National Institutes of Health

[Planning for Prostate Cancer Research]{.smallcaps}

> Harold E. Varmus, M.D.
>
> Director, NIH
>
> Richard D. Klausner, M.D.
>
> Director, NCI
>
> Submitted June 1999

[Planning for Prostate Cancer Research:]{.smallcaps}

[Expanding the Scientific Framework]{.smallcaps}

[&]{.smallcaps}

[Professional Judgment Estimates]{.smallcaps}

Table of Contents

# Preface [i](#preface) {#preface-i .TOC-1}

# Executive Summary [ii](#executive-summary) {#executive-summary-ii .TOC-1}

# [Part I: Expanding the Scientific Framework]{.smallcaps} [1](#part-i-expanding-the-scientific-framework) {#part-i-expanding-the-scientific-framework-1 .TOC-1}

The Burden of Prostate Cancer [2](#the-burden-of-prostate-cancer)

Prostate Cancer Funding and Professional Judgment
[3](#prostate-cancer-funding-and-professional-judgment)

Prostate Cancer Research Activities
[4](#prostate-cancer-research-activities)

The Cancer Genome Anatomy Project
[5](#the-cancer-genome-anatomy-project)

The Prostate Cancer Progress Review Group
[6](#the-prostate-cancer-progress-review-group)

The Process of Reviewing the Prostate Cancer Portfolio
[7](#the-process-of-reviewing-the-prostate-cancer-portfolio)

Identification of Needs and Resources
[7](#identification-of-needs-and-resources)

Overall Results of the PRG Analysis of the NCI Portfolio in Prostate
Cancer
[8](#overall-results-of-the-prg-analysis-of-the-nci-portfolio-in-prostate-cancer)

Portfolio in Biology and Epidemiology
[8](#portfolio-in-biology-and-epidemiology)

Portfolio in Preventing Prostate Cancer
[9](#portfolio-in-preventing-prostate-cancer)

Portfolio in Detection and Diagnosis of Prostate Cancer
[9](#portfolio-in-detection-and-diagnosis-of-prostate-cancer)

Portfolio in Treating Prostate Cancer
[10](#portfolio-in-treating-prostate-cancer)

Portfolio in Prostate Cancer Survivorship and Morbidity
[11](#portfolio-in-prostate-cancer-survivorship-and-morbidity)

Portfolio in Prostate Cancer Surveillance
[11](#portfolio-in-prostate-cancer-surveillance)

Portfolio in Scientific and Public Resources
[11](#portfolio-in-scientific-and-public-resources)

Recommendations of the PRG [12](#recommendations-of-the-prg)

New Initiatives in Prostate Cancer Research
[13](#new-initiatives-in-prostate-cancer-research)

Clinical Trials in Prostate Cancer
[18](#clinical-trials-in-prostate-cancer)

Clinical Trials Restructuring and Genitourinary Cancers
[20](#clinical-trials-restructuring-and-genitourinary-cancers)

# [Part II: Five Year Professional Judgment Estimates]{.smallcaps} [21](#part-ii-five-year-professional-judgment-estimates) {#part-ii-five-year-professional-judgment-estimates-21 .TOC-1}

National Institutes of Health: Total Professional Judgment Estimate
[22](#national-institutes-of-health-total-professional-judgment-estimate-1)

National Cancer Institute [22](#national-cancer-institute)

NCI's Clinical Science [24](#ncis-clinical-science)

Statement of Needs [24](#statement-of-needs)

Strategies & Plans: Early Clinical Trials
[25](#strategies-plans-early-clinical-trials)

Strategies & Plans: Multi-center Clinical Trials Program
[25](#strategies-plans-multi-center-clinical-trials-program)

Strategies & Plans: Informatics and Clinical Trials
[27](#strategies-plans-informatics-and-clinical-trials)

Strategies & Plans: Clinical Early Detection Markers
[27](#strategies-plans-clinical-early-detection-markers)

Strategies & Plans: Image-Guided Therapy
[28](#strategies-plans-image-guided-therapy)

Strategies & Plans: Prevention Trials
[28](#strategies-plans-prevention-trials)

Strategies & Plans: Investigator-Initiated Research
[29](#strategies-plans-investigator-initiated-research)

NCI's Translational Science [30](#ncis-translational-science)

Statement of Needs [30](#statement-of-needs-1)

Strategies & Plans: Drug Discovery
[31](#strategies-plans-drug-discovery)

Strategies & Plans: Specialized Programs of Research Excellence
[32](#strategies-plans-specialized-programs-of-research-excellence)

Strategies & Plans: Tissue Banks [33](#strategies-plans-tissue-banks)

Strategies & Plans: Director\'s Challenge for Molecular Diagnostics
[33](#strategies-plans-directors-challenge-for-molecular-diagnostics)

Strategies & Plans: Early Detection Markers
[34](#strategies-plans-early-detection-markers)

Strategies & Plans: Imaging Technology Development
[34](#strategies-plans-imaging-technology-development)

Strategies & Plans: Investigator-Initiated Research
[35](#strategies-plans-investigator-initiated-research-1)

NCI's Risk, Burdens & Outcomes Science
[35](#ncis-risk-burdens-outcomes-science)

Statement of Needs [35](#statement-of-needs-2)

Strategies & Plans: Epidemiology, Genetics and the Environment
[36](#strategies-plans-epidemiology-genetics-and-the-environment)

Strategies & Plans: Surveillance [38](#strategies-plans-surveillance)

Strategies & Plans: Survivorship [40](#strategies-plans-survivorship)

Strategies & Plans: Special Populations
[42](#strategies-plans-special-populations)

Strategies & Plans: Special Populations Networks
[43](#strategies-plans-special-populations-networks)

Strategies & Plans: Investigator-Initiated Research
[44](#strategies-plans-investigator-initiated-research-2)

NCI's Basic Research & Discovery Science
[44](#ncis-basic-research-discovery-science)

Statement of Needs [44](#statement-of-needs-3)

Strategies & Plans: Investigator-Initiated Research
[45](#strategies-plans-investigator-initiated-research-3)

Strategies & Plans: Animal Models [46](#strategies-plans-animal-models)

Strategies & Plans: Cancer Genome Anatomy Project
[48](#strategies-plans-cancer-genome-anatomy-project)

National Institute of Diabetes and Digestive & Kidney Diseases
[48](#national-institute-of-diabetes-and-digestive-kidney-diseases)

National Human Genome Research Institute
[55](#national-human-genome-research-institute)

National Center for Research Resources
[57](#national-center-for-research-resources)

National Institute of Environmental Health Sciences
[57](#national-institute-of-environmental-health-sciences)

National Institute on Aging [60](#national-institute-on-aging)

National Institute of Nursing Research
[61](#national-institute-of-nursing-research)

National Institute of Mental Health
[62](#national-institute-of-mental-health)

National Institute of Deafness and Other Communication Disorders
[62](#national-institute-of-deafness-and-other-communication-disorders)

#  {#section .unnumbered}

# Preface 

This report has been prepared by the National Institutes of Health (NIH)
of the Department of Health and Human Services in response to the
following requests from Congress.

In its report on the Fiscal Year 1999 budget for the Department of
Health and Human Services, the House Appropriations Committee stated:

> *The Committee requests the Director of NIH together with the Director
> of NCI to submit a report by January 1, 1999, outlining the activities
> the NIH is undertaking to enhance prostate cancer research. (HR
> 105-635 page 63)*

In its report on the Fiscal Year 1999 budget for the Department of
Health and Human Services, the Senate Appropriations Committee stated:

> *The Committee encourages NCI to explore the feasibility of developing
> a national model research, education, training, and treatment center
> focusing on early diagnosis, prevention, and treatment of prostate
> cancer.*
>
> *The Committee also requests that the Director of the National
> Institutes of Health, together with the Director of NCI, submit a
> report to the Appropriations Committees, no later than April 1, 1999,
> outlining activities NIH is undertaking to enhance prostate cancer
> research programs. (SR 105-300 page 88)*

In its report on the Fiscal Year 1999 budget for the Department of
Health and Human Services, the Conference Appropriations Committee
stated:

> *....NIH is strongly urged to make prostate cancer a top priority in
> allocating funding increases. The agency is expected to accelerate
> spending on prostate cancer, taking into account the recommendation
> contained in the Senate report and bill. It is further expected that
> NIH will consult closely with the research community, clinicians,
> patient advocacy groups, and the Congress to identify promising new
> avenues of basic and clinical research. The agency is directed to
> develop a report to be presented to the House and the Senate
> Committees on Appropriations within six months outlining the
> professional judgment for prostate cancer research for the next five
> years. The Secretary and the Director should also be prepared to
> discuss actions taken in planning, funding, and implementing the
> agency's prostate cancer research portfolio for fiscal years 1999 and
> 2000. (HR 105-805 page 1273)*

The NIH has coordinated a single comprehensive report to address these
Congressional issues. The first section of the report, "Planning for
Prostate Cancer Research: Expanding the Scientific Framework," discusses
scientific research supported at the NIH.

The second section of the report, "Planning for Prostate Cancer
Research: Five Year Professional Judgment Estimates," highlights the
research opportunities and their potential costs that NIH has identified
in the area of prostate cancer.

# Executive Summary

Prostate cancer is the single most common form of cancer in men in the
United States. According to the American Cancer Society's [Cancer Facts
and Figures -- 1999]{.underline} and as shown in the reports of the
National Cancer Institute's Surveillance, Epidemiolgy and End Results
Program, in 1999 alone, an estimated 179,300 men will be diagnosed with
prostate cancer, and some 37,000 men will die of their disease. Prostate
cancer exacts a particularly devastating toll on African American men;
incidence rates are substantially higher among African Americans, and
mortality rates in African American men remain more than twice as high
as rates in white men.

The Congress has expressed a keen interest in monitoring and advancing a
national response to this serious health problem. In appropriating 1999
funding for the National Institutes of Health (NIH), Congress asked for
several actions regarding prostate cancer research:

-   describe prostate cancer research activities,

-   evaluate the concept of a national model research education,
    training and treatment center,

-   increase funding for these programs, and

-   provide a five year professional judgment for prostate cancer
    research.

In response, NIH, with the leadership of the National Cancer Institute
(NCI), has aggressively sought participation from researchers,
advocates, and patients in reviewing the prostate cancer research
portfolio and charting a plan for a vigorous expansion of the prostate
cancer research program.

The initial evaluation of the research program and a broad outline of
future directions were completed in August 1998 and are described in
part I of this report to Congress, "Planning for Prostate Cancer
Research: Expanding the Scientific Framework." The NIH efforts in
coordinating a research plan for prostate cancer have focussed on
continuing development of a widely disseminated research program
coordinated and supported by the NIH and accompanied by continuing
involvement of researchers, advocacy groups and patients. The report of
the NCI-convened Prostate Cancer Progress Review Group described a
nationwide program involving a significant investment in infrastructure
across the nation. It is recognized that each of the 35 NCI
Comprehensive Cancer Centers, geographically dispersed throughout the
nation, devote significant effort to education, training, treatment and
research on prostate cancer and cover the full spectrum of prevention,
early diagnosis and treatment.

Part II of this document, "Planning for Prostate Cancer Research: Five
Year Professional Judgment Estimates," describes prostate cancer
research opportunities from 1999 through 2003. This plan estimates that
\$420 million of potential research opportunities could be supported in
2003. NIH has increased prostate cancer research funding significantly
from a 1998 level of \$114 million to a current projection of \$180
million in 1999. This plan includes many efforts already initiated in
1999. In fact, we are pleased to report that the original 1999 estimate
of \$168 million for prostate cancer research has been increased by \$12
million as additional funding opportunities have been identified,
primarily by the NCI. Two institutes not previously focussed on prostate
research are now newly included in the NIH prostate efforts. It must be
noted that this estimate is based on our assessment of scientific
opportunities over the next five years, without consideration of
economic constraints or other competing priorities of the Federal
government. This level of support must be integrated with other research
efforts of the NIH.

There is a notable program of multifaceted research within the NIH. Nine
institutes have important intersecting interests that contribute to the
NIH prostate cancer research effort and have been consulted in the
development of this plan. The Institutes and Centers, in order of
funding opportunities estimated for prostate research, are:

#### National Institutes of Health: Total Professional Judgment Estimate

  --------------------------------------------------------------------------- ------------ ----------- -----------
  (in thousands)                                                              1998         2003        98-03
                                                                              (baseline)   Estimate    Change

  National Cancer Institute                                                   \$86,907     \$340,000   \$253,093
  (NCI)....................................................................                            

  National Institute of Diabetes and Digestive & Kidney Diseases              16,223       56,900      40,677
  (NIDDK).................                                                                             

  National Human Genome Research Institute                                    4,343        7,327       2,984
  (NHGRI)........................................                                                      

  National Center for Research Resources                                      2,086        5,500       3,414
  (NCRR)..............................................                                                 

  National Institute of Environmental Health Sciences                         1,261        4,910       3,649
  (NIEHS)...............................                                                               

  National Institute on Aging                                                 1,402        3,000       1,598
  (NIA)................................................................                                

  National Institute of Nursing Research                                      625          1,100       475
  (NlNR).................................................                                              

  National Institute of Mental Health                                         415          915         500
  (NIMH).....................................................                                          

  National Institute of Deafness & Other Communication Disorders Research     349          458         109
  (NIDCD)\...                                                                                          

  Total National Institutes of Health                                         113,611      420,110     306,499
  (NIH)......................................................\...                                      
  --------------------------------------------------------------------------- ------------ ----------- -----------

We look forward to achieving the goals of this ambitious plan and we are
pleased to provide this analysis of programs and professional judgment
of research opportunities and their potential costs.

National Institutes of Health

Planning for Prostate Cancer Research

# [Part I: Expanding the Scientific Framework]{.smallcaps}

## The Burden of Prostate Cancer

The incidence and mortality statistics for prostate cancer -- 179,300
new cases this year and 37,000 deaths -- does little to convey the very
real pain, fear, and uncertainty experienced by every man who is
diagnosed with prostate cancer. Despite advances over the past decade,
our treatments for prostate cancer are inadequate, the side effects of
treatment are unacceptable, and troubling questions remain about the
relative benefit of early detection for the disease. Every day, too many
men in the United States hear the life-changing words "You have prostate
cancer." Every day, too many men are faced with the agonizing decision
of how to treat their prostate cancer. And every day, too many men are
dying too young of this disease.

In this report, the focus is on the prostate cancer research activities
of the National Cancer Institute (NCI), and also highlights the research
programs of other Institutes and Centers. This plan describes a number
of initiatives, projects, and mechanisms with the potential to directly
improve the quality of life of prostate cancer patients and survivors,
as well as those at risk for the disease. Fully 70 percent of the cost
of potential research opportunities presented here is targeted at
clinical or translational research -- research that will have a direct
impact on patients, survivors, and at-risk men.

An important goal is to ensure that every man with prostate cancer has
access to participation in a clinical trial. The Multicenter Clinical
Trials Program and the new QuickTrials initiative would enable us to
make progress toward achieving this. Our goal is to use our new
understanding of prostate cancer at the molecular level to develop
"intelligent" drugs that will kill the tumor but spare surrounding
tissue. The Molecular Target-Based Drug Discovery Initiatives would give
us the tools we need. Our goal is to move new drugs as speedily and
efficiently as possible from the laboratory to the men who desperately
need them. The new Rapid Access to Intervention Development (RAID)
program would be designed for this purpose. These initiatives would be
certain to move us closer to the day when prostate cancer is no longer a
burden.

Each of these initiatives is described in further detail in this report.
The plan describes our intention in clinical trials to find agents that
would allow us to prevent prostate cancer altogether, and our efforts to
understand prostate cancer at its most basic levels, as it is only by
understanding the disease that we will ultimately defeat it. Following
this plan would ensure the development of new treatments, new
preventives, and new interventions with the potential to improve,
extend, or even save the lives of all men touched by prostate cancer. If
our efforts are successful, as we believe they must be, our sons and
grandsons will grow old in a world in which they no longer fear prostate
cancer.

Prostate cancer is the most common cancer and the second leading cause
of cancer death among men in the United States. Despite significant
advances in diagnosis and treatment, many patients still suffer from the
sequelae of unresectable disease, including debilitation, pain, and
premature death. The continuing challenge to the scientific and medical
communities and to the NCI, in particular, is to develop successful
preventive strategies to reduce the overall incidence of prostate
cancer. We need to develop effective early detection strategies for all
men and appropriate treatment strategies for men with prostate cancer,
especially those with advanced lesions.

