan, Ira Gene Discovery BC10298

Pienta, Kenneth Project 5: Inhibition of Human Prostate Cancer Metastasis CA-94-031 CA69568-Sub-05

Piwnica-Worms,

David R Washington University Molecular Imaging Center CA-01-014 CA94056

Pommier, Yves DNA Repair and Cell Cycle Checkpoints as Targets for Anticancer Drugs BC06150

Rangnekar, Vivek Mechanism of Apoptosis by Par4 PA-99-081 CA60872

Reiter, Robert Prostate Stem Cell Antigen (PSCA) in the Biology and Therapy of

Prostate Cancer PAR-99-167 CA92131-Sub-01

Romanov, Victor Peptide Inhibitors of Prostate Cancer Cells Adhesion CA92931

Sanda, Martin Project 6: Vaccinia PSA for Androgen-Modulated, Post-Surgical

Recurrence of Prostate Cancer CA-94-031 CA69568-Sub-06

Sarkar, Fazlul Molecular Mechanism of Genistein in Prostate Cancer CA83695

Table B-39 (cont.)
B-71

Appendix B NCI-Supported Research Projects Relevant to Prostate Cancer That Were Active in 2002

NATIONAL CANCER INSTITUTE

Principal

Investigator Title RFA or PA Project ID

Sawyers, Charles Targeted Therapy of PTEN Null Prostate Cancer PAR-99-167 CA92131-Sub-02

Scher, Howard Biologic Effects of 17AA Geldanamycin CA85506

Scher, Howard Mechanism Based Therapy for Prostate Cancer PAR-99-167 CA92629-Sub-04

Shankar, Geetha Lysophospholipid Receptors as Targets for Cancer Therapy CA92925

Sherman, David Combinatorial Creation of New Anticancer Agents CA-98-009 CA83155

Sherman, Merry R Pegylated Prolactin Receptor Antagonists as Cancer Drugs CA96283

Shih, Charles Anti-Androgenic Mechanism of a New Compound CA97647

Shih, Charles Cell-Based High Throughput Screening for Anti-Androgens CA96189

Shuman, Marc Proteases in Cancer—Biology and Drug Development CA72006

Simons, Jonathon Project 5: Cellular and Molecular Basis of Prostate Metastasis

to Bone CA-94-031 CA58236-Sub-05

Small, Eric Project 6: Anti-CTLA4 Antibody Immunologic Therapy for

Prostate Cancer PAR-99-167 CA89520-Sub-06

Smith, David Phase II Trial of Tetrathiomolybdate in Prostate Cancer PA-00-047 CA94510

Soff, Gerald Project 3: Generation of, and Angiostatin Levels in, Prostate Cancer PAR-99-167 CA90386-Sub-03

Spencer, David Regulated Apoptosis in the Treatment of Prostate Cancer CA77266

Taylor, John-Stephen Nucleic Acid Triggered Prodrug and Probe Activation CA92477

Tempero, Margaret Mechanism Based Evaluations of ErbB Targeted Agents CA-00-001 CA90788

Tew, Kenneth Determinants of Estramustine Resistance and Response CA83778

Topalian, Suzanne L Specific Immune Recognition of Tumor-Associated Antigens by

Human T Cells SC06664

Trump, Donald L Vitamin D in Prostate Cancer: Tumor Vasculature Effects CA95045

Vaughn, James Improving ErbB2 Antisense Efficacy for Cancer Therapy CA83953

Vile, Richard Use of Fusogenic Membrane Glycoproteins for Gene Therapy of

Prostate Cancer PAR-99-167 CA91956-Sub-05

Woods, Catherine Novel Prostate Homing Peptides as Potential Diagnostics CA92933

Woynarowska,

Barbara DNA Damaging Agents and Apoptosis in Prostate Cancer CA78706

Yang, Meng GFP Imaging for In Vivo High-Throughput Drug Screening PAR-00-030 CA89779

Zhang, Wei-Wei Complementary Adenoviral Vectors for Treatment of Cancer CA-98-022 CA83156

Zheng, Gang Photodynamic Therapy for Prostate Cancer PAR-01-045 CA95330

Table B-39 (cont.)
NATIONAL CANCER INSTITUTE

B-72

Appendix B NCI-Supported Research Projects Relevant to Prostate Cancer That Were Active in 2002

Principal

Investigator Title RFA or PA Project ID

Balk, Steven The Androgen Receptor in Hormone Refractory Disease PAR-99-167 CA90381-Sub-05

Celis, Esteban An Immune-Based Therapeutic Approach for Prostate Cancer PAR-99-167 CA91956-Sub-04

Dahut, William L The Evaluation of Novel Therapeutics for Genitourinary Malignancies SC10098

Figg, William D Development of Angiogenesis Inhibitors Using Prostate Cancer

as a Tumor Model SC06538

Fletterick, Robert J Inhibition of Androgen Receptor Activation PAR-01-045 CA95324

Foster, Barbara A Vitamin D Analogs for Chemoprevention of Prostate Cancer CA95367

Gallagher, Robert Arsenic Trioxide in Advanced Prostate Cancer PA-99-070 CA86794

Gleave, Martin Characterization of Anti-Apoptotic Genes Induced during Androgen

Independent Progression and Chemotherapy PAR-00-087 CA97186-Sub-03

Hood, Leroy Transcriptome and Proteome Stratification of Prostate

Adenocarcinoma Phenotypes PAR-00-087 CA97186-Sub-04

Houghton, Alan The Development of DNA Vaccines against Prostate Cancer with

PSMA as a Target PAR-99-167 CA92629-Sub-03

Imperato-Mc Ginley,

Julianne Androgens Regulate IGF Pathway and Prostate Diseases PAR-98-023 CA85435

Johnson, Candace Glucocorticoids and Vitamin D: Role in Anti-Tumor Effects CA85142

Koch, Tad New Drugs Targeted to Metastatic Cancer and Angiogenesis CA92107

Kufe, Donald Phase I Trials of New Anticancer Agents CA62490

Lee, Chung Project 1: Clusterin as a Negative Prognostic Indicator in Prostate

Cancer PAR-99-167 CA90386-Sub-01

Morris, John Gene Therapy of Prostate Cancer Using Radioiodine PAR-99-167 CA91956-Sub-06

Ratliff, Timothy L Enhancement of Gene Transfer and Prostate Cancer Immunity CA96691

Reiter, Robert Prostate Stem Cell Antigen (PSCA) in the Biology and Therapy

of Prostate Cancer PAR-99-167 CA92131-Sub-01

Sawyers, Charles Targeted Therapy of PTEN Null Prostate Cancer PAR-99-167 CA92131-Sub-02

Scher, Howard Mechanism Based Therapy for Prostate Cancer PAR-99-167 CA92629-Sub-04

Sellers, William Single Nucleotide Repeat Polymorphism Analysis of Recurrent

Prostate Cancer after Radiation Therapy PAR-99-167 CA90381-Sub-03

Shih, Charles Anti-Androgenic Mechanism of a New Compound CA97647

Shih, Charles Cell-Based High Throughput Screening for Anti-Androgens CA96189

Wang, Zhou Project 2: Suppressive Role of Androgen-Response Gene

Calreticulin in Prostate Cancer PAR-99-167 CA90386-Sub-02

Table B-40

NCI Projects Supported in 2002 Addressing the PRG Priority:

What is the optimal treatment for androgen-independent disease?
B-73

Appendix B NCI-Supported Research Projects Relevant to Prostate Cancer That Were Active in 2002

NATIONAL CANCER INSTITUTE

Principal

Investigator Title RFA or PA Project ID

Dahut, William L The Evaluation of Novel Therapeutics for Genitourinary Malignancies SC10098

Jenkins, Robert Biologic and Clinical Studies of Overrepresented 8q24 Region

Associated with Prostate Cancer Progression PAR-99-167 CA91956-Sub-03

Kadmon, Dov Project 4: Biological Therapy for Prostate Cancer PAR-00-087 CA58204-Sub-04