Recent trends in prostate cancer incidence and mortality are
encouraging. Prostate cancer incidence began to accelerate dramatically
in the mid-1980s to a peak of 190.9 per 100,000 in 1992, and then began
decreasing; the corresponding rate in 1994 was 147.8 and was down to
137.2 in 1995. Mortality from prostate cancer had also been increasing
for some time, reaching its peak in 1991 of 26.7 per 100,000 and
subsequently decreasing to 25.9 in 1994 and to 24.9 in 1995. Additional
information regarding trends in prostate cancer incidence and mortality
including comparisons of racial and ethnic patterns can be found in the
NCI monograph *SEER Prostate Cancer Trends, 1973-1995*. The document
offers one of the most comprehensive population-based evaluations ever
published on demographic and clinical features of prostate cancer cases.
It provides insights into the likely directions for prostate cancer
research over the next decade related to etiology, prevention, early
detection and therapy. The monograph is web-accessible at
*\<http://www-seer.ims.nci.nih.gov/Publications/ProstMono/\>.*

## Prostate Cancer Funding and Professional Judgment

This professional judgment plan builds from our investment in 1998,
increases significantly in 1999, and extends to 2003. The NIH Plan is
currently in its first year of operation. A major acceleration in
prostate cancer research funding has already begun in 1999 and is
integrated and balanced with the opportunities and needs of the entire
research effort. In fact, the original 1999 estimates of \$170 million
for prostate cancer research have been increased by \$10 million as
additional funding opportunities have been identified primarily by the
NCI, and also in the National Institute of Mental Health and the
National Institute of Deafness and Other Communication Disorders. With
this research program we see the potential to establish a vibrant,
geographically dispersed but well coordinated national program for
research, education, training, and treatment of prostate cancer.

The first year, 1999, sets a target for NIH investment of \$180 million,
almost a 60 percent increase over 1998 funding of \$114 million. This
spending is generally guided by the report of the Prostate Review Group
completed in August 1998. The full plan identifies \$420 million worth
of potential research opportunities that could be supported in 2003. It
should be noted that this estimate is based on our assessment of
scientific opportunities over the next five years without regard to
economic constraints or other competing priorities of the Federal
government.

The NCI budget for prostate cancer has risen considerably in recent
years. In the 1980s the funding level increased gradually from a
1981estimate of \$6.4 million (the first year in which this data was
gathered) to about \$13 million at the end of the decade. Recently this
area has increased with even greater speed reaching \$87 million in 1998
and projected to be \$141 million in 1999.

Over the past three years NIH has implemented a number of initiatives
that capitalize on certain extraordinary opportunities presented by
contemporary science and technology. We are also moving to strengthen
crucial elements of the nation's cancer research infrastructure -- its
cancer centers, clinical trials groups, training programs, and resources
for research reagents and information. The NIH intends to increase its
support for studies relating to prostate cancer. We wish to speed the
generation of new insights into the biology and behavior of this common
tumor and increase the rate at which new insights are translated into
more effective interventions for prevention, detection, diagnosis, and
treatment.

While research activities related to prostate cancer are centered at the
NCI and the National Institute of Diabetes and Digestive and Kidney
Diseases, other institutes also have research activities aimed at
reducing the burden of prostate cancer for all Americans. These
institutes are committed to this goal. Staff of the involved institutes
are in frequent contact with one another. Related programs exist in the
National Human Genome Research Institute, the National Center for
Research Resources, the National Institute of Environmental Health
Sciences, the National Institute on Aging, the National Institute of
Nursing Research, the National Institute of Mental Health, and the
National Institute of Deafness and Other Communication Disorders. These
collaborations maximize the return on NIH's efforts in prostate cancer.
Each of the institutes with prostate cancer research programs, and the
NIH as a whole, recognize that our ultimate success will be measured by
tangible progress against cancer.

## Prostate Cancer Research Activities

The following are intended as a capsular summary of NIH's range of
activities in prostate cancer research, elaborated on in this report:

-   NCI established the Cancer Genome Anatomy Project (CGAP). The goals
    of CGAP are to build an infrastructure of resources, information,
    and technologies. These will provide a platform for the
    establishment of an index of all genes that are expressed in tumors
    and support development of new technologies that will allow high
    throughput analysis of gene and protein expression as well as
    mutation detection. The tumor type with the highest representation
    in the CGAP effort is prostate cancer.

-   NCI established a Prostate Cancer Progress Review Group (PRG) that
    has reviewed NCI's 1997 prostate cancer research portfolio in the
    context of the emerging opportunities for research. The report of
    the Prostate Cancer PRG was issued in August 1998. The portfolio
    review identified approximately 500 NCI projects related to prostate
    cancer.

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-   In 1997-1998, NCI funded (in total or in part) 246 clinical trials
    in prostate cancer including 80 Phase III studies (clinical trials
    involving new interventions closest to approval) and 37 Phase I
    trials (representing the newest potential therapeutic agents for
    prostate cancer). Thirteen NCI trials in prostate cancer are
    underway at the NIH Clinical Center.

-   NCI clinical studies in prostate cancer have significant African
    American participation. One NCI study shows that 14.7 percent of men
    enrolled onto NCI sponsored prostate cancer treatment trials are
    African American while 10.3 percent of the 179,300 Americans
    diagnosed with prostate cancer are African American.

-   NCI staff and the Department of Defense have collaborated in a study
    of treatment data and shown that equal treatment yields equal
    outcome within stage. This finding suggests that all NCI efforts to
    improve prevention, diagnosis and treatment of this disease benefit
    all patients equally. However, NCI staff analyzing Surveillance,
    Epidemiology and End Results (SEER) Program data have shown that
    there are tremendously different patterns of care among African
    American and White men with prostate cancer.

-   NCI's ongoing Prostate Cancer Prevention Trial (PCPT) involves
    18,000 healthy men over the age of 55 to determine if the drug
    finasteride can prevent prostate cancer.

-   NCI's ongoing Prostate, Lung, Colorectal, and Ovarian Cancer
    Screening Trial (PLCO) is assessing the efficacy of prostate cancer
    screening. New PLCO sites are being added to enhance minority
    patient accrual.

-   NCI is sponsoring two trials in which \"watchful waiting" is being
    compared in terms of outcome with surgical removal of the prostate
    and with radiation therapy. These trials are intended to distinguish
    patients needing more aggressive treatment from those with slow
    growing tumors that will never threaten their lives.

-   NCI has established the Urologic Oncology Branch within the Division
    of Clinical Sciences. Major areas of emphasis of this branch are
    prostate and kidney cancer.

-   NCI has established a new fellowship program in urologic oncology
    that will have as a major focus the training of
    clinician-investigators to reduce the burden of prostate cancer in
    all segments of our society.

-   NCI has conducted a large interview-based study of prostate cancer
    in African Americans and Whites. Analysis of the results has not yet
    revealed any specific factor that could explain the racial
    differences in risk. However, further studies are underway,
    including an extensive evaluation of the role of different
    components of the diet.

-   NCI funded or co-funded 11 prostate cancer epidemiologic studies
    beginning in September 1995 with study durations of three to five
    years. Eight of the 11 studies include an assessment of risk factors
    among African American men.

-   An NCI Intramural Prostate Cancer Working Group has been formed, the
    goal of which is the investigation of genetic alterations underlying
    human prostate cancer development and progression. Emphasis is
    placed on the integration of basic research, clinical information,
    and developing technologies and methodologies.

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-   NIDDK has strong programs in basic and clinical investigations on
    prostate disorders. The NIDDK supports an active portfolio of basic
    and clinical investigations on prostate disorders -- benign
    prostatic hyperplasia (BPH), prostatitis, and research related to
    prostate cancer--including genetic and hormonal aspects of prostate
    growth regulation. Basic research includes studies of genes and
    factors -- including hormones, enzymes, neural factors, and vitamins
    -- that affect or may affect or regulate prostate growth or
    transformation to the malignant state; prostate cell structure and
    function in BPH; biomarkers of BPH; and prostate stem cells and stem
    cell genes.

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-   NIEHS and NHGRI focus on identifying genetic changes in the cell
    which lead to initiation and progression of prostate cancer as well
    as the role of gene-environment interactions in prostate cancer
    development.

-   NCRR provides infrastructure for advancing clinical and basic
    studies throughout the nation.

-   NIA addresses the problem from its epidemiological characteristics
    as a disease of high prevalence in old age.

-   NINR supports important efforts in research on symptom management
    following prostate cancer surgery such as urinary incontinence and
    pain and also conducts research on nursing interventions to improve
    quality of life including sexual functions.

-   NIDCR seeks a more complete understanding of bombesin receptor
    function in cancer.

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-   NIMH studies the effects of stress and emotion in men with prostate
    cancer.

### The Cancer Genome Anatomy Project 

The CGAP is an interdisciplinary program to establish information,
reagents, and technological tools needed to decipher the molecular
anatomy of a cancer cell. The overarching purpose of the CGAP is the
comprehensive molecular characterization of normal precancerous and
malignant cells. The Human Tumor Gene Index was initiated in May 1998
with the initial goal of identifying genes expressed during development
of five major cancer sites -- breast, colon, lung, ovary, and prostate.
Over 80 cDNA libraries have been prepared and more than 300,000 partial
cDNA sequences have been generated. To date, about 10,000 putative new
genes have been discovered as a result of the CGAP. All CGAP data and
reagents are made available to the research community without
restriction via the CGAP website located at *http:/ /www. ncbi.nlm.
nih.gov/ncicgap/.*

To begin to examine gene expression profiles during human prostate
cancer progression we prepared and sequenced clones from 20 cDNA
libraries. We used a range of prostate-derived tissue sources, including
microdissected cells (normal epithelium, prostatic intraepithelial
neoplasia, invasive tumor, metastatic tumor), bulk tissue samples
(normal, tumor), and matched normal and tumor prostate cell lines. A
total of 40,637 sequence reads were performed which identified 7,677
unigene clusters expressed in normal or cancerous prostate tissues, 354
novel human genes, 146 prostate specific genes, 389 prostate unique
genes, and 400 candidate differentially expressed genes. Comparison of
cDNA library sequences derived from microdissected cells, cell lines,
and bulk tumor libraries identified both an overlapping and distinct
population of expressed genes from each group. Library normalization
increased both the diversity of sequences and rate of novel gene
discovery.

### The Prostate Cancer Progress Review Group

The NCI has supported and continues to support a very wide range of
basic, clinical, and population-based research projects to elucidate the
causes and biology of prostate cancer and to develop strategies and
technologies for preventing, detecting, diagnosing, and treating
prostate cancer. New data suggest that the application of these research
results may save lives, as evidenced by the declining mortality rate for
prostate cancer among some populations. This ongoing research effort has
provided a wealth of new scientific opportunities that if pursued may
further advance our understanding of prostate cancer and our ability to
care for men with this disease and those at risk of it. The NCI Director
constituted the Prostate Cancer Progress Review Group (PRG) that began
its work in April 1997. The Prostate PRG is one of two pilot groups that
were established to help NCI sharpen the focus of its large,
site-specific research programs. The other PRG focused on breast cancer.
The PRGs are part of NCI's new overall planning framework, which also
relies on Working Groups and Program Review Groups for evaluation, and
planning of the research portfolio.

Specifically, the PRG was given six charges: 1) Identify and prioritize
scientific needs and opportunities that are critical to hasten progress
against prostate cancer. 2) Review an NCI-prepared portfolio analysis of
the current research program. 3) Review recommendations from the
research community generated through Prostate Cancer Roundtable meeting
and Expert Panel reports. 4) Review recommendations from the prostate
cancer advocacy community and from stakeholders. 5) Define and
prioritize the research agenda. 6) Develop an action plan encompassing
both operational and strategic components of the NCI's prostate cancer
enterprise, using the current research program as the baseline for
recommended actions.

Members of the PRG were selected from among prominent members of the
scientific, medical, industrial, and advocacy communities to represent
the full spectrum of expertise needed to develop comprehensive
recommendations on NCI's prostate cancer research agenda. The membership
was also selected for its ability to take a broad view in identifying
and prioritizing scientific needs and opportunities that are critical to
advancing the field of prostate cancer research. The full report of the
Prostate Cancer Progress Review Group can be read on line at
*http://wwwosp.nci.nih.gov/Planning/PRG/default.htm* A hard copy can be
ordered by calling 1-800-422-6237, or by sending an e-mail message to
*nciosppcaprg-r@mail.nih.gov*.

### The Process of Reviewing the Prostate Cancer Portfolio

The PRG assessed the current NCI research portfolio in prostate cancer.
The aim of the portfolio review was to describe the ongoing NCI prostate
cancer research effort, which would then serve as a baseline for the PRG
in formulating its recommendations. The NCI prostate cancer research
portfolio was reviewed within the context of scientific questions and/or
research areas. It became apparent during the Portfolio Analysis that if
the NCI could develop a Common Scientific Outline that could be used for
any specific cancer for comparing research between scientific
organizations, this would be very beneficial to NCI and the cancer
community at-large. The PRG, in addition to its main charge, played a
critical role in providing a basis for the NCI to build this new and
important tool, which will provide a standardized way to scientifically
categorize NCI supported research. This scientific categorization will
allow for thoughtful prioritization of research by identifying
strengths, weaknesses, and trends within the NCI research portfolio. The
Common Scientific Outline may be applied to each type of cancer
individually (e.g., prostate, breast, lung, ovarian, etc.) to identify
gaps in research, commonalities among cancer research fields that may be
capitalized upon, or duplicative efforts that could be streamlined. A
concrete example is the current collaboration between the NCI and the
Department of Defense (DoD). The DoD is piloting the NCI Common
Scientific Outline within the DoD's recent Prostate Cancer Research
Program Announcement. The information from this pilot should provide the
basis for future use of a Common Scientific Outline by both agencies.
This could allow the NCI and DoD, for the first time ever, to compare
effectively their individual research portfolios and to identify those
areas that are undersupported or instances of duplication of effort
between the two agencies.

### Identification of Needs and Resources

The PRG used the portfolio analyses as a "baseline" in formulating their
recommendations. Throughout their deliberations, the PRG relied
extensively on input from outside experts. Key sources of information
included:

*PRG Roundtable.* In June 1997, over 100 members of the prostate cancer
communities, including academic and industrial scientists, clinicians,
and advocates, met in Chantilly, Virginia for intensive discussion. PRG
members nominated the participants. The Roundtable was an open forum
designed to identify and formulate key scientific questions that should
be addressed in the next five to 10 years in prostate cancer research.

*Expert Panels.* The PRG formed seven panels of between three and 20
experts in the fields of Clinical Trial Design and Implementation,
Prognostic Marker Validation, Radiobiology, Screening and Early
Detection, Gene Therapy and Vaccines, Gene Technology and Gene
Identification, and Molecular Epidemiology. The Expert Panels examined
in detail the opportunities, questions, issues, and resources that will
enhance the field of prostate cancer research. The Expert Panels were
encouraged to "be visionary" and to establish expectations of where the
field could be, or should be, in five years and beyond. Panels met
between December 1997 and January 1998.

*Stakeholder Groups.* To ensure that the professional and advocacy
communities were fully represented, the PRG invited the input of 32
"stakeholder" groups --- professional societies and advocacy groups with
an interest in prostate cancer research. Letters were sent to
representatives of the groups encouraging participation, and a special
web site was set up to collect feedback.

### Overall Results of the PRG Analysis of the NCI Portfolio in Prostate Cancer

After reviewing the portfolio of grants funded by NCI, the PRG estimated
that there was over \$82 million in 1997 supporting research in prostate
cancer. While the process of attribution of many scientific projects was
difficult --- funded research projects often address diverse research
topics as well as cancers in multiple tissues --- the PRG was able to
identify the major focus of projects and sorted them according to the
major research areas. It is important to note that some projects overlap
topic areas and are found in two or more categories. Epitomizing the
issue of overlap are animal models for prostate cancer. Reliable and
robust animal models for prostate cancer are recognized by all concerned
as being of critical importance, and so the PRG dealt with this as a
separate category. However, the models are being used to study biology,
detection, diagnosis, prevention, and therapy, thus making it difficult
to code a given project in only one category.

Projects related to prostate cancer conducted within the NCI Intramural
Research Program as well as those sponsored by the Extramural Research
Program were included in the portfolio review conducted by the Prostate
Cancer PRG. In the sections that follow, an attempt is made to convey
the breadth of the NCI portfolio in prostate cancer research.

### Portfolio in Biology and Epidemiology

Understanding the molecular genetic changes associated with progression
from pre-malignant to malignant states is essential to interrupt the
process. The overall emphasis in research supported in this area is to
understand how hormonal, extracellular matrix and possibly infectious
factors modulate the expression of specific genes and, more importantly,
the functional significance of these genetic changes. Investigations
include: the delineation of genetic events in the development of
prostate cancer; the role of sex hormones, various growth factors, their
receptors and binding proteins in the malignant transformation; and the
role of cell-cell and cell-matrix interactions in prostatic
carcinogenesis

One of the major challenges in understanding the pathogenesis of
prostate cancer continues to be the development of relevant models that
mimic changes that occur in human prostatic neoplasms. Currently
available models to study prostatic carcinogenesis include
carcinogen-induced or transgenic animal models, normal prostatic
epithelial cells exposed to various transforming agents in vitro, and
use of human prostatic tissues (normal, benign and malignant).

A high proportion of indolent lesions characterizes prostatic neoplasms
while only a small percentage of these lesions become invasive. Since it
is not possible to predict the biological potential of these lesions
based on histology alone, molecular mechanisms that distinguish
non-invasive from aggressive lesions is a research area of high
priority. Hormones and other signal transducers contribute to the
complex cascade of the metastatic process including cell adhesion and
motility, matrix degradation and angiogenesis.