Kufe, Donald Phase I Trials of New Anticancer Agents CA62490

Merajver, Sofia Prevention of Mammary Cancer in HER-2/Neu Transgenic Mice CA77612

Pasqualini, Renata Targeted Delivery of Genes to Angiogenic Vasculature PAR-98-096 CA88106

Ratliff, Timothy Host/Tumor Interactions in Immunotherapy of Prostate Cancer PA-99-081 CA89062

Sanda, Martin Project 6: Vaccinia PSA for Androgen-Modulated, Post-Surgical

Recurrence of Prostate Cancer CA-94-031 CA69568-Sub-06

Shoji, Mamoru Inhibition of Tissue Factor Mediated Angiogenesis CA82995

Table B-41

NCI Projects Supported in 2002 Addressing the PRG Priority:

At what point in the progression of prostate cancer should novel therapeutic

agents be initiated (e.g., anti-angiogenic and anti-metastatic agents)?
NATIONAL CANCER INSTITUTE

B-74

Appendix B NCI-Supported Research Projects Relevant to Prostate Cancer That Were Active in 2002

Principal

Investigator Title RFA or PA Project ID

Beer, Tomasz Calcitriol in Recurrent Prostate Cancer CA85585

Rhoads, George PSA Screening and Prostate Cancer Mortality CA71734

Young, Charles Human Kallikreins as Novel Markers of Prostate Cancer PAR-99-167 CA91956-Sub-02

Table B-42

NCI Projects Supported in 2002 Addressing the PRG Priority:

When should a patient with a rising PSA be treated?
B-75

Appendix B NCI-Supported Research Projects Relevant to Prostate Cancer That Were Active in 2002

NATIONAL CANCER INSTITUTE

Principal

Investigator Title RFA or PA Project ID

Gallo, James Optimized Cancer Chemotherapy via Pharmacodynamic Models CA76254

Glazer, Robert I Structure Based Discovery of Akt Inhibitors PAR-01-045 CA95378

Petereit, Daniel G Enhancing Native American Participation in RT Trials CA-02-002 CA99010

Trump, Donald L Vitamin D in Prostate Cancer: Tumor Vasculature Effects CA95045

Table B-43

Additional NCI Treatment Projects Supported in 2002

B-77

Appendix B NCI-Supported Research Projects Relevant to Prostate Cancer That Were Active in 2002

NATIONAL CANCER INSTITUTE

Principal

Investigator Title RFA or PA Project ID

Bokhour, Barbara Prostate Cancer Survivor Narratives and Doctors’ Responses PAR-99-006 CA91737

Deimling, Gary Quality of Life of Older Long-Term Cancer Survivors CA-97-018 CA78975

Denberg, Thomas D Disparities in Prostate Cancer Decision-Making and QOL PAR-02-037 CA99505

Diefenbach,

Michael A A Multimedia Prostate Cancer Intelligent Expert System PA-99-163 CA90904

Etzioni, Ruth PSA Screening and U.S. Prostate Cancer Trends CA-99-013 CA88160

Ferrans, Carol Quality of Life of African American Cancer Survivors CA89418

Kattan, Michael Natural History of Prostate Cancer, Prognostic Models, and

Decision Making PAR-99-167 CA92629-Sub-01

McCarthy, Ellen Patterns of Care for Cancer Patients at End of Life CA79052

McClellan, Mark Economics of Cancer CA74760

McVary, Kevin Project 4: Molecular Mechanisms of Neuropathic Erectile

Dysfunction PAR-99-167 CA90386-Sub-04

Meltzer, David Cost-Effectiveness of Prostate Cancer Screen/Treatment CA92443

Northouse, Laurel Prostate Cancer—Family Care for Patients and Spouses CA90739

Sanda, Martin G Survivor QOL/Spouse Satisfaction after Prostate Therapy CA95662

Scott, Charles QOL and LENT in Survivors of Head and Neck/Prostate Cancer CA79034

Troxel, Andrea Clinical Trials with Quality of Life and Compliance Data CA79470

Zabora, James Family Dynamics and Problem Solving Education for Caregivers CA88769

Table B-44

NCI Projects Supported in 2002 Addressing the PRG Priority:

What is the impact of treatment on outcomes? How do the benefits differ in subsets

of patients by age, morbidity, race, etc.? What are the outcomes in the community

setting compared with those from clinical trials or centers of excellence? How do

provider characteristics (e.g., volume and expertise) affect outcomes? How do

patients value tradeoffs between length of survival and quality of life?

FY 2002 Cancer Control, Survivorship, and

Outcomes Projects
NATIONAL CANCER INSTITUTE

B-78

Appendix B NCI-Supported Research Projects Relevant to Prostate Cancer That Were Active in 2002

Principal

Investigator Title RFA or PA Project ID

Carver, Charles Quality of Life in Adult Cancer Survivors CA-97-018 CA78995

Cella, David Project 6: QOL Item Banking and Adaptive Testing in

Prostate Cancer PAR-99-167 CA90386-Sub-06

Deimling, Gary Quality of Life of Older Long-Term Cancer Survivors CA-97-018 CA78975

Meltzer, David Cost-Effectiveness of Prostate Cancer Screen/Treatment CA92443

Sanda, Martin G Survivor QOL/Spouse Satisfaction after Prostate Therapy CA95662

Troxel, Andrea Clinical Trials with Quality of Life and Compliance Data CA79470

Table B-45

NCI Projects Supported in 2002 Addressing the PRG Priority:

How are different types of outcomes defined and standardized (e.g.,

quality of life, morbidity, and patient satisfaction)?
B-79

Appendix B NCI-Supported Research Projects Relevant to Prostate Cancer That Were Active in 2002

NATIONAL CANCER INSTITUTE

Principal

Investigator Title RFA or PA Project ID

Etzioni, Ruth PSA Screening and U.S. Prostate Cancer Trends CA-99-013 CA88160

Phillips, Kathryn Use of Cancer Screening in a Managed Care Environment PA-99-014 CA81130

Rhoads, George PSA Screening and Prostate Cancer Mortality CA71734

Tsodikov, Alexander Survival Effects of Prostate Cancer Surveillance CA-02-010 CA97414

Table B-46

NCI Projects Supported in 2002 Addressing the PRG Priority:

What is the impact of early detection and screening on outcomes?
NATIONAL CANCER INSTITUTE

B-80

Appendix B NCI-Supported Research Projects Relevant to Prostate Cancer That Were Active in 2002

Principal

Investigator Title RFA or PA Project ID

Antoni, Michael Center for Psycho-Oncology Research OD-99-005 CA84944

Bass, Sarah Use of Internet Health Information by Cancer Patients CA90145

Berry, Donna Nursing Support of Decisions by Men with Prostate Cancer CA77372

Bowman, Karen Family Members and the Survivorship Phase of Cancer PAR-99-006 CA91577

Brink, Susan Interactive Prostate Cancer Decision Support System CA75801

Brink, Susan Recurrent Prostate Cancer: Decision Support Guide CA88557

Davar, Gudarz Endothelin 1 Induced Pain and Metastatic Prostate Cancer CA80153

Demark-Wahnefried,

Wendy Promoting Health in Prostate and Breast Cancer CA81191

Dodd, Marylin Exercise—An Intervention for Fatigue in Cancer Patients CA83316

Earp, Shelton NCCU/UNC Lineberger Partnership in Cancer Research CA-01-008 CA92075

Guadagnoli, Edward Managed Care Penetration and Cancer Care PA-99-015 CA92588

Harewood, Kenneth NCCU-BBRI/UNC-Lineberger Partnership in Cancer Research CA-01-008 CA92077

Matthews, Alicia Information Needs of African American Cancer Patients CA77525

Partridge, Edward Deep South Network for Cancer Control CA-99-003 CA86128

Redd, William East Harlem Partnership for Cancer Awareness (EHPCA) CA-99-003 CA86107