Classical epidemiologic studies have identified heritability, i.e.,
familial clustering, positive family history, and Mendelian inheritance
patterns, as one of the determinants of prostate cancer. In extending
these findings while the search for predisposing gene(s) continues,
currently supported investigations are pursuing several research
directions. Future challenges will include elucidating the effects of
environmental modulation of gene expression and gene-environment
interactions and assessing risk of combined factors, such as a heritable
component, intrinsic host and behavioral patterns, and environmental
exposures.

Earlier studies have considered various environmental, biological, and
lifestyle factors with conflicting results, often due to methodological
issues. As molecular technology provides the capability for precision
and increased power in epidemiologic studies, research will be needed to
address relevance, validity, and applicability of molecular
determinations in populations. Utilizable biological specimen banks will
be invaluable. Most limiting and complex are the unanswered questions
regarding the identification of influential environmental exposures.

### Portfolio in Preventing Prostate Cancer

There is a 100-fold variation in prostate cancer incidence worldwide.
The factors involved in this extreme variation of prostate cancer
incidence must be investigated and identified to allow development of
rational prostate cancer prevention strategies. Although research on
hormonal factors of prostate cancer is the currently favored model,
research on other modulable exposures, for example selenium intake, will
require further investigation.

Chemoprevention of prostate cancer development is an important research
area given the likelihood that modulable exposure (dietary factors,
carcinogens etc.) may explain the 100-fold variation in prostate cancer
incidence observed worldwide. There will continue to be a substantial
need for developing cellular models for screening of agents and, in
addition, reliable animal models for testing new agents before use in
human subject clinical trials.

### Portfolio in Detection and Diagnosis of Prostate Cancer

The effect of screening on prostate cancer mortality statistics is
unknown. The primary method of screening for prostate cancer, at
present, is by serum analysis for prostate-specific antigen (PSA).
Elevation of PSA may indicate prostate cancer; however, several other
common benign conditions, including Benign Prostatic Hyperplasia (BPH),
are known to be associated with an elevated PSA. The widespread
measurement of Prostate Specific Antigen (PSA) levels in blood has led
to an increased detection rate for prostate cancer. Approximately 30
percent of early stage disease will progress to clinically relevant
disease within the lifetime of the patient. Thus, there is a critical
need to be able to identify those patients at risk of progression who
would benefit from aggressive therapy while sparing low-risk patients
the morbidity resulting from aggressive treatment of indolent disease.

The metastatic potential of prostate tumors is determined by the
capacity of the tumor cells to escape the environment of the prostate
gland, to survive distribution throughout the body, to implant at a
distant site and to stimulate the new environment to produce the
necessary vascularization and metabolic conditions to facilitate
cellular proliferation. Identifying molecular alterations in tumor cells
that reflect the tumor cells acquisition of any of these biological
capacities would identify those patients at highest risk of metastatic
disease.

Many prostate cancer patients initially respond to hormone therapy, only
to fail with the appearance of recurrent disease that is no longer
responsive to androgen or androgen analogs. The biological basis for
androgen insensitivity is not well understood; significant efforts are
being made to determine the role of the androgen receptor in the disease
process. Extremely sensitive molecular technologies detect prostate
specific mRNAs, such as PSA mRNA, in the blood and bone marrow in a
subset of patients with organ confined disease. Initial studies have
shown that patients with extraprostatic cells following surgery or
radiation therapy are at high risk of treatment failure. Continuing
studies are attempting to identify markers specifically associated with
prostate cancer cells that will improve the specificity of the assay.

Prostate cancer is a heterogeneous disease with apparently independent
foci of cancer scattered throughout the gland. The cancer foci have
different malignant potentials and do not pose equal risks for the
patient. Heterogeneity confounds the interpretation of prostate biopsies
since it is not possible to be certain that the most clinically relevant
foci of cancer have been detected.

Families have been identified in which the number of family members
afflicted with prostate cancer is significantly higher than might be
expected based on the rate of disease in the entire population. These
families are particularly characterized by the early age of disease
onset.

The incidence and severity of prostate cancer varies in different ethnic
populations. African American men are more than twice as likely to die
of prostate cancer than Caucasian men. In African American men, prostate
cancer is also generally more advanced at the time of diagnosis. The
biological basis for this racial difference in prostate cancer is not
understood.

There are a number of high-priority research and development areas for
imaging modalities in the detection and diagnosis of prostate cancer.
Ultrasound technology continues to be an important tool in the detection
of prostate cancer. Another focus of prostate imaging research is the
use of magnetic resonance imaging and spectroscopy that have advanced
technologically to the point where large-scale clinical trials could be
initiated for the prostate.

### Portfolio in Treating Prostate Cancer

Clinical management of prostate cancer has, until recently, been
restricted by a limited armamentarium of classical modalities ---
surgery, radiation, androgen deprivation, and (minimally active)
cytotoxic chemotherapy. There remains a need for a broad program for
testing novel approaches, compounds, and targets, for prioritizing
these, and for answering the practical questions necessary for preparing
these for clinical testing.

Management of prostate cancer presents some unique complexities for
oncologists and other clinicians. One set of difficulties is the
inability to reliably distinguish in advance those tumors whose behavior
will be aggressive from the larger subset of indolent tumors, the very
long intervals before clinical trials become mature, and the fact that
good surrogate endpoints are not yet known. The entire clinical trials
capacity for prostate cancer needs to be expanded since the
participation of large numbers of patients can reduce somewhat the time
to definitive analysis of these clinical trials. Moreover, only about 30
percent of patients diagnosed with limited stage prostate cancer will
eventually progress to have clinically relevant disease. This
complicates profoundly the evaluation of therapies because the majority
of patients whose clinical course is inherently benign can overwhelm
recognition of treatment effects in the minority.

Progress in clinical therapy of other malignancies has generally
accompanied our capacity to refine both risk classification and
prediction of therapeutic response or non-response. This has made it
possible to test treatments in more homogeneous clinical cohorts, with
the result that ineffective therapy can be abandoned in favor of earlier
testing of novel approaches. The exploration of defects in cellular
regulatory, signaling, and apoptosis pathways in prostate cancer as
determinants of hormonal resistance is likely to provide a productive
field for testing in the clinical arena in the near future.

Clinical intervention trials, both therapeutic and chemopreventive, have
been hampered by the insensitivity of clinical evaluations for prostate
cancer, the unwillingness of patients and clinicians to undertake
repeated uncomfortable invasive procedures, and the lack of reliable
non-invasive methodologies for response assessment. This is an area in
which the research portfolio is currently virtually empty. Imaging
technologies per se, however, make up an extremely active field of
research and development, with the potential to dramatically improve our
evaluation of potential chemopreventative approaches and of local
therapies such as various modalities of radiation, cryosurgery, etc. and
of the role of adjunctive hormonal, anti-invasive, or other therapy.

### Portfolio in Prostate Cancer Survivorship and Morbidity

The Prostate Cancer Outcomes Study (PCOS) is a major NCI study being
conducted by six out of the 10 registry organizations that participate
in the NCI\'s Surveillance, Epidemiology and End Results (SEER) Program.
The objective of PCOS is to evaluate recent diagnostic and treatment
practice patterns among men diagnosed with prostate cancer in order to
evaluate the prevalence of long-term urinary, bowel, and sexual function
complications subsequent to initial treatment. It is recognized that
more needs to be done in managing incontinence and sexual dysfunction.

Prostate cancer, as the most commonly diagnosed cancer among men in the
U.S., exerts an enormous impact on patients. In addition to the expense
of an estimated \$5 billion spent annually in direct medical care costs
there are questions about quality of life. The NCI portfolio includes
support for the development of instruments to assess quality of life and
interventions to increase health-related quality of life of prostate
cancer patients. Symptom management specific to the sequelae of prostate
cancer therapy should be examined more broadly.

### Portfolio in Prostate Cancer Surveillance

Diet is monitored among the general population, using nationally
representative samples, and among special populations defined by gender,
age, race, and ethnicity. Selected research priorities include
monitoring trends in intakes of specific food groups and nutrients;
identifying food sources of nutrients; and assessing demographic and
other factors that affect changes in dietary behaviors over time.

NCI monitors the dissemination of state-of-the-art diagnostic and
treatment modalities. This research is being conducted using survey
data, tumor registry information from the Surveillance, Epidemiology,
and End Results (SEER) Program, and from administrative data sources
such as Medicare claims linked with SEER data. Innovative approaches are
being developed to relate current and future trends in PSA usage to
prostate cancer incidence and mortality. Other innovative methodologic
approaches that are being used to model trends in prostate cancer
include incidence-based mortality and change point techniques.

### Portfolio in Scientific and Public Resources

The National Cancer Act of 1971 explicitly instructed the Director of
the NCI regarding communication, and the NCI sees communication as a
critical component of the NCI's mission. The NCI not only engages in
education and communication but also supports research into how to
educate and communicate effectively. Many of these efforts are
crosscutting, but some relate to specific cancer sites.

Cancer center support grants (CCSG) provide support to the peer-reviewed
research base of a cancer center within the parent institution. In
addition, development grants (R21) for new research programs in prostate
cancer are exploratory-developmental grants to promote the development
of institution-wide multidisciplinary research programs in prostate
cancer.

Specialized Programs of Research Excellence (SPOREs) focus on
translational research, i.e., the bi-directional exchange between basic
and clinical science in order to move basic research findings from the
laboratory to applied settings involving patients and populations. The
ultimate goal of the SPORE program is to bring novel ideas that have the
potential to reduce cancer incidence and mortality, improve survival,
and to improve the quality of life to clinical care settings. At
present, there are three Prostate Cancer SPOREs: at the Baylor College
of Medicine, at the Johns Hopkins Cancer Center, and at the University
of Michigan Cancer Center. Among the prostate cancer research resources
supported through the NCI are the Community Clinical Oncology Program
(CCOP). These are organizations comprising one or more facilities (e.g.,
community hospitals, clinics, doctors' offices) which together function
as an infrastructure for the implementation of clinical trials in the
community.

Human tissue resources include the Cooperative Human Tissue Network, a
tissue procurement network that provides tissues on request to
investigators. Approximately 10 percent of the tissues provided through
this network are prostate. This effort is spread over the four sites:
Case Western University, Ohio State University, the University of
Alabama, and the University of Pennsylvania. The Developmental
Therapeutics Program (DTP) uses contract resources to discover, test and
develop anti-cancer agents. DTP\'s developmental resources provide for
chemical synthesis, formulation, pharmacology, and toxicology testing
for promising agents through the NCI\'s Decision Network Committee.

### Recommendations of the PRG

While the dollar amount and number of grants attests to a substantial
commitment of NCI to research in prostate cancer, the PRG nonetheless
identified gaps in the research agenda and major new opportunities that
could move the pace of research in prostate cancer forward over the
coming decade. The PRG examined the research portfolio and developed a
ranked listing of priorities for research and the resources needed to
support an expanded program of research. Their recommendations can be
summarized as follows:

*Prostate Cancer Biology, Progression, and Metastasis:* To improve
diagnosis, prevention, and treatment of prostate cancer, it is crucial
to focus future research on molecular, cellular, physiological, and
pathological events that lead to uncontrolled cell growth and
metastasis. In addition, it is critical that we define 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.

*Etiology and Primary Prevention:* To gain a better understanding of the
genes that are important in the development of prostate cancer, NCI
should support an infrastructure that will aid studies of families with
apparently hereditary prostate cancer. NCI should also support studies
of environmental and behavioral factors, such as diet and exercise.
Finally, NCI should support research and development of new technologies
to identify risk factors and how environmental factors modify
predisposing risks.

*Early Detection, Diagnosis, and Prognosis:* Progress in this area will
depend on the development and refinement of tests to detect prostate
cancer to ensure that, whenever possible, the tests detect only those
cancers with the potential to kill their host if left untreated. NCI
should also place major emphasis on the development, validation, and
application of biologic markers or determinants that can provide
reliable prognostic information. At the same time, NCI should continue
to support clinical trials to determine whether screening for prostate
cancer reduces the risk of dying from this disease and should
substantially expand studies of the effects of early detection on
morbidity and quality of life.

*Laboratory and Clinical Models:* A constellation of models must be
developed to mimic distinct characteristics of human prostate cancer.
These models then must be validated to permit a predictable level of
extrapolation to humans. Additional prostate cancer cell lines must also
be developed.

*Staging and Treatment of Localized Prostate Cancer:* New techniques to
detect metastatic cells, predict the response of individual cancers to
different forms and intensities of therapy, and diminish
treatment-related side effects are needed. In addition, the Review Group
noted that prostate cancer appears to be a particularly promising
candidate for gene therapy and recommended significant research in this
area.

*Systemic Therapy:* Systemic therapies are needed for tumors that can no
longer be cured by local treatments, such as surgery or radiation
therapy, alone. The PRG noted that the design and execution of clinical
trials of systemic therapies for prostate cancer is critically
important, and called for substantial and sustained investment in the
infrastructure needed to support clinical trials, develop clear
endpoints, and follow up treatment outcomes.

*Outcomes Research:* "Outcomes" include disease-specific and
patient-focused endpoints used to describe the results of various
interventions in the management of prostate cancer. Better instruments
are needed to assess more accurately the impact of both the treatment
and the disease on patient-focused outcomes. In addition, more data are
needed about all aspects of prostate cancer patients' and survivors'
quality of life.

*Resources Needed:* The PRG unanimously agreed that the education and
training of investigators who will pursue research in prostate cancer
should receive top priority. Other resource needs include databases and
bioinformatics to ensure that the vast amount of information being
generated can be assimilated and exploited; the establishment of a
National Prostate Cancer Repository to procure and distribute tissue
samples from prostate cancer patients; the development and dissemination
of new animal models and cell lines; the development and dissemination
of new technologies for research in prostate cancer prevention,
diagnosis, and treatment; and increased activity in the area of clinical
trials design, including the development of a special prostate cancer
trials consortium.

### New Initiatives in Prostate Cancer Research

Partially in response to the report of the Prostate Cancer PRG and also
as a part of its normal planning process, the NCI has begun a number of
new initiatives with relevance to research in prostate cancer. NCI is
also seeking to communicate more effectively both new and long-standing
initiatives to the extramural research community to stimulate their
increased involvement in the battle against prostate cancer. Toward that
end, NCI has recently added to its website a page describing initiatives
applicable to prostate cancer research these initiatives. The page can
be accessed at *\<http://www.nci.nih.gov/prostate.html\>*. It contains
descriptions of initiatives, hotlinks to other relevant sites, and NCI
contact information. The topics covered in this webpage are:

*Funding Grants as Exceptions to the Payline*. Three times a year the
NCI funds, as \"exceptions\" to its grant policies, a certain number of
grants whose priority scores fall below the payline established as the
cutoff for that year. This is one particularly important way of
supporting meritorious proposals in particular areas. We plan to do this
selectively for meritorious proposals in prostate cancer, particularly
those that deal with topic areas that the Prostate PRG considered
especially compelling or important gaps in NCI\'s prostate cancer
portfolio.

*The Cancer Genome Anatomy Project.* NCI established the Cancer Genome
Anatomy Project (CGAP) to build an infrastructure of resources,
information, and technologies that will provide a platform for the
establishment of an index of all genes that are expressed in tumors.
CGAP will also support development of new technologies that will allow
high throughput analysis of gene and protein expression as well as
mutation detection. The tumor type with the highest representation in
the CGAP effort is prostate cancer. NCI is particularly interested in
engaging members of the research community with access to specimens
representing the different stages/grades of prostate cancer with the aim
of understanding genes relevant to prostate cancer progression and
metastasis. A focus of this effort will be enhancing our understanding
of the relationship between prostate and bone (to which prostate cancer
frequently metastasizes).

*Director\'s Challenge for Molecular Diagnostics.* This initiative
challenges the scientific community to develop a tumor classification
system that is based firmly on the cell biology of cancers, rather than
on microscopic appearance. The assumption behind this initiative is that
a biologically based classification scheme will be vastly more
informative than a morphological one and will lead directly to better
ways of predicting the behavior of cancers and selecting effective
therapy for patients. Prostate cancer is a particularly important area
of application for this initiative, because its behavior is so variable
from patient to patient. Many prostate cancers remain confined to the
gland itself, even after years of observations, while others spread
rapidly to distant organs. Current morphological classification schemes
capture only a small portion of this variability and suggest little
about optimal ways to select therapy.

*Early Detection Research Network*. This Network addresses the crucial
problem of how to develop clinical useful blood tests to detect cancers
early, before they have had a chance to spread beyond the point at which
cure is assured. The goals of the network will be to discover and
coordinate the preclinical development, evaluation, and application of
biomarkers/reagents for the earlier detection of cancer and risk
assessment. We imagine the output of this Network to be a series of
tests for various cancers that can be used effectively to screen for
cancer in large populations or in populations at particular risk.
Prostate cancer will be a particularly important focus of activity
within the new network, and we anticipate that the PSA test is a
harbinger of better things to come.

*Cancer Genetics Network.* For prostate cancer, as for other tumor
types, the genes a person carries is one determinant of his chances of
getting the disease. The identification of susceptibility genes for
prostate cancer is currently at the very early stages. The Network will
serve as a platform for studies of genetic susceptibility to cancer and
for the education of patients and their families. Incorporating all
necessary measures for assuring confidentiality, it will, for example,
include a registry of families with multiple cases of cancer. The
Network will serve as an educational resource to provide counseling to
members of such families and will provide information about studies in
early diagnosis and prevention that they might be interested in joining.
The Network will also provide a means of enabling discovery of the set
of genes responsible for prostate cancer susceptibility.

*International Consortium on Prostate Cancer Genetics (ICPCG*). This
consortium of over 25 groups and multiple investigators performs
collaborative studies on the epidemiology of prostate cancer and, in
particular, on the discovery and characterization of prostate cancer
susceptibility genes.

*Diagnostic Imaging*. Assessing a tumor's location accurately is clearly
crucial to the planning of curative therapy, whether surgery or
radiation. The recently funded imaging network will function as a
national consortium for the evaluation of new imaging technologies
applicable to all body sites. Prostate cancer will be a core component
of their agenda. NCI expects also to announce later this year an
initiative supporting the development of image-guided minimally invasive
treatment for prostate cancer. The goal will be to develop techniques
that will accurately define the anatomic extent of localized prostate
cancer and to concentrate tumor killing modalities (radiation, heat,
cold) within the involved area in a way that spares normal tissue,
preserves function, maximizes quality of life, and reduces cost of care.
We also anticipate that the further development of \"molecular imaging\"
-- the ability to display the molecular pathways and intracellular
functions that determines how a tumor behaves -- will have important
applications to prostate cancer treatment. NCI will soon establish a
number of centers for molecular and functional imaging, whose work will
concentrate on these goals.

*Clinical Trials Restructuring.* NCI is currently re-engineering its
national clinical trials program, to make it faster, more flexible, more
easily accessible to patients, and more responsive to the key questions
in therapy that need to be asked and answered quickly. Tumors of the
lung and the genitourinary system, including prostate, will be a
particular focus of the implementation effort. A number of features of
this massive effort are particularly noteworthy:

-   During the next year we will begin a series of \"State of the
    Science\" meetings to define the key areas for emphasis in prostate
    cancer research.

-   We will implement a new competitive grant program intended to
    support investigators with novel ideas for prostate cancer
    treatment. This program will feature a streamlined applications
    procedure and rapid review.

-   We will convene a meeting of experts in prostate cancer and clinical
    trial methods to coordinate development of a common methodology for
    the conduct and analysis of prostate cancer trials, including common
    endpoints.

-   We will convene an expert group to develop a consensus around the
    important clinical question of how best to manage the patient with a
    rising PSA after surgery or radiation therapy of the primary tumor.

*Informatics and Clinical Trials.* In close coordination with the
overall clinical trials restructuring efforts, we are coordinating the
development of an up-to-date national infrastructure for clinical
research. The obvious need here is to enable the linkage, transfer, and
analysis of biomedical information relating to cancer. The initial
emphasis is on systems to support clinical trials. NCI is currently
collaborating with parallel efforts supported by CapCure targeted
specifically to needs in prostate cancer. We also expect significant
collaborations with interested elements in the computer industry.

*Tissue Banks.* Successful development of molecular diagnostics depends
on availability of tumor tissue specimens. NCI will shortly announce an
initiative to create a National Prostate Cancer Tissue Resource, similar
to its already successful Cooperative Breast Cancer Tissue Resource.

*Correlative Studies Using Specimens from Treatment Trials*.
Establishing correlations between the molecular characteristics of
tumors and the results of treating patients is a direct way of applying
new knowledge about tumor biology to the clinic in an effort to benefit
patients. NCI has invited investigators to submit proposals that
correlate laboratory findings from tumor tissue stored in the tissue
banks of its clinical cooperative groups with the actual results of
therapeutic studies performed by the cooperative groups. Once such
correlations are established by studies like these, the results can be
used in the general care of patients to provide much more accurate
information about likely outcome and optimal choice of treatment.

*Animal Models.* A very high NCI priority is the development of animal
models that truly reflect the behavior of human cancer and its
responsiveness to therapeutic and preventive maneuvers. Such models
would have a profound effect on our ability to test new drugs and new
approaches to treatment. Prostate cancer investigators have already had
some success developing more relevant models. To extend this success,
NCI will establish a consortium that will develop and validate models
for human cancer. We will assure that prostate cancer model development
will take advantage of this initiative. In particular, models for
progression and metastasis to bone are of high priority.

*Clinical Trials in Prevention and Early Detection*. The rationale for
early detection and prevention of prostate cancer is obvious and needs
no further elaboration here. We expect during the next year to fund a
number of clinical trials in prostate cancer prevention. It is likely
that these trials will test the efficacy of dietary constituents, singly
and in various combinations. We will also fund other trials assessing
biomarkers of risk and early detection.

*Rapid Access to Intervention Development (RAID).* Investigators in
academia and in small businesses may be faced with the prospect of
having no means of getting compounds with promise for treatment into
clinical testing. They may, for example, lack access to the resources
necessary for preclinical development (scale-up chemical synthesis,
formulation, pharmacology, and toxicology), that is necessary before
clinical trials can be started. The RAID program places NCI's
development resources at the services of academia and small business, on
a competitive basis, so that no promising compound is barred from early
testing in the clinic merely for lack of development resources. We
expect that the RAID program will dovetail with the new pilot clinical
grant program for prostate cancer described under item 8 above.

*Rapid Access to Prevention Intervention Development (RAPID).* This
program will do for the prevention area in prostate cancer research what
RAID does for treatment.

*Health Services & Economics Research in Prostate Cancer*. The NCI
supports studies within its Cancer Surveillance Research Program (CSRP)
on patterns of care and outcomes of prostate ‑ cancer screening and
treatment, including assessments of the quality of life. CSRP has
conducted studies to describe the relationship between diagnostic
testing patterns and prostate cancer incidence. It also supports the
development of statistical and simulation models that help explain
trends in incidence and mortality and evaluate the cost and
effectiveness of cancer control interventions. Studies using
administrative claims such as the linked data between Medicare and SEER
are also supported.

*Genetic Epidemiology Studies.* The interaction between the genes we
carry and the environment we live in is a subject of great current
interest in cancer research. It seems likely that the great majority of
cancer incidence will eventually be explained by interactions between
genes and exposures. The NCI has recently issued Requests for
Applications (RFA) and Program Announcements PA) in several areas that
support prostate cancer research. [Molecular Epidemiology of Prostate
Carcinogenesis]{.underline} (PA) emphasizes interdisciplinary
collaborations between laboratory scientists in molecular genetics and
biology and cancer epidemiologists to develop and validate biomarkers
for assessment of risk in population subgroups (for example, racial or
ethnic groups), evaluate gene‑environment interactions, and develop
resources such as cohorts and repositories. The RFA on
[Interdisciplinary Studies in the Genetic Epidemiology of
Cancer]{.underline}, offered jointly with the National Institute on
Aging, seeks investigations to identify and evaluate the interactions of
genetic and environmental risk factors leading to enhanced cancer
susceptibility in individuals, families, and populations. This RFA also
seeks research on factors influencing the increase in susceptibility
with age, a key feature of prostate cancer incidence and mortality.
[Diet, Lifestyle, and Cancer in U.S. Special Populations]{.underline}
(PA) focuses attention on the causes of cancer in population groups that
experience unusually high cancer incidence and mortality, such as the
experience of African Americans with prostate cancer.

*Diet Nutrition, and Prostate Cancer.* Several associations of dietary
patterns with prostate cancer have been reported, but the evidence needs
much more interdisciplinary research and analysis. Diets high in
vegetables have been reported to decrease risk, and high fat, saturated
fat, and animal fat to increase risk. Several micronutrients may affect
prostate cancer occurrence, and the effect of food constituents on
molecular events in the prostate is unknown. There is a 100 fold
variation in prostate cancer incidence worldwide. NCI has been studying
international incidence of prostate cancer for a number of years and is
particularly interested in research projects related to understanding
modulable factors (e.g., diet) in international variations in different
racial and ethnic groups.

*Surveillance.* NCI plans a number of enhancements to its Cancer
Surveillance Research Program. This program includes the Surveillance,
Epidemiology, and End Results (SEER) database, which tracks trends in
the incidence and impact of cancer in an approximately 14 percent sample
of the US population. The enhancements will largely take the form of
targeted special studies permitting the development of hypotheses
concerning the origins of observed trends in incidence and mortality
within the population. Prostate cancer is a particularly important area
for emphasis, since the mortality from prostate cancer differs greatly
according to ethnic group and we have little understanding of the basis
for this variation. Similarly, the impact of screening on incidence,
stage at diagnosis, survival, and mortality is an area of great current
interest.

*Leadership Initiatives.* This outreach initiative is directed to
special populations. It is intended to establish and maintain a
structure for dissemination of cancer awareness and educational
activities in minority and underserved communities. An additional goal
is to build a community infrastructure to support participation in
NCI-funded research. These programs will help convey information
concerning prostate cancer and encourage participation of special
populations in the clinical trials to answer many of the important
questions in this disease.

### Clinical Trials in Prostate Cancer

In 1997 and 1998, NCI funded (in total or in part) 246 clinical trials
in prostate cancer including 80 Phase III studies (clinical trials
involving new interventions closest to approval) and 37 Phase I trials
(representing the newest potential therapeutic agents for prostate
cancer). At the NIH Clinical Center 13 NCI trials in prostate cancer are
underway. NCI clinical studies in prostate cancer have significant
African American participation. In one NCI study 14.7 percent of men
enrolled onto NCI sponsored prostate cancer treatment trials are African
American while 10.3 percent of Americans diagnosed with prostate cancer
are African American.

NCI's ongoing Prostate Cancer Prevention Trial (PCPT) involves 18,000
healthy men over the age of 55 to determine if the drug finasteride can
prevent prostate cancer. NCI's ongoing Prostate, Lung, Colorectal, and
Ovarian Cancer Screening Trial (PLCO) is assessing the efficacy of
prostate cancer screening. NCI is sponsoring two trials in which
"watchful waiting" is being compared in terms of outcome with surgical
removal of the prostate and with radiation therapy. NCI has conducted a
large interview-based study of prostate cancer in African Americans and
Whites. NCI funded or co-funded 11 prostate cancer epidemiologic studies
beginning in September 1995 with study durations of 3-5 years. Eight of
the 11 studies include an assessment of risk factors among African
American men.

Prostate cancer incidence is higher among African Americans (1987-1991;
163 per 100,000) than Whites (121 per 100,000). The disease generally
occurs more frequently among Whites in the United States than in Europe.
Asians, in comparison, have very low rates of occurrence (for China,
less than one percent of the rate among African Americans). In the
United States, mortality due to prostate cancer is two-fold greater
among African Americans (52 per 100,000) than Whites (24 per 100,000)
(Cancer Rates and Risks, 1996). NCI investigations are ongoing to
identify risk factors for prostate cancer in several populations,
including studies of African Americans and Whites in the United States
and of Chinese in Shanghai.

The Human Genome Project has undertaken an effort to identify genes
associated with the familial transmission of risk. The NCI plans studies
to evaluate genetic determinants of susceptibility in the general
population, including the impact of metabolic (e.g., polymorphism for
5-alpha reductase) and functional polymorphism (e.g., polymorphism in
the androgen receptor). These studies will take advantage of the natural
variation in polymorphism frequency between African American, White, and
Asian populations. Vasectomy has been linked to prostate cancer among
U.S. Whites, but several other studies provided inconsistent results.
This remains an area of continued investigation. An etiologic link with
benign prostatic conditions is also being investigated. Dietary fat has
been linked to prostate cancer in several studies. This and other
dietary factors (e.g., level of consumption of fruits and vegetables)
are now being examined as risk factors in the African American, White,
and Chinese study groups, providing an opportunity to assess risk over a
broad range of dietary patterns.

The Cancer Therapy Evaluation Program (CTEP) is the program within the
Division of Cancer Treatment and Diagnosis (DCTD) of the NCI. This
program plans, assesses, and coordinates all aspects of clinical trials
including extramural clinical research programs, internal resources,
treatment methods and effectiveness, and compilation and exchange of
data as it pertains to the development and evaluation of anticancer
agents. Many of the compounds in early development or preclinical
development will be suitable for studies in prostate cancer, since broad
phase II solicitations typically include the common solid tumors,
including prostate cancer.

Some agents specifically being developed for patients with prostate
cancer include:

-   Vaccine trials for patients with recurrent disease and for patients
    in an adjuvant setting, including vaccinia and fowlpox based
    vaccines. PSA-3 peptide vaccine and rF-PSA, the recombinant fowlpox
    PSA vaccine, are both scheduled for IND filing in 1999.

-   Combinations of estramustine with tubulin interactive agents
    (taxanes, CI-980, TCA, dolastatin 10)

-   A phase II trial has just been proposed to combine taxotere with
    follow-up treatment with thalidomide

-   Other relevant interesting biologic agents are in development.
    Trials of herceptin are being reviewed currently. Growth factor
    antibodies (anti-VEGF, anti-EGFR), and Newcastle disease virus for
    intratumoral injection should have prostate clinical trials this
    year.

-   Compounds with novel targets including arsenic trioxide, farnesyl
    transferase inhibitors (from several sources), rebeccamycin,
    epothilones (active in taxane resistant lines), rapamycine
    analyogue, PS 341 proteosome inhibitor, halichrondrin, and
    benzoylphenylurea are all potentially applicable to prostate cancer
    in 1999. Fenretinide will begin Phase II trials in prostate cancer
    shortly, to explore its anti-apoptoic mechanism, and other retinoids
    are being considered for clinical evaluation.

Other agents that target angiogenesis and the metastatic phenotype
including vitaxin, endostatin, Sugen 5416 which inhibits VEGF signaling
through Flk-1, and thalidomide as well as newer generation matrix
metalloproteinase inhibitors will be used in trials in prostate cancer
and a number of new clinical trials will begin in 1999. Patients with
hormone sensitive disease will be eligible for a planned trial of
leuprokide to maximal PSA reduction and then maintenance thalidomide,
with reinstitution of leuprolide when PSA rises, plus thalidomide if not
previously received.

Pharmaceutical collaborators will be sponsoring prostate cancer studies
with a number of agents that are being co-developed with NCI, including:
antisense BCL-2 and Onyx 015, E1B deleted adenovirus.

Among the more interesting of the new approaches being studied in
CTEP-sponsored trials in 1997 and 1998 are: vaccine trials involving
fowlpox or vaccinia viruses that express PSA, thalidomide (as an
anti-angiogenic agent) + combined androgen blockade, and a number of
agents that may target critical signaling pathways, bryostatin-1,
phenylbutyrate + all-trans-retinoic acid, flavopiridol, perillyl
alcohol, and dolastatin -10.

CTEP anticipates initiating Phase I or II clinical trials with
approximately 25 new agents or combinations in the next 12 to 18 months.
In addition, 15 clinical trials in prostate cancer are in review and
should be active shortly, including six Phase I, five Phase II,
three-Phase III and one correlative science study. Overall, 40 to 50
clinical trials are likely.

### Clinical Trials Restructuring and Genitourinary Cancers

The NCI is engaged in a major restructuring of its entire extramural
large scale clinical trials program, its mechanism for carrying out the
research with the greatest immediate effect on patient care. This
restructuring, the most far reaching such reorganization in 15 to 20
years, is one outcome of extensive analysis and review of NCI programs
by extramural scientists, patients, and advocates carried out over the
last several years at the request of the NCI Director. NCI proposes to
jump-start an expansion of clinically related research on urologic
cancers by making these malignancies the focus of the set of pilot
projects that together constitute a new framework for promoting and
developing a rationale and innovative clinical research program for any
and all types of cancer. A permanent ongoing series of nationally
constituted State of the Science meetings in genitourinary cancers
intended to identify needed resources (such as standardized outcomes
endpoints), gaps in clinical research portfolios, and new clinical
research opportunities. The recommendations and work products of these
State of the Science meetings will be disseminated broadly to active
investigators, specialty societies, advocacy organizations, and to the
public via NCI information resources. It is anticipated that broad
availability of this information will serve to stimulate innovative
proposals for clinical trials in genitourinary malignancies, especially
where important opportunities are identified.

1999 will see the establishment of a new entity that will accept
developed clinical phase III trial proposals from any source and select
all those that are considered of high merit to utilize the funding and
resources of the NCI\'s clinical program and network. This Genitourinary
Cancer Concept Review Committee will be nationally representative and
composed of oncologists and Genitourinary physicians, clinical and
laboratory scientists with special expertise related to genitourinary
cancer, patients and patient advocates, biostatisticians, and some NCI
staff. This committee will review, critique, and rank all proposals for
randomized trials. The highest-ranked trials will be opened in the
national network of qualified clinical investigators and physicians, and
their patients, and will receive NCI funding for the scientific
leadership and for reimbursement for research personnel costs on a
per-case basis.