Roth, Andrew Psychostimulants for Fatigue in Ambulatory Men with PC CA85229

Schildkraut, Joellen Carolina and Georgia Genetics Network Center CA78157

Snyder, Brian Biomechanics of Metastatic Defects in Bone CA40211

Weber, Bryan Dyadic Social Support for Men with Prostate Cancer PAR-99-006 CA96204

Wilkie, Diana Computerized Pain Report and Nursing Pain Consult Protocol CA62477

Wilkie, Diana Computerized Symptom Report Consult for Cancer Patients CA-98-014 CA81918

Table B-47

Additional NCI Cancer Control, Survivorship, and

Outcomes Projects Supported in 2002
C-1

Appendix C U.S. Patents Resulting from NCI-Funded Research on Prostate Cancer: 1998–2002

NATIONAL CANCER INSTITUTE

APPENDIX

C

U.S. Patents Resulting from

NCI-Funded Research on

Prostate Cancer: 1998–2002

U.S. Patents Resulting from NCI-Funded Research on Prostate Cancer

Pending as

of 2002a

2002

a The U.S. Patent database only includes data on Published Applications in accordance with the 18 month pre-grant publication rules. Pending

patent applications where the applicant has elected to not publish prior to grant remain confidential. b These patents were granted in 2003.

Year Patent Title

X Alpha-difluoromethylornithine (DFMO) suppresses polyamine levels in the human prostate

(Serial No. 938846)

X Anti-tumor effects of prostate carcinoma tumor antigen-1 (Serial No. 948227)

X Chimeric prostate-homing peptides with pro-apoptotic activity (Serial No. 765086)

X Chromosome 17p-linked prostate cancer susceptibility gene and a paralog and

orthologous genes (Serial No. 988626 and Serial No. 988687)

X Compounds for cancer imaging and therapy (Patent No. 6,517,811)b

X Genetic markers for breast, ovarian, and prostatic cancer (Patent No. 6,512,091)b

X Human thymosin beta15 gene, protein, and uses thereof (Serial No. 726422)

X Methods for detecting prostate cancer (Serial No. 957376)

X Novel discalamide compounds and their use as antiproliferative agents (Serial No.

835692)

X Novel prostate cancer cell lines (Serial No. 919196)

X Oligonucleotide inhibitors of cancer cell proliferation (Serial No. 141263)

X Prostate cancer-related compositions, methods, and kits based on DNA macroarray

proteomics platforms (Serial No. 813380)

X Real-time mechanical imaging of the prostate (Serial No. 819419)

X Reversal of cancer phenotype by inhibiting expression of prostate tumor inducing gene

(Serial No. 263178)

X Roles for Nkx3.1 in prostate development and cancer (Serial No. 756151)

X RTVP-based compositions and methods for the treatment of prostate cancer (Serial No.

876225)

X Sequences for targeting metastatic cells (Serial No. 151055 and Serial No. 797969)

X Suppressors of human breast cancer cell growth (Serial No. 972758)

X Use of retinoids plus histone deacetylase inhibitors to inhibit the growth of solid tumors

(Serial No. 061101)

X 17-azolyl steroids useful as androgen synthesis inhibitors (Patent No. 6,444,683)

X Benzamide compounds for cancer imaging and therapy (Patent No. 6,447,748)

X Circulating insulin-like growth factor-I and prostate cancer risk (Patent No. 6,410,335)

X Discalamide compounds and their use as anti-proliferative agents (Patent No. 6,476,065)

X Method for detection of micrometastatic prostate cancer (Patent No. 6,479,263)

X Methods for diagnosing cancer or precancer based upon hnRNP protein expression

(Patent No. 6,500,625)

X Prostate cancer assays and related methods (Patent No. 6,352,834)

X Thymosin beta-15 promoter and uses thereof (Patent No. 6,489,463)
NATIONAL CANCER INSTITUTE

C-2

Appendix C U.S. Patents Resulting from NCI-Funded Research on Prostate Cancer: 1998–2002

Year Patent Title

X 17-azolyl steroids useful as androgen synthesis inhibitors (Patent No. 6,200,965)

X Antibodies specific for human thymosin beta15 protein and uses thereof (Patent No.