Another key aspect of the new framework (and a distinct departure from
prior practice) will be the creation of a system that will provide all
qualified investigators and eligible patients, regardless of their
institutional or other affiliation, access to enrollment on any NCI
supported phase III clinical trial in genitourinary cancers. Another new
entity, a Cancer Trials Support Unit (CTSU) will be created to
facilitate the transition from the old system to the new system and to
provide a way to verify the accuracy of data arriving from doctors not
affiliated with the study leadership, and for reimbursing the costs
associated with recruitment of patients.

We anticipate that, taken as a package, this would be a much more
comprehensive approach than the more conventional approach of increasing
the number of centers of excellence, or adding consortia or Cooperative
Groups. By opening up the clinical trials system to investigators and
patients, these new initiatives should serve to expand substantially the
pool of new approaches and clinical trials in prostate and genitourinary
cancer, as well as providing the means to promote and make accessible to
all patients the studies of the highest priority questions.

National Institutes of Health

Planning for Prostate Cancer Research

# [Part II: Five Year Professional Judgment Estimates]{.smallcaps}

## National Institutes of Health: Total Professional Judgment Estimate

Planning for discovery is both laced with uncertainty. The NIH
facilitates asking questions and creating tools and resources. We do not
order specific study designs or specific products. Thus, our
professional judgment report largely describes vehicles that the larger
scientific, clinical, and industrial enterprise would fill with specific
ideas, clinical trials, experiments, and technologies. Exactly which of
these will flesh out the NIH Plan will be determined by the final
availability of resources, by what projects come forward, what projects
are ready to go, and what projects are deemed best through independent,
competitive peer-review processes. In summary, this report identifies
potential prostate cancer research opportunities worth about \$420
million in 2003.

#### Five Year Professional Judgment Estimate

  --------------- ------------ ----------- ----------- ----------- ----------- ----------- -----------
  (in thousands)  1998         1999        2000        2001        2002        2003        98-03
                  (baseline)   Estimate    Estimate    Estimate    Estimate    Estimate    Change

  NCI..........   \$86,907     \$141,500   \$211,000   \$267,000   \$307,500   \$340,000   \$253,093

  NIDDK...\...    16,223       26,100      31,300      37,900      46,200      56,900      40,677

  NHGRI...\...    4,343        4,769       5,893       6,326       6,803       7,327       2,984

  NCRR.......     2,086        2,532       4,000       4,500       5,000       5,500       3,414

  NIEHS......     1,261        2,300       3,110       3,610       4,210       4,910       3,649

  NIA..........   1,402        1,540       3,000       3,000       3,000       3,000       1,598

  NlNR........    625          690         800         900         1,000       1,100       475

  NIMH.......     415          478         615         715         815         915         500

  NIDCD...\...    349          394         458         458         458         458         109

  Total NIH\...   113,611      180,303     260,176     324,409     374,986     420,110     306,499
  --------------- ------------ ----------- ----------- ----------- ----------- ----------- -----------

## National Cancer Institute

For each area of the Plan, we state the needs, or goals, in terms of
priority questions for which answers are needed. This is followed by a
description of the strategies and plans by which we hope the questions
will be answered and the goals met. While some of the initiatives
described here are not specific to prostate cancer, they are so relevant
to prostate cancer that we included them expecting that they will help
us answer important prostate cancer questions. For each goal we have
tried to be as explicit as possible. We have attempted to cost out
carefully and accurately the type, number, and size of the projects and
investments that we can reasonably predict that the current pipeline of
research and development would demand and on which the current research
capacity is capable of rapidly acting. In the following pages, we
describe in depth four areas of research opportunities by which we have
formulated this professional judgment budget: Clinical Science;
Translational Science; Risk, Burdens, and Outcomes Science; and Basic
Research and Discovery. The order of these sections relates to the time
expected to elapse between the research and the potential effects on
patients with, or at risk for, prostate cancer.

The near-term goals achievable through clinical science, such as
clinical trials, are, in a sense, easier to plan, and are listed first.
The mid-term goals of translational research and research on cancer
burdens and outcomes follow. And, finally, we describe the more
long-term investments in basic research. For each of these four areas,
we expect progress to be made through individual and collaborative
investigator-initiated research, as well as through more directed
programs.

#### How NCI Plans for Discovery in Prostate Cancer

To capture the many new opportunities in all types of cancer research,
the NCI has engaged, for several years, in an extensive process of
planning and implementation. Our strategy covers the cycle of evaluating
the state of the science, identifying opportunities, and reviewing the
results of our efforts preparatory to launching a subsequent scientific
effort. These steps are:

-   *Conduct Cancer Research Program Reviews:* The NCI's Program Reviews
    were conducted to review and reform, when needed, the major
    infrastructures by which cancer research takes place in this
    country. Outside panels conducted the reviews and made
    recommendations that we have begun to implement. The Program Reviews
    covered: Cancer Centers, Clinical Trials, Drug Discovery and
    Development, Cancer Prevention, and Cancer Control. The charge to
    each of the review groups was to recommend whatever changes were
    needed to make sure that the best science was supported in the most
    effective and efficient ways, to most rapidly and most predictably
    reduce the burden of cancer. Each group's report can be found at
    *http: //deainfo. nci. nih. gov/ advisory/ bsaprgr.htm.*

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-   *Identify Extraordinary Opportunities:* We established areas of
    extraordinary opportunity for new investment priorities. This has
    resulted in the initiation of dozens of new programs aimed at
    speeding progress in cancer research. Expanded investment in each of
    these Extraordinary Opportunities will help us overcome current
    limitations in the speed of progress against cancer, will impact all
    cancers, and can be articulated in terms of tangible plans with
    achievable objectives. The Extraordinary Opportunities are described
    in NCI's Bypass Budget document, [The Nation's Investment in Cancer
    Research]{.underline} *([http: //wwwosp. nci. nih. gov/ NCIWEB/
    planning. htm)](http://wwwosp.nci.nih.gov/NCIWEB/planning.htm)).*

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-   *Develop Disease-Specific Progress Reviews:* These reviews assess
    our current portfolio of disease-specific research; identify gaps,
    barriers to progress and needs; and recommend what we need to make
    progress against the specific cancer site being reviewed. Progress
    Reviews in Breast and Prostate Cancer were completed in 1998.

The request by the Congress to outline the NIH professional judgment for
prostate cancer research over the next five years comes at an opportune
time. This past year, we received the Report of the Prostate Cancer
Progress Review Group which is described in the first phase of this two
part report to Congress**, "**Planning for Prostate Cancer Research:
Expanding the Scientific Framework." This report made dozens of
prioritized recommendations for a National Prostate Cancer Research
program. We were gratified to see that many existing initiatives and
process reforms already provide the vehicles for implementation of this
report. Since the report was presented in September 1998, the NCI has
been actively developing specific implementation plans. We have already
begun to enact this National Prostate Cancer Research Program in three
ways:

-   Linking current and potential prostate cancer researchers to a
    "menu\" of new research initiatives, resources and funding
    opportunities.

-   Modifying existing NCI initiatives to tailor them to the prioritized
    needs of the prostate cancer research community.

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-   Creating new initiatives to fill in gaps in identified, high
    priority areas. Examples include a mechanism to rapidly fund new
    clinical trials in prostate cancer and a new, national, prostate
    cancer tissue resource.

Achieving these goals will require the active participation of the full
prostate cancer research community and adequate resources. To ensure the
former, we have engaged the prostate cancer and urology research
communities in an outreach and communication campaign to make
researchers aware of the full range of new opportunities in prostate
cancer research. We have created a special page on the NCI web site
calling attention to new opportunities in prostate cancer research
*(http://www.nci.nih.gov/prostate.html)*, and we are advertising this
site at meetings and in medical and scientific journals.

## NCI's Clinical Science

### Statement of Needs

The progression of a new drug or biological agent, whether for cancer
prevention or treatment, from laboratory discovery to clinical testing
occurs through an integrated series of steps. These span: preparing the
new agent for administration to people; testing it in people to
establish safety and assess benefit; and comparing it to standard
approaches to see whether it really represents an advance. As described
below, our Prostate Cancer Research Plan will enable us to circumvent
barriers that currently exist at each of these steps. The Plan will
expedite the several pre-clinical steps that develop new molecules into
innovative drug candidates (see our section on Translational Research).
It will accelerate and amplify our early clinical trials program and
reorient it to provide scientific and clinical validation of new
approaches; this will pave the way for more informative clinical testing
and more effective discovery. And finally, it will broaden and speed our
approach to the large randomized trials involving many centers, so that
the most promising findings in early trials are subjected quickly and
efficiently to definitive tests of efficacy.

In addition to strengthening clinical trials and drug discovery
capabilities, the NCI has begun to explore an increasingly visible area
of treatment -- complementary and alternative medicine (CAM). Americans
are turning in record numbers to complementary and alternative therapies
for cancer and other diseases and conditions. In response, the NCI has
established the Office of Cancer Complementary and Alternative Medicine
(OCCAM). This office seeks to promote and support research in the
various disciplines and modalities associated with the field of
complementary and alternative medicine as they relate to the diagnosis,
prevention and treatment of cancer and the management of cancer
patients. We anticipate that that this Office will be actively involved
in efforts to evaluate strategies proposed by the CAM community that are
relevant to prostate cancer.

Our Prostate Cancer Research Plan for clinical sciences can be separated
into two distinct parts. The first three Strategies will help us develop
the infrastructure we need to speed new ideas from the laboratory to the
clinic; expand our nation's clinical trials system so that all who would
benefit can easily participate; and develop a sophisticated informatics
system linking centers, physicians, researchers, and patients. While
these Strategies are not prostate-specific, they lay a "foundation for
discovery" that will facilitate enhanced research capability in prostate
cancer as well as all other types of cancer. In the second set of
strategies, our expanded infrastructure will help us to answer key
scientific questions, such as whether early detection of prostate cancer
really does lead to decreased mortality, and the potential morbidities
associated with prostate cancer screening; test exciting new treatments,
such as image-guided therapy; and conduct much needed clinical trials in
prostate cancer prevention.

### Strategies & Plans: Early Clinical Trials

Goals:

-   Develop the infrastructure and processes needed to quickly assess
    and validate treatment interventions.

-   Test new agents that have not been used against prostate cancer.

-   Test agents and approaches directed at novel and specific targets
    relevant to prostate cancer.

Initiatives:

"[QuickTrials" Program for the Rapid Approval of Early Clinical
Trials]{.underline}

This would be a new grants program to provide a rapid and efficient way
to move new ideas for therapeutic interventions into Phase I and II
clinical trials for prostate cancer. This program would be set up in
recognition of the urgent need for new types of interventions that are
effective at different stages of prostate cancer, as well as the growing
number of intervention ideas that are ready to be tested in patients.

This program would also be developed in response to the unsuitability of
conventional application and review procedures, which have lengthy
review cycles more suitable for larger scale or more protracted
projects, and in which evaluation of untested leads tends not to fare
well because of the absence of preliminary data. The NCI's goals would
be to increase the number of patients participating in early clinical
trials by two- to three-fold and to initiate 10 to15 new trials.

###### Cancer Therapy Evaluation Trials 

There is a changing emphasis in cancer research to use molecular-target
based drug discovery and to create research tools for discovery and
development. These changes provide the research tools needed to conduct
clinical trials that can answer the questions about why a particular
therapeutic intervention does, or does not, lead to a beneficial
response. There is likely to be a high volume and continuously
increasing stream of compounds and research approaches in the pipeline
that would need to be brought rapidly into clinical testing.

This year, through NCI's Cancer Therapy Evaluation Program in Prostate
Cancer, we will initiate approximately 35 new Phase I/II trials with
agents directed against a number of particularly promising molecular
targets and mechanisms. The targets include:

-   angiogenesis and metastasis, the processes by which cancers induce
    new blood-vessel formation, invade these blood vessels, and spread
    throughout the body;

-   growth factors and their receptors, which mediate growth signals to
    cancer cells; and

-   the expression of tissue-specific genes expressed selectively in
    prostate or prostate cancer cells, thus allowing for the targeting
    of tumor-killing substances to these cells.

Compared to the 1998 level of effort, NCI plans to more than double the
number of early clinical trials in prostate cancer in the first year.

### Strategies & Plans: Multi-center Clinical Trials Program

Goals:

Enrich scientific input into clinical trials conception and design,
streamline operations, and broaden access to trials participation among
both patients and physicians across the country.

-   Target critical, pressing clinical questions facing patients with
    prostate cancer.

-   Restructure the clinical trials system to be as effective,
    efficient, and accessible as possible.

Initiatives:

[Treatment Trials in Prostate Cancer]{.underline}

In large clinical trials we compare promising new therapies to standard
treatment approaches. These studies are designed to show definitively
what works and what doesn't, and to provide the evidence base for
determining the standard of cancer care.

We expect several new Phase III trials to be initiated this year that
will attempt to optimize hormonal and chemotherapeutic approaches for
the most common clinical presentations. These include:

-   after prostatectomy: adjuvant therapy with androgen deprivation,
    with and without mitoxantrone and prednisone;

-   after prostatic irradiation: adjuvant therapy with androgen
    deprivation, with and without estramustine + etoposide + paclitaxel;

-   before radiation, comparison of the now-standard 8 weeks of androgen
    deprivation with more prolonged (28 weeks) androgen deprivation;

-   after initial hormone failure: secondary hormonal therapy with
    ketoconazole / hydrocortisone versus chemotherapy with
    estramustine/paclitaxel versus biological therapy with vitamin D2;

-   for androgen-independent disease (including rising Prostate Specific
    Antigen only): estramustine + docetaxel versus mitoxantrone +
    prednisone.

We described above the new multi-center trials that will be activated in
the next few months. In subsequent years the choice of which new trials
to activate will depend on the outcome of current planning efforts, as
well as on the small pilot studies of novel approaches that are
currently in early stages. It seems likely that our future clinical
trials agenda will focus on the following questions:

-   for patients with androgen-independent disease (including rising
    PSA): studies of chemotherapy with and without bisphosphonates;

-   for asymptomatic patients with androgen-independent disease
    manifested only by a rising PSA: studies of matrix metalloproteinase
    inhibitors, antiangiogenesis agents, bisphosphonates, vaccines,
    molecules that interfere with cell signaling, interactions with
    growth factors, or other cancer-relevant pathways;

-   for patients with rising PSA after primary therapy with
    prostatectomy or radiation: Trials of high-priority agents in which
    the agents (alone or combined with standard therapy) are compared to
    standard therapy or to each other;

-   for patients with newly diagnosed, high-risk presentations (high
    grade or bulky disease) receiving radiation as primary therapy: (a)
    large-scale evaluations of brachytherapy or three-dimensional
    conformal radiation; (b) radiotherapy with sensitization using gene
    transfer;

-   for patients with newly diagnosed localized tumors of "normal"
    risk: (a) definitive study of prostatectomy versus
    brachytherapy; (b) adjuvant trials combining anti-angiogenesis
    agents with current hormonal strategies.

[Restructuring the NCI Clinical Trials Program]{.underline}

NCI and many of the clinical researchers the Institute supports are
fundamentally re-engineering the Institute's clinical trials program.
The aim is to enrich the scientific input into clinical trials
conception and design, streamline operations, and broaden access to
trials participation among both patients and physicians across the
country. Pilot implementation steps are planned that will test new
systems for identifying the best trials, improving trial planning,
speeding trial activation, and improving availability of trials to
patients throughout the country.

Prostate and lung cancers will be the two major tumor categories that
will serve as the primary testing grounds for these new planning and
expanded access efforts. NCI has already begun coordinating development
of a common methodology for the conduct and analysis of prostate cancer
trials, including common endpoints. In addition, during the next year
NCI expects to begin a series of State of the Science meetings to define
the key areas for emphasis in clinical research on prostate cancer.

### Strategies & Plans: Informatics and Clinical Trials

Goals:

-   Enable the linkage, transfer, and analysis of biomedical information
    relating to cancer.

-   Use informatics to make clinical trials more efficient and more
    accessible.

Initiatives:

###### National Cancer Informatics Infrastructure for Prostate Cancer Clinical Trials

As part of its clinical trials restructuring initiative, and in close
collaboration with outside experts in academia and industry, NCI is
developing a national Cancer Informatics Infrastructure to enable the
linkage, transfer, and analysis of biomedical information relating to
cancer. The initial emphasis of this project is on systems to support
clinical trials. NCI is currently collaborating with CapCure, a private,
national prostate cancer organization, in the development of a consensus
terminology for prostate cancer and common standards for form design.

### Strategies & Plans: Clinical Early Detection Markers

Goals:

-   Determine whether early detection impacts mortality and whether
    routine screening of asymptomatic men carries a net benefit.

-   Identify the effects of early detection on morbidity, mortality, and
    quality of life.

Initiative:

###### Enhancements to the Prostate, Lung, Colorectal and Ovarian Screening Trial

The ongoing PLCO Cancer Screening Trial is designed to determine whether
yearly screening for prostate cancer using the Prostate Specific Antigen
(PSA) blood test and Digital Rectal Examination (DRE) will decrease
mortality from prostate cancer. The PLCO Trial will enroll 75,000 men,
who will be randomized into a screened group (37,500 men) and a "usual
care" group (37,500 men). The screened group will be screened at yearly
intervals for four years for prostate cancer. The "usual care" arm has
been asked to continue their usual medical care with their physician.
Both groups will be followed up with respect to cancer occurrence,
morbidity and/or mortality for ten years after entry into the PLCO
Trial.

Planned enhancements to the PLCO Trial would include two additional
years of screening for the screened group and an additional three years
of follow-up in both groups for a total of thirteen years of follow-up.
These enhancements would increase the ability to detect possible
beneficial effects of screening, such as decreased morbidity or
mortality. The two additional PSA screenings would also provide for two
additional specimens to be collected from every screened participant.
These additional specimens would be placed in the PLCO Biorepository.
The PLCO Biorepository would provide a important resource for doing
future studies, including: evaluation of emerging candidate early
detection or prognostic markers; studies of risk factors; and
investigations into nutrients or lifestyle factors that reduce risk of
prostate cancer.

### Strategies & Plans: Image-Guided Therapy

Goals:

For localized tumors that require therapy, imaging has benefits that are
getting closer to realization. The combination of using precise imaging
techniques with therapeutic sources of radiation and high-performance
computing has greatly improved our ability to target radiation
treatments to a tumor\'s three-dimensional contours. In principle,
imaging techniques can be interfaced with other tumor-destroying
modalities as well, so that tissue destruction can be more precisely
guided and is therefore less likely to harm normal surrounding tissue.
In addition, medical therapies such as gene therapy vectors or toxic
chemicals can also be delivered directly to tumor tissue using
image-guided therapy in conjunction with catheter delivery systems.

These minimally invasive approaches to local treatment all depend on
precise delineation of the treatment volume and accurate means of
delivering the energy/agent to tissues and monitoring its effects. These
methods hold great potential for minimizing surgical trauma, shortening
recovery time, and reducing health costs. These methods are all
potentially applicable to prostate cancer; however, difficulties in
accurately delivering the therapy to the target tissue, sparing normal
tissue, and monitoring the tissue damage created by the therapy have all
posed serious limitations to wider clinical testing and usage.

-   Assess and validate technologies to facilitate image-guided therapy.

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-   Develop and refine technologies for image-guided therapy and make
    them available for clinical application.

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-   Integrate imaging technologies into the design of therapeutic
    interventions and in following the outcomes of treatment.

Initiative:

###### Technology Development and Testing in the Diagnostic Imaging Program

The Diagnostic Imaging Program would develop an initiative using a
variety of support mechanisms to stimulate further technical development
of these minimally invasive local therapies. This would require creating
multidisciplinary research groups including biologists, clinicians,
engineers, physicists, and computer scientists. When techniques are
developed that are suitable for clinical testing, these would be carried
out within the institutions and networks that NCI already supports under
existing grant mechanisms. An example is the newly funded American
College of Radiology Imaging Network, which will conduct imaging
clinical trials relating to cancer diagnosis and therapy.

### Strategies & Plans: Prevention Trials

Goal:

Progress and opportunities in prostate cancer chemoprevention are
closely tied to the integration of promising chemopreventive agents, the
identification of intermediate endpoint biomarkers, and development of
new trial cohorts and more efficient clinical trial designs.

-   Evaluate promising preventive agents in clinical trials.

Initiatives:

[Developmental Clinical Prevention Trials (Proof of
Principle)]{.underline}

The time is ripe for evaluating a growing list of promising
chemopreventive agents through the identification of several new
high-risk study populations, including:

-   Approximately one million newly identified subjects per year with
    biochemical abnormalities (elevated PSA and negative biopsy) and

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-   First degree relatives of prostate cancer patients (probands) with
    familial or hereditary prostate cancer syndromes.

These early chemoprevention trials would use intermediate endpoint
biomarkers as primary endpoints. Incorporation of new genetic and chip
technology would enhance the identification of select panels of prostate
specific genes and proteins as surrogate endpoints.

Several types of agents and approaches are of particular interest and
include: proapoptotics, signal transducers, antiangiogenics,
isoflavones, differentiating agents, rational combinations
(antiandrogens with selenium), and gene therapy. New pilot trials of
novel agents and micronutrients (selenium, lycopene, vitamin E, vitamin
D analogs and soy isoflavones) are planned and would be submitted for
review.

Intermediate Clinical Prevention Trials (Proof of Efficacy)

The time is right for conducting several prevention trials of
intermediate size (500 to 1000 subjects) using cancer incidence as the
measured endpoint in two specific study populations:

-   High-risk subjects and

-   Subjects with prostatic intraepithelial neoplasia.

These trials would efficiently establish the role of chemoprevention for
prostate cancer in selected high-risk populations.

###### Large-Scale Prostate Cancer Prevention Trials in the General Population 

Several agents, including selenium and vitamin E, are ready to be tested
in a large prostate cancer chemoprevention trial. These primary
prevention trials would be completed in study subjects with risks
similar to the general population and therefore require larger numbers
of subjects in order to observe an effect of the chemopreventive agents.
These trials would definitively establish the benefit (efficacy and
safety) of select antioxidant micronutients for prevention of prostate
cancer in the general population.

### Strategies & Plans: Investigator-Initiated Research

Goal:

-   Maintain excellence and accelerate progress in
    investigator-initiated research by increasing the pool of
    researchers and clinicians and the number of grants funded in
    clinical science.

Initiatives:

###### Research Project Grants in Clinical Science

A principal support mechanism used by the NCI to foster enhanced
investigator-initiated research into prostate cancer is the Research
Project Grant. This mechanism permits both basic investigations into
cellular and molecular questions, and research into creating
interventions that translate our knowledge into improvements in
treatment, prevention, and care. NCI fully expects the research
community to respond with research proposals applicable to prostate
cancer. NCI will pay particular attention to applications that address
those aspects of prostate cancer research identified by the Prostate
Cancer Progress Review Group. It is anticipated that during the course
of this Five-Year Plan, approximately 215 additional
investigator-initiated research grants focused on prostate cancer would
be supported. Of these, approximately 55 would specifically address
clinical science questions in prostate cancer.

Additional Investigator-Initiated Research Grants in Prostate Cancer:
Funding Grants as Exceptions to the Payline

NCI expects to use a portion of its grant funds to support high-priority
applications relevant to prostate cancer. We expect to give special
attention to applications that fall within the defined areas of
extraordinary opportunity in the Bypass Budget but fail to meet the
established payline. The NCI would pay particular attention to
applications addressing aspects of prostate-cancer research that are
described as high-priority and important gap areas by the Prostate
Cancer Progress Review Group.

## NCI's Translational Science

### Statement of Needs

"Translational Science" is an overarching term encompassing the steps
that must be taken to move or "translate" a new detection or diagnostic
method or preventive or treatment intervention from the laboratory bench
to its ultimate clinical use for patients. As we learn more about how
prostate cancer develops and progresses, a number of promising
approaches to prevention and treatment have been identified. These
include inhibiting angiogenesis (the formation of tiny blood vessels
that feed the tumor); inhibiting steps in the cell cycle in order to
promote the death of cancer cells; and manipulating the immune system.
However, to capitalize on this new knowledge, we will need substantial
and sustained investment in the infrastructure to allow development and
testing of important emerging basic science discoveries into clinically
useful products.

Because "Translational Science" is an extremely broad area, our Prostate
Cancer Research Plan in Translational Science is necessarily diverse,
covering such things as:

-   Discovery of new prostate cancer treatments and preventive agents
    based on the molecular mechanisms that underlie prostate cancer
    initiation and progression;

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-   Procurement and dissemination to the research community of
    well-characterized prostate tissue;

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-   Establishment of the molecular profiles of premalignant changes and
    of cancers at different stages of development for the purpose of
    improving tumor classification;

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-   Development and validation of new biomarkers that distinguish
    between aggressive and indolent prostate cancers;

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-   Enhancement of the capabilities of imaging technologies to identify
    the biological properties of a precancerous or cancerous cell that
    will predict clinical behavior; and

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-   Enhancement of the NCI's Specialized Programs of Research Excellence
    to facilitate translational research.

### Strategies & Plans: Drug Discovery

Goals:

-   Base discovery and clinical testing of new agents for cancer on the
    molecular mechanisms that underlie neoplastic transformation, cancer
    growth, and metastasis.

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-   Fund the rapid movement of agents from academic and other
    laboratories into the clinic.

Initiatives:

###### Rapid Access to Intervention Development (RAID) Program 

This program enables investigators to begin clinical trials with novel
molecules discovered in academic laboratories. It does this by giving
academic investigators access, on a competitive basis, to NCI's
preclinical drug development resources and expertise. Investigators
having molecules that hold promise for cancer treatment but without
access to the development resources required for initiation of clinical
studies are invited to submit applications twice a year. Those selected
for support are provided assistance with any necessary development steps
to enable IND filing and the initiation of proof-of-principle clinical
trials. For 1999 the goal is the development of three to five new
therapeutic agents, each relevant to prostate cancer. Projects already
approved include development of a bioreductive compound with potential
as a radio and chemosensitizer, and a gene therapy approach that will
convert inactive pro-drugs into toxic agents within prostate cancer
cells. Over five years, fifteen new therapeutic agents for prostate
cancer would be planned for development.

[Rapid Access to Prevention Intervention Development
(RAPID]{.underline})

The RAPID program is designed to provide assistance for research and
development of new agents that might be useful for cancer prevention.
Under RAPID, NCI expertise and resources will be made available to the
research community for the preclinical and early Phase I clinical
development of potential cancer preventive agents. The program is
intended to provide assistance in translating research evidence of
preclinical efficacy in cancer prevention into opportunities for the
demonstration of efficacy in clinical trials. This program has just been
initiated; we will receive the first applications for support in
November 1999.

[Molecular Target-Based Drug Discovery (MTDD) Initiatives]{.underline}

As our knowledge of the events associated with the development and
progression of prostate cancer increases, we need to shift our emphasis
in the discovery, development, and testing of new agents to the
molecular mechanisms that underlie neoplastic transformation, tumor
growth, and metastasis. Our plan would be to use investigator-initiated
grants, as well as supplements to grantees, to create an entirely new
national capability for harnessing biological and technical advances for
target-based discovery.

We anticipate that five new projects in MTDD could be created each year
for five years, of which one or two a year would be prostate-relevant.
Under these agreements, extramural scientists would develop molecular
target screens of biologically relevant targets. In addition, we
anticipate that up to three supplements a year could be provided to
investigators to: 1) produce target molecules in sufficient amounts for
use in assays to better define how to develop the compound and 2)
delineate the structure of the molecular target through structure-based
laboratories. We anticipate that one supplement a year would be awarded
for prostate-related research.

### Strategies & Plans: Specialized Programs of Research Excellence 

Goals:

-   Expand the funded Specialized Programs of Research Excellence
    (SPOREs) in prostate cancer from the current three to nine or ten by
    2003.

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-   Stimulate translational research in prostate cancer by taking
    maximum advantage of existing research activities while continuing
    to expand basic research in the area.

Initiatives:

SPOREs (Specialized Programs of Research Excellence)

The NCI's challenge is to stimulate more translational research in
prostate cancer by taking maximum advantage of existing research
activities while continuing to expand basic research in prostate cancer.
Much of this can be accomplished by proactively expanding the number of
SPOREs that are dedicated to translational research in prostate cancer.
SPOREs conduct research that relates to a wide range of the priority
areas defined by the NCI Prostate Cancer Progress Review Group,
including:

-   Essential infrastructure such as tissue acquisition and storage;

-   Development and testing of new clinical and laboratory models;

-   Providing scientific approaches in early detection, diagnosis,
    prognosis and prevention;

-   Development and implementation of innovative pilot and early phase
    therapeutic trials;

-   Development and testing of new technologies; and

-   Conducting inter-SPORE scientific studies in therapy and risk
    assessment that overcome traditional institutional barriers.

Currently, the NCI supports three prostate cancer SPOREs. This year,
these consortia will receive support to work together to create more
powerful resources for developing and testing interventions in prostate
cancer. Projects we would undertake through the SPORE program include:

-   Consortia to develop better analytic tools for tissues primarily to
    provide prognostic markers for patients and identify sub-groups of
    prostate cancer.

-   Establishment of gene expression patterns in metastatic disease to
    look for predictors of metastasis and therapeutic targets.

-   Drug target development to develop new classes of drugs for the
    treatment of prostate cancer.

NCI anticipates the SPORE program could be expanded by six new SPOREs
over the next five years. To meet this goal it would be necessary to
intensively work with all of the known and developing groups in prostate
cancer research to help them attain the scientific excellence necessary
to compete successfully for a SPORE grant.

[Centers of Excellence]{.underline}

Centers of Excellence consisting of multidisciplinary teams straddling
the laboratory and clinical arenas would be supported by SPORE-like
research grants, but would specifically focus on underlying molecular
mechanisms, rather than disease. These teams would be focused on the
problem of creating the essential tools necessary to do mechanism-based
early clinical trials, such as clinically usable probes or assays to be
used in biochemical, molecular, or imaging techniques or technologies.

The teams would likely to be composed of investigators from diverse
disciplines such as synthetic chemists, radiochemists, pharmacologists,
imagers, clinicians, immunologists, biologists, animal modelers,
electrical engineers, and informatics experts. Within a particular
mechanism-based area (e.g., apoptosis, cell cycle, signaling,
angiogenesis, vaccines, etc.), the team would focus on the creation of
tools appropriate to investigate their family of targets. The NCI would
play a crucial role in identifying these mechanism-based areas and
bringing the groups together. These Centers of Excellence would be very
attractive partners for companies and potential collaborators for
extramural scientists working in NCI's drug discovery process.

### Strategies & Plans: Tissue Banks

Goals:

-   Procure and distribute well-characterized prostate tissue

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-   Create clinical and epidemiological information links to these
    tissues to enable researchers to investigate effects on clinical
    outcomes such as morbidity and mortality

Initiatives:

###### Prostate Specimen Repositories 

Successful development of molecular markers for detection and diagnostic
markers depends on ready availability of tumor tissue specimens. NCI
plans to develop a national prostate cancer tissue resource modeled on
the NCI's existing Cooperative Breast Cancer Tissue Resource. NCI is
considering a pilot project to test the feasibility of prospective
collection and storage of frozen specimens. In addition to tumor
specimens, this resource would contain clinical outcome information to
allow correlation between molecular test results and cancer outcomes
such as morbidity and mortality. Tissue specimens without the clinically
associated information are much less useful to researchers and thus
represent a key component of the repository. The collection of this
information would involve careful design of the registry to provide
complete protection of patient confidentiality.

### Strategies & Plans: Director\'s Challenge for Molecular Diagnostics

Goal:

Establish the molecular profiles of premalignant changes and of prostate
cancer at different stages of development for the purpose of improving
tumor classification. The assortment of molecules present in cells
changes during tumor development. These molecular changes provide the
defining signatures of developing cancer cells. Recently developed tools
for obtaining a "snapshot" of molecular changes are making it possible
to identify these molecular signatures. Tumor signatures hold the
promise of providing a more accurate diagnosis and prognosis for
individual patients. They also should aid individualized selection of
the most effective therapies and ultimately lead to the development of
new therapies that target alterations in tumor cells. To ensure that
this promise is realized, the NCI Director has challenged the cancer
research community to demonstrate that molecular signatures can be used
to improve the classification of tumors

Initiative:

###### Director\'s Challenge

Interested investigators are currently preparing applications in
response to the Director's Challenge for submission for April 1999 and
November 1999 receipt dates. NCI anticipates that a substantial subset
of the applications will target prostate cancer. One goal of the
initiative is to make the molecular data from these studies available to
the entire cancer research community as rapidly as possible.

Reissuing the Director's Challenge specifically targeting prostate
cancer would increase the number of investigators working on prostate
cancer and would significantly improve the prospect of making rapid
progress against this difficult disease. The development of molecular
profiles of prostate tumors could provide a rational basis for
determining which patients with organ-confined disease need to be
treated and which could benefit from watchful waiting without having to
endure the debilitating side effects of surgery, radiation or
chemotherapy. Better understanding of the factors that lead to prostate
cancer development could result in novel strategies for prevention and
control of early stage disease.

### Strategies & Plans: Early Detection Markers 

Goal:

-   Develop and validate new markers that distinguish between aggressive
    and indolent prostate cancers. One of the most perplexing aspects of
    prostate cancer is that more cancers develop in men over age 50 than
    ever become clinically apparent or prove lethal. Consequently, men
    face a serious dilemma: if their cancer goes undetected, they could
    develop a debilitating, potentially lethal disease; however, if
    their tumor would have remained quiescent for the rest of their
    natural life, detection could lead to the adverse consequences of
    unnecessary treatment. Progress in early detection requires that
    tests used for detection be further refined to ensure that, whenever
    possible, the cancers detected are those with the potential to be
    aggressive and effectively differentiate them from slow-growing
    tumors that are unlikely to cause symptoms or loss of life.

Initiative:

[New Markers for Early Detection of Prostate Cancer: Early Detection
Research Network]{.underline}

The NCI is establishing a new multi-institutional consortium to discover
and develop markers that detect all prostate cancers that are aggressive
and have the potential to cause symptoms or loss of life. This Network
will link centers of expertise in tumor biology, diagnostics
technologies, and clinical trials methodology within academia and
industry to develop high-throughput assays suitable for clinical
testing. The Network will have the capacity to establish estimates of
the operating characteristics (sensitivity and specificity) of candidate
assays as early-detection tools. NCI intends prostate cancer to be one
focus of activity within the new Network. To expedite the discovery and
development of more sensitive and specific markers for early disease,
NCI would also establish links between activities of the Network and
programs in academia and industry that are developing libraries of all
known secreted proteins in mammalian cells. The goal is to develop two
centers for development and early clinical testing of prostate cancer
markers.

### Strategies & Plans: Imaging Technology Development

Goal:

Develop imaging technologies to identify the biological properties of a
pre-cancerous or cancerous cell that will aid in predicting clinical
behavior.

Initiative:

###### Diagnostic Imaging Program

The Diagnostic Imaging Program is making a major effort to promote the
discovery and development of a new generation of non-invasive imaging
technologies. The goal is to have clinically usable tools that can
precisely locate and biologically characterize pre-cancerous and
malignant lesions. These tools will enable us to know precisely where a
lesion is and how it is likely to behave. As one of NCI\'s Extraordinary
Opportunities, imaging is receiving particular attention in NCI\'s
planning efforts, and the benefits of vastly improved and expanded
imaging approaches are likely to extend to the detection, diagnosis,
treatment, and prevention of cancer. The NCI plans to embark on
developing initiatives for innovative work on \"smart\" probes/contrast
agents focused on pathways of likely significance for prostate cancer,
and also plans to have initiatives for clinical trials of image-guided
therapy for localized prostate cancer.

### Strategies & Plans: Investigator-Initiated Research

Goal:

-   Maintain excellence and accelerate progress in
    investigator-initiated research by increasing the pool of scientists
    and clinicians and the number of grants funded in translational
    science.

Initiatives:

###### Research Project Grants in Translational Science

A principal support mechanism used by the NCI to foster enhanced
investigator-initiated research into prostate cancer is the Research
Project Grant. This mechanism permits both basic investigations into
cellular and molecular questions, and research into creating
interventions that translate our knowledge into improvements in
treatment, prevention, and care. NCI fully expects the research
community to respond with research proposals applicable to prostate
cancer. NCI will pay particular attention to applications that address
those aspects of prostate cancer research identified by the Prostate
Cancer Progress Review Group. It is anticipated that during the course
of this Five-Year Plan, approximately 215 additional
investigator-initiated research grants focused on prostate cancer would
be supported. Of these, approximately 60 would specifically address
translational science questions in prostate cancer.

Additional Investigator-Initiated Research Grants in Prostate Cancer:
Funding Grants as Exceptions to the Payline

NCI expects to use a portion of its grant funds to support high-priority
applications relevant to prostate cancer. We expect to give special
attention to applications that fall within the defined areas of
extraordinary opportunity in the Bypass Budget but fail to meet the
established payline. The NCI would give particular attention to
applications addressing aspects of prostate-cancer research that are
described as high-priority and important gap areas by the Prostate
Cancer Progress Review Group.

## NCI's Risk, Burdens & Outcomes Science

### Statement of Needs

Although in the past decade we have made tremendous leaps forward in the
detection, diagnosis, and treatment of prostate cancer, there remains
much we don't know. For example, we don't fully understand the factors,
genetic or environmental, that place a man at increased risk for
prostate cancer. We don't know why some racial and ethnic groups --
notably African Americans -- are diagnosed with and die of prostate
cancer at a significantly higher rate than others, while other groups,
particularly Asians, experience a substantially reduced burden. We
haven't fully addressed the unique needs of survivors of prostate
cancer. And, although we have developed a number of interventions to
reduce morbidity and mortality, including the PSA screening test and
surgical, radiation, and hormonal therapies, we have yet to prove that
all are truly efficacious. The lingering uncertainty about the risks and
benefits of these interventions underscores the necessity for increased
surveillance of the early detection, treatment, and outcomes of prostate
cancer in the population. In short, measures of progress against
prostate cancer include not only incidence and mortality but also risk
factors, the use of interventions, costs, and long-term, health-related
quality of life among survivors.

The NCI's professional judgment for addressing prostate cancer risk,
burdens, and outcomes is multifaceted. We are undertaking the
comprehensive study of prostate cancer epidemiology and risk in order to
identify genes and environmental risk factors for this disease. Through
our surveillance program, we would address deficiencies in the
understanding of population trends in prostate cancer incidence,
mortality, and use of screening and treatment, and assess the impact of
these trends on both the general population and survivors of this
disease. We would identify and address the unique concerns of the
ever-growing population of prostate cancer survivors. Finally, we must
and would address the alarming differences in prostate cancer incidence,
aggressiveness, mortality, and treatment among men of different racial
and ethnic groups.

### Strategies & Plans: Epidemiology, Genetics and the Environment

Goals:

-   Identify the genetic and exogenous risk factors that account for
    differences in incidence and mortality between different racial and
    ethnic groups.

-   Identify the risk of cancers resulting from environmental exposures
    in the general population, and the susceptibility genes that modify
    that risk.

-   Identify the genes responsible for familial and hereditary forms of
    cancer.

Initiatives:

###### Gene Discovery for Inherited Predisposition to Prostate Cancer

Men with a family history of prostate cancer are at increased risk for
the disease. The NCI, through its research programs, is committed to
identifying the genetic bases of prostate cancer susceptibility.

The Cancer Genetics Network (CGN) would provide a new national resource
to support collaborative investigations into the genetic basis of cancer
susceptibility, integrate this new knowledge into medical practice, and
address the psychosocial, ethical, legal, and public health issues
associated with inherited susceptibility to cancer. The aim would be to
create a multi-center and interdisciplinary collaborative structure that
would enable the participating institutions to draw upon each other, and
to have access to research resources, information, and expertise beyond
the scope of any single institution. The result would be perhaps the
largest virtual collaboration dedicated to the study of cancer genetics.

This year participating centers without existing programs for specific
recruitment of probands/families at increased risk of prostate cancer
may request a supplement for direct costs to implement recruitment
programs targeted at this group. Participating centers currently
recruiting probands/families for genetics studies in prostate cancer may
request a supplement for direct costs to expand ongoing recruitment
efforts or enhance the existing program.

In addition, we are planning studies that would augment the current
linkage-based approaches for discovery of major genes responsible for
familial prostate cancer, with a large study of affected sibling pairs
with clinically significant disease. Men with prostate cancer diagnosed
over a previous three-year period from population or hospital-based
registries would be contacted to identify those with living affected
brothers. These pairs would be evaluated by questionnaire and whole
genome scanning. A study of 3,000 such pairs is planned.

Studies of Environmental/Lifestyle Causes and Gene-Environment
Interactions that Lead to Prostate Cancer

The NCI supports several ongoing or planned efforts to study
gene-environment interactions and lifestyle choices that may increase
prostate cancer risk. Additional effort could be applied to the projects
identified below.

-   An RFA entitled Interdisciplinary Studies in the Genetic
    Epidemiology of Cancer, would be offered jointly with the National
    Institute on Aging. This RFA would seek to support investigations to
    identify and evaluate the interactions of genetic and environmental
    risk factors leading to enhanced cancer susceptibility in
    individuals, families, and populations, and factors influencing the
    increase in susceptibility with age, a key feature of prostate
    cancer incidence and mortality.

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-   The NCI plans to conduct large cohort and case-control studies
    focused on the identification of susceptibility genes and
    gene-environment interactions. Efforts would be made to identify the
    risk factors and mechanisms underlying the suggestive associations
    reported from existing small studies, including hormones, growth
    factors, diet anthropometry, physical activity, sexually transmitted
    factors, and occupational exposures. Efforts also would be made to
    identify reasons for the high mortality rates for prostate cancer
    reported in certain parts of the country.

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-   The NCI is very interested in the effects of diet and nutrition on
    prostate cancer incidence. Several associations of dietary patterns
    with prostate cancer have been reported, but the evidence needs much
    more interdisciplinary research and analysis. Diets high in
    vegetables have been reported to decrease risk, while diets high in
    fat, saturated fat, and animal fat to increase risk. Several
    micronutrients may affect prostate cancer occurrence, and the effect
    of food constituents on molecular events in the prostate is unknown.
    Studies in this area could lead to new chemoprevention studies in
    the future.

    Research on the Natural History of Latent and Aggressive Prostate
    Cancer

It is critical that we define the epidemiology and natural history of
screening-detected prostate cancer, including genetic and environmental
risk factors, and serologic and molecular markers of those lesions most
likely to be aggressive. This goal could be reached by additional
funding for the Prostate, Lung, Colorectal, and Ovarian Cancer Trial
(PLCO) to provide adequate data and specimen collections from prostate
cancer cases subsequent to their diagnosis. In addition, to increase the
numbers of early cases for evaluation who have been minimally treated or
untreated, a similar collection of data and specimens could be obtained
from patients entered into NCI-sponsored clinical trials for the
treatment of early-stage disease.

Studies of the Underlying Biology of Intra-Prostatic Exposures

NCI anticipates opportunities for a focused, collaborative
methodological and exploratory effort involving epidemiologists and
laboratory scientists (analytic chemists, molecular biologists,
geneticists) to study the difficult issues of intra-prostatic exposures,
particularly from hormones and their metabolites, growth factors,
infectious agents, and their relation to prostate cancer risk. A
resource of fresh and fixed tissues from prostate cancer cases and
controls along with questionnaire data and other biologic specimens
(blood, urine) would be established. A variety of assays, including gene
expression, protein and hormone determinations and a search for
non-culturable viral sequences, would be performed to ascertain their
presence and levels, determinants, interrelationships and surrogate
measures in more accessible biologic specimens, plus their associations
with prostate cancer risk.

### Strategies & Plans: Surveillance

Goals:

-   Assess the reasons for and impact of trends in prostate cancer
    incidence and mortality, with particular focus on differences among
    population sub-groups;

-   Identify the effects of variations in the use of screening,
    diagnostic, and treatments on multiple measures of disease burden in
    the U.S. population;

-   Identify the impact of clinical decision making regarding screening
    and treatment on population trends in incidence, mortality, and
    quality of life outcomes.

-   Determine how the benefits, economic costs, and morbidity due to
    screening and treatment differ in subsets of the population (age
    groups, racial and ethnic groups, etc.)

Initiatives:

###### National Prostate Cancer Outcomes Studies 

The Prostate Cancer Outcomes Study (PCOS) was initiated in 1994 to
assess reasons for variations in prostate cancer practice patterns in
the general population and evaluate the impact of therapies on
disease-specific health related quality of life. This has been the most
comprehensive survey ever undertaken of prostate cancer outcomes. The
study was funded as a contract modification within the SEER Program,
with six out of ten SEER registries participating since the inception. A
five-year follow up survey is planned for October 1999. We see
opportunities to expand the study over five years to assess differences
in care by geography, race/ethnicity, socioeconomic status and insurance
status.

NCI plans to continue follow-up of the PCOS cohort, consisting of
approximately 3,500 men, through 10 years post-diagnosis. Beginning in
1999, all six original participating registries will be funded by
contract and will continue to be directed by SEER Program staff. The
main purpose of this follow up will be to ascertain and verify deaths,
maintain contacts with respondents, and conduct a 10-year survey to
assess long-term changes in disease-related quality of life. In
addition, we would review and abstract medical records to identify
endpoints such as disease progression, metastases, and the use of
secondary treatments. Ongoing analyses of the data collected could also
be supported.

Since the initiation of the PCOS, there have continued to be changes in
prostate cancer incidence, treatments, and PSA testing in the
population. Therefore, a second PCOS could be supported to collect
extensive new information not included in the first PCOS, address gaps
in the first study, and examine new questions. The study would be
designed to include more minority patients so that treatment patterns
and quality of life could be compared across sub-populations. The second
PCOS would be funded as an RFA Cooperative Agreement to permit broader
participation outside SEER areas. Approximately 5,000 patients would be
enrolled at between seven and ten sites with expertise in
population-based outcomes research, starting in 2001 and continuing
through 2003.

###### Prostate Cancer Screening Initiatives

One of the most difficult questions facing men today is whether to
undergo screening for prostate cancer. Although there is no doubt that
such tests as digital rectal examination and the PSA test do detect
prostate cancer, we have yet to prove that they reduce prostate cancer
mortality overall. The NCI has several ongoing or planned initiatives
that will complement ongoing randomized trials of screening by
describing trends and population impact of prostate cancer screening.

The objective of the Prostate Cancer Surveillance Consortium (PCSC) is
to measure the operating characteristics (sensitivity and specificity)
and clinical outcomes of PSA screening in the general population. The
PCSC's activities include monitoring and tracking patterns of PSA
testing in the community, and measuring the outcomes of PSA testing as
performed in everyday community medical practices. Data collection
methods would be pilot tested in two or three SEER sites as a contract
modification to SEER. In 2002, the full consortium would be funded under
a cooperative agreement, and would consist of between seven and ten
sites with broad population representation of ethnic and socioeconomic
sub-groups.

The Cancer Information and Surveillance Modeling Network (CISNET) would
be a cooperative agreement centered around the use of microsimulation
modeling to assess national trends in prostate, breast, and colorectal
cancer. Comparing modeled and observed incidence and mortality trends
can help us better understand the underlying disease process and the
benefits of the PSA test in the U.S. population. This network would be
created to facilitate collaboration among two to three groups of
investigators with complementary expertise in modeling prostate cancer.
The first two to three awards would be made in 2000. Two follow up
awards would be planned to begin in 2002. These grants would span four
years of research effort.

The California Health Interview Survey (CHIS) is designed to provide
population-based standardized state and local health data for small
population groups. This presents an opportunity to monitor and track the
PSA testing in California counties as well as to follow up positive
tests, including biopsies and cancers detected, in 30,000 respondents,
through CHIS. In this way, NCI would obtain better estimates on certain
racial-ethnic populations that compose a significant percentage of
California's population. Support would be provided to the California
Department of Health via an interagency agreement.

###### Clinical Decision Making Studies 

Significant information about trends in prostate cancer screening and
treatment can be gained by surveying health care providers, both
physicians and insurers, and by examining the processes of patient
decision making that influence patterns of medical practice.

No recent national studies of provider knowledge, attitudes, and
practices regarding prostate cancer screening and management have been
conducted. A series of surveys of primary care physicians and
specialists involved in the screening, diagnosis, and treatment of
prostate cancer in the U.S. would be valuable. This could be
accomplished through a contract mechanism using the Surveillance Master
Agreement Order. A nationally recognized survey research firm would
conduct the surveys. A survey of approximately 1,000-1,500 primary care
physicians would assess beliefs in the efficacy of screening and factors
shaping physicians' screening recommendations. A survey of the same
number of specialists would assess diagnostic follow-up and treatment
recommendations. Both surveys would ascertain physicians' use of
decision aids and perceptions of additional information needed to
enhance their ability to make appropriate screening and treatment
recommendations. A complementary survey of 300-400 health plans would
provide information on the policies and organized programs of health
plans regarding prostate cancer screening and treatments. These surveys
would be conducted in 2001 and 2002.

A related initiative would develop innovative methods and materials for
use by clinicians and patients for enhancing their ability to make
informed decisions about prostate cancer screening and treatment. Given
the extent of uncertainty about the efficacy of interventions, patients
desire more information in order tailor medical decisions to their own
preferences. This initiative would be designed to elucidate factors
involved in decision making and how best to communicate information. The
initiative would be achieved by soliciting administrative supplements
from existing research grants, where clinical decision making is within
the scope of work.

An example of an existing structure for conducting collaborative studies
is the HMO Cancer Research Network (HMO-CRN), initiated in 1999 as a
cooperative agreement among a consortium of 10 large HMOs covering
approximately 10 million lives focusing on cancer control research
activities. The HMO-CRN and grants addressing prostate cancer survivors
are potentially useful mechanisms to conduct studies on prostate cancer
decision making.

### Strategies & Plans: Survivorship 

Cancer Survivorship Research is the study of the unique physical,
psychosocial, and economic sequelae of cancer diagnosis and its
treatment. It also includes issues like health care delivery, access,
and follow-up care within its domain. Survivorship research focuses on
the health and life of a person with a medical history of cancer beyond
the acute diagnosis and treatment phase and seeks to both prevent and
control the aforementioned sequelae, and to provide guidelines for
optimal follow-up care and surveillance. Interventions that enhance
prevention or control of these sequelae, such as coping, dietary
modifications, physical activity, and social support are also of
significance.

The Office of Cancer Survivorship (OCS) was established in late 1996 to
provide a focus within the NIH for the support of different facets of
survivorship research. Since then, the OCS has supported two
initiatives, one a supplement to existing cancer centers grants and
cooperative agreements, and the other the generation of an RFA entitled
"Long Term Cancer Survivors: Research Initiatives." Prostate cancer
research was not well represented in the pool of applications submitted
in response to either initiative. Additionally, a review of the 1998
NCI-wide portfolio of survivorship research revealed few studies (two
R01 Grants) focusing solely on prostate cancer survivors.

Survivorship research in general, and prostate cancer survivorship
research in particular, are still emerging areas. Thus, major efforts
are needed to stimulate the development and establishment of this
relatively new area of research. Major efforts are necessary to
stimulate both extramural and in-house research. We need to evaluate the
long term physical effects of survivorship from prostate cancer, the
context of the prostate cancer survivorship experience across different
age groups (men in their 40\'s or 50\'s versus older men) and ethnic,
cultural, and socio-economic status categories. We also need to evaluate
the development and evaluation of interventions specifically targeted
towards ameliorating the negative consequences of survivorship.

Goals:

-   Improve "Quality of Survivorship" for men diagnosed with prostate
    cancer. This goal encompasses physical health, reproductive and
    sexual, cognitive, and economic issues, as well as overall quality
    of life.

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-   Determine and address the unique survivorship issues faced by men in
    different age, racial, and ethnic groups.

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-   Decrease the physiologic and psychologic morbidity associated with
    long-term prostate cancer survivorship by addressing specific
    prioritized research areas.

Initiatives:

###### Priority Areas for Prostate Cancer Survivorship Studies

NCI is planning qualitative and quantitative research to identify
specific survivor concerns for men by age group, ethnicity, and culture:

-   As part of a larger national survivor prevalence study, we would
    describe the status of prostate cancer survivors in terms of
    physical health, quality of life, relationships with partners, and
    economic consequences.

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-   We need to evaluate the quality of prostate cancer survivorship
    relating to adaptation of the patient to personal consequences of
    the cancer diagnosis and treatment, adjustment to the social
    consequences of cancer, and the impact on the family.

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-   In addition, we would assess the prevalence and longitudinal
    incidence of physiologic late effects, incorporating two related
    areas: long-term effects (chronic physiologic sequelae persisting
    beyond the acute treatment phase), and late effects (delayed
    physiologic health effects occurring months to years after
    treatment).

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-   Finally, the prevalence and magnitude of sexual dysfunction must be
    elucidated for prostate cancer survivors and their partners by age
    and ethno-cultural background.

    Opportunities for Studies in Prostate Cancer Survivorship

Through the National Prevalence Study, we would use the contract
mechanism in FY 2000 -- 2003 to obtain data needed to create a national
profile of men who have had prostate cancer. We would hope to study
approximately 5000 prostate cancer survivors as part of this effort.
These data are needed to develop effective behavioral interventions and
to encourage epidemiologic investigations

A Program Announcement entitled "Prostate Cancer Survivorship Research"
would seek to support investigations to evaluate the quality of prostate
cancer survivorship in terms of adaptation to personal consequences of
the disease and its treatment, adjustment to its social consequences,
and impact on the family. The research plan would also target the
prevalence and longitudinal incidence of physical late or long term
effects and morbidities, including sexual dysfunction. This initiative
would span 2000 through 2003.

A Request for Applications (RFA) entitled "Coping Interventions and HRQL
\[Health-Related Quality of Life\] in Prostate Cancer" would stimulate
the development and evaluation of interventions focusing on coping
mechanisms that could significantly decrease the negative sequelae of
treatment. The RFA would be released in 2000 for funding through 2003.
Based on results from research conducted for other disease sites, it is
likely that positive coping strategies thus developed would enhance the
quality of life of long-term survivors of prostate cancer.

This research is especially important since some of the side effects
experienced by survivors of prostate cancer, such as incontinence and
sexual dysfunction, affect not only the patients themselves but also
their families. Additionally, these side effects may have different
social or emotional consequences in younger men compared to older
individuals, and across cultural and ethnic groups.

In conjunction with the surveys proposed for surveillance of prostate
cancer, we could conduct a national survey to assess health care
providers' knowledge, attitudes, beliefs, and behaviors regarding the
unique issues faced by prostate cancer survivors. This survey of
approximately 1000 physicians who see cancer survivors would be
conducted under a Master Agreement Order. The information from this
survey is critical if we are to develop effective medical and continuing
education programs for providers. Based on the survey results, we would
develop practical tools for providers to use in communicating with
patients.

### Strategies & Plans: Special Populations

The scientific questions concerning prostate cancer are pertinent and
pressing to men of all races. There are pronounced racial disparities in
prostate cancer incidence and mortality; indeed, the disparity in
mortality rates from prostate cancer is greater between white and black
men than for any other type of cancer in the U.S. and possibly in the
world. Significant questions regarding racial differences include: What
are the causes of prostate cancer and what is the basis of differences
noted in incidence and mortality among different racial/ethnic groups?
Why are some prostate tumors high-grade and aggressive, whereas others
exhibit low-grade, less aggressive behavior? What is the underlying
biological basis of such differences, and why do black men tend to have
more aggressive disease? Why do men of Asian heritage tend to have less
aggressive disease? How can the benefits of medical research best be
applied so that all may benefit?

Goals:

-   Understand and address the reasons for differences in prostate
    cancer incidence, aggressiveness, mortality, and treatment patterns
    among men in different racial and ethnic groups.

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-   Educate diverse publics about prostate cancer screening and
    treatment using concepts and materials appropriate to each age,
    racial, and ethnic group.

-   Determine the ways in which the benefits of treatment differ in
    subsets of patients by age, morbidity, race, etc.

Initiatives:

Studies to Understand Racial/Ethnic Differences in Prostate Cancer

The NCI has several efforts ongoing to understand the differences in
prostate cancer by race and ethnic group:

-   A Program Announcement entitled Molecular Epidemiology of Prostate
    Carcinogenesis has been established. This program emphasizes
    interdisciplinary collaborations among laboratory scientists. Areas
    to be investigated include molecular genetics and biology and
    cancer, epidemiology of developing and validating biomarkers for
    assessment of risk in population subgroups (for example, racial or
    ethnic groups), evaluating gene-environment interactions, and
    developing resources such as cohorts and repositories.

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-   A Program Announcement entitled Diet, Lifestyle, and Cancer in U.S.
    Special Populations focuses on the causes of cancer in population
    groups that experience unusually high cancer incidence and
    mortality.

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-   Further investigate the differences in prostate cancer incidence
    through a population-based, interdisciplinary case-control study in
    Asia and Africa, and among Asian Americans, African Americans and
    Caucasians in the U.S. This effort could focus on establishing a
    South African tumor registry and tissue bank. These major efforts
    could focus on elucidating the origins of prostate cancer. Special
    attention would be given to identifying the genetic and
    environmental determinants of the marked racial/international
    differences in the risk of clinically significant disease and the
    changing patterns among migrant populations. The South African Tumor
    Registry and Tissue Bank would address the observations that men of
    African heritage in the U.S., Brazil and Jamaica have been shown to
    have relatively high prostate cancer rates. Although age-adjusted
    incidence and mortality rates suggest that sub-Saharan Africans may
    also have elevated prostate cancer rates, cancer incidence data from
    the developing countries of Africa are largely inadequate and
    incomplete. In order to clarify this issue, the NCI, in
    collaboration with the Medical University of South Africa, could
    establish a population-based registry of cancer incidence and
    mortality in four provinces (Eastern Cape, Western Cape, Northern
    Province, and Gauteng Province) in South Africa. Such a registry
    would allow for comparisons between black Americans and black
    Africans with regard to demographic data and a variety of postulated
    risk factors related to hormones, diet and nutrition, and other
    lifestyle characteristics. It also would provide data allowing
    comparisons of cancer rates among white and black Africans. The
    registry would be augmented and its value to epidemiologic research
    enhanced by establishing a tumor and serum bank allowing for genetic
    studies.

There is a suggestion that a gene or genetic mutation is associated with
an increased risk for prostate cancer. The National Human Genome
Research Institute, working with the NCI, is now conducting a study of
genetic determinants of prostate cancer in cohorts of black families
with a strong history of prostate cancer. The study is focused on
determining whether a mutation in HPC-1 or other genes may be associated
with the increased prostate cancer risk noted in African American men.
Expanding this search for a prostate cancer gene could increase the
number of families studied and intensify the search for new genes
related to prostate cancer.

Opportunities exist to augment recruitment to the Cancer Genetics
Network so that established centers can carry out educational efforts to
recruit volunteers from minority communities. Funds could be used to
contract with medical care facilities serving ethnic/racial minority
communities that do not traditionally participate in research.

### Strategies & Plans: Special Populations Networks 

Education of special populations about prostate cancer issues is
crucial. The Institute is committed to funding programs to help convey
accurate and up-to-date information concerning prostate cancer and
encouraging participation of special populations in clinical trials and
studies so that the many important questions in this disease can be
answered.

To this end, beginning in 1999, NCI is funding a new initiative entitled
Special Populations Networks for Cancer Awareness, Research and Training
(SPN). This is an effort to foster cancer awareness, community-based
educational activities, and, particularly, the establishment of an
infrastructure to support research in cancer control in minority
populations and to enable investigators from these communities to
compete successfully for research support. The SPN will be critical in
efforts to support minority accrual to treatment, prevention, and
control trials. The SPN will also carry out educational activities
concerning cancer screening. The SPN could be expanded to emphasize
prostate cancer awareness and other educational activities and to
enhance prostate cancer control efforts focused specifically on African
American men. An individual responsible for special populations efforts
would be appointed to each region covered by the NCI's Cancer
Information Service. This person would coordinate work in the Special
Populations Networks with other NCI- and CDC-funded organizations to
educate men about prostate cancer and the need for participation in
clinical trials.

Supplements to Prostate SPORE

The NCI currently funds three Specialized Programs of Research
Excellence (SPOREs) conducting prostate cancer research. These programs
could be augmented to increase their emphasis on cancer etiology,
especially etiology in African American populations and comparisons
between African American and Asian American men.

### Strategies & Plans: Investigator-Initiated Research

Goal:

-   Maintain excellence and accelerate progress in
    investigator-initiated research by increasing the pool of
    scientists, clinicians and health care practitioners and the number
    of grants funded for risk, surveillance and outcome research.

Initiatives:

Research Project Grants in Risk, Burdens, and Outcomes Science

A principal support mechanism used by the NCI to foster enhanced
investigator-initiated research into prostate cancer is the Research
Project Grant. This mechanism permits both basic investigations into
cellular and molecular questions, and research into creating
interventions that translate our knowledge into improvements in
treatment, prevention, and care. NCI fully expects the research
community to respond with research proposals applicable to prostate
cancer, and will pay particular attention to applications that address
those aspects of prostate cancer research identified by the Prostate
Cancer Progress Review Group. It is anticipated that during the course
of this Five-Year Plan, approximately 215 additional
investigator-initiated research grants focused on prostate cancer would
be supported. Of these, approximately 20 would specifically address
risk, burdens, and outcomes science questions in prostate cancer.

Additional Investigator-Initiated Research Grants in Prostate Cancer:
Funding Grants as Exceptions to the Payline

NCI expects to use a portion of its grant funds to support high-priority
applications relevant to prostate cancer. We expect to give special
attention to applications that fall within the defined areas of
extraordinary opportunity in the Bypass Budget but fail to meet the
established payline. The NCI would pay particular attention to
applications addressing aspects of prostate cancer research that are
described by the Prostate Cancer Progress Review Group as high-priority
and important gap areas.

## NCI's Basic Research & Discovery Science

### Statement of Needs

Cancer is a group of diseases that occur when cells become abnormal,
dividing and forming more cells without control or order. For cancer to
occur, a series of changes in genes that control cell growth and
behavior must take place. A critical basic question in cancer research
is how and why these genetic errors occur, and just as important, why
the errors are not corrected by the cell\'s normally efficient
surveillance mechanisms.

Prostate cancer research poses many of the same questions that are
encountered for cancer in general; however, as with other types of
cancer, prostate cancer has some unique scientific issues that must be
addressed. Prostate cancer growth and development represents a continuum
of biological processes, originating from early embryonic development,
through growth and maturation, to aging and neoplastic transformation.
To improve diagnosis, prevention, and treatment of prostate cancer, it
is crucial to focus future research on the molecular, cellular,
physiological, and pathogenic events that lead to uncontrolled growth
and metastasis.

The foundation and engine for progress in these areas is basic,
untargeted research. But while basic research studies in all areas of
prostate cancer initiation, progression, and metastasis are critical,
this Plan focuses on three important areas. First, we lack a real
understanding of the biology of the normal prostate; our Plan would
correct this. Second, our best tools for prostate cancer research are
model systems -- mammals, but also other organisms, cell lines, and
computer simulations. Current models are inadequate for a number of
reasons, but under this Plan, we would develop and disseminate the
models the research community so desperately needs. Finally, NCI's
Cancer Genome Anatomy Program (CGAP) is a critical component of our
Prostate Cancer Plan. CGAP, whose aim is to identify genes and
characterize novel biomarkers that are differentially expressed or
suppressed in cancer progression and metastasis, would provide a wealth
of information about the molecular and genetic contributions to prostate
cancer.

### Strategies & Plans: Investigator-Initiated Research

Goals:

-   Maintain excellence and accelerate progress in
    investigator-initiated research by increasing the pool of
    researchers and the number of grants funded in basic research and
    discovery.

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-   Identify the biochemical and molecular events that govern the
    continuation of prostate development from early embryogenesis to
    adulthood

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-   Identify the processes and determinants of all stages of prostate
    neoplastic growth and spread.

Initiatives:

Research Project Grants in Basic Science

A principal support mechanism used by the NCI to foster enhanced
investigator-initiated research into prostate cancer is the Research
Project Grant. This mechanism permits both basic investigations into
cellular and molecular questions, and research into creating
interventions that translate our knowledge into improvements in
treatment, prevention, and care. NCI fully expects the research
community to respond with research proposals applicable to prostate
cancer. NCI will pay particular attention to applications that address
those aspects of prostate cancer research identified by the Prostate
Cancer Progress Review Group. It is anticipated that during the course
of this Five-Year Plan, approximately 215 additional
investigator-initiated research grants focused on prostate cancer would
be supported. Of these, approximately 80 would specifically address
basic science questions in prostate cancer.

Additional Investigator-Initiated Research Grants in Prostate Cancer:
Funding Grants as Exceptions to the Payline

NCI expects to use a portion of its grant funds to support high-priority
applications relevant to prostate cancer. We expect to give special
attention to applications that fall within the defined areas of
extraordinary opportunity in the Bypass Budget but fail to meet the
established payline. The NCI would pay particular attention to
applications addressing aspects of prostate-cancer research that are
described as high-priority and important gap areas by the Prostate
Cancer Progress Review Group.

Biology of the Prostate: From Normal Biology to Malignant Disease

The normal biology of the prostate is relatively poorly understood, and
the Progress Review Group strongly recommended addressing this problem
aggressively. Within the NCI portfolio of supported research there are
few examples of studies on normal biology and physiology of the prostate
gland. This is understandable since, by and large, the Institute funds
projects and research with a focus on cancer and not on healthy, normal
tissue. Lack of fundamental knowledge in the normal developmental
biology of the prostate is hampering prostate researchers on many
levels.

To correct the situation, the NCI, in conjunction with the National
Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and the
National Institute of Aging (NIA), would release a Program Announcement
to invite investigator-initiated research grant applications to examine
the molecular, cellular, and physiological alterations associated with
the growth and development of the neoplastic, normal and aging prostate
gland. The purpose of this announcement would be to encourage new
projects focusing on the biology that underlies the development and
progression of malignant prostatic disease (e.g., understanding
metastasis of prostate cancer to lymph nodes, lung, liver and bone).
Multidisciplinary collaborations among basic and clinical scientists
would be encouraged.

### Strategies & Plans: Animal Models

The Prostate Cancer PRG noted that many aspects of prostate research
require the refinement or derivation of models and ready access to them.
Ideally, if there were a single model system that encompassed all the
biological aspects of human prostate cancer, from initiation through
metastatic progression, the research community could apply the model to
test new prevention and therapeutic strategies. However, the reality is
that there currently is no single model that can address all of these
needs. A variety of model systems including animals, cell lines,
multi-cellular systems, and computerized simulations are needed.
Research opportunities outlined below involve four strategies; the first
two would be expansions of existing initiatives for mouse models, and
the others would be new initiatives.

Goal:

Foster development and validation of new prostate cancer models that
imitate human prostate cancer initiation, progression, and metastasis.

Initiatives:

Develop and Validate Mouse Prostate Cancer Models

Participants in the Mouse Models of Human Cancers Consortium (MMHCC)
would use an assortment of new experimental tactics to generate and
validate mouse prostate cancer models. To provide a focal point for the
application of information about human prostate cancer to model
development, we would plan to have MMHCC participants who model prostate
cancer initiate a Prostate Cancer Models Forum. The Forum would have a
Chairman's grant for workshops and meetings to augment the expertise of
the MMHCC and to strengthen its ties to the entire prostate cancer
research community. The Chairman's grant would also support the
evolution of an interactive web site with the tools to accrue the
knowledge for expediting prostate model derivation and validation. Based
on workshops, progress in model derivation and validation in the MMHCC
and elsewhere, and newly identified advances in prostate cancer
research, the Forum could recommend pilot project concepts for the NCI
to consider for implementation.

Develop and Validate State-of-the-Art Prostate Cancer Models in other
Species

The MMHCC is designed to derive and validate