6,300,479)

X Chromosome 17p-linked prostate cancer susceptibility gene and a paralog and

orthologous genes (Patent No. 6,333,403)

X CYP3A4 NFSE variant and methods of use therefore (Patent No. 6,174,684)

X Detection of metatstatic cancer cells using PCTA-1 (Patent No. 6,255,049)

X Epithelial protein and DNA thereof for use in early cancer detection (Patent No. 6,251,586)

X Immortalized and malignant human prostatic cell lines (Patent No. 6,255,058)

X Molecules that home to various selected organs or tissues (Patent No. 6,232,287)

X Prostate implant planning engine for radiotherapy (Patent No. 6,200,255)

X Sequences for targeting metastatic cells (Patent No. 6,252,058)

X Tumor suppressor designated TS1023.3 (Patent No. 6,262,242)

X Therapeutic methods for prostate cancer (Patent No. 6,177,410)

X Ultrasonic tissue-type classification and imaging methods and apparatus (Patent No.

6,238,342)

X Benzamide compounds containing a heterocyclic ring for tumor imaging and therapy

(Patent No. 6,015,543)

X Discodermolide compounds and methods of use (Patent No. 6,127,406)

X Method for diagnosis of cancer (Patent No. 6,150,117)

X Method of inhibiting cancer growth (Patent No. 6,100,248)

X Prediction of prostate cancer progression by analysis of selected predictive parameters

(Patent No. 6,025,128)

X Prostate-specific regulatory nucleic acid sequences and transgenic non-human animals

expressing prostate-specific antigen (Patent No. 6,100,444)

X Use of inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase as a modality in

cancer therapy (Patent No. 6,040,334)

X 17-azolyl steroids useful as androgen synthesis inhibitors (Patent No. 5,994,335)

X Benzamide compounds for cancer imaging and therapy (Patent No. 5,993,777 )

X Epithelial protein and DNA thereof for use in early cancer detection (Patent No. 5,994,062)

X Isolated nucleic acid molecule encoding alternatively spliced prostate-specific membrane

antigen and uses thereof (Patent No. 5,935,818)

X Methods for cancer imaging and therapy using benzamine compounds (Patent No.

5,911,970)

X Method for molecular staging of prostate cancer (Patent No. 5,976,794)

X Nomograms to aid in the treatment of prostatic cancer (Patent No. 5,993,388)

X Treatment of cancer with human chorionic gonadotropin (Patent No. 5,877,148)

X Method for prognosis of prostate cancer (Patent No. 5,858,681)

U.S. Patents Resulting from NCI-Funded Research on Prostate Cancer (cont.)

2001

2000

1999
C-3

Appendix C U.S. Patents Resulting from NCI-Funded Research on Prostate Cancer: 1998–2002

NATIONAL CANCER INSTITUTE

Year Patent Title

X Bone and prostate-derived protein factors affecting prostate cancer growth, differentiation,

and metastasis (Patent No. 5,728,815)

X Genetic markers for breast, ovarian, and prostatic cancer (Patent No. 5,821,328)

X Human prostate tumor inducing gene-1 and uses thereof (Patent No. 5,851,764)

X Human prostatic cell lines immortalized by adenovirus 12-simian virus 40 (AD12/SV40)

hybrid virus (Patent No. 5,814,452 and Patent No. 5,716,830)

X Human thymosin beta15 (Patent No. 5,721,337)

X Human thymosin beta15 gene, protein, and uses thereof (Patent No. 5,831,033)

X Immortalized and malignant human prostatic cell lines (Patent No. 5,824,488)

X Method for detecting prostate cancer using a reagent which binds prostate cancer-1 protein

(Patent No. 5,824,490)

X Method of inhibiting cancer growth (Patent No. 5,837,696)

X Method for molecular staging of prostate cancer (Patent No. 5,840,494)

U.S. Patents Resulting from NCI-Funded Research on Prostate Cancer (cont.)

1998


June 2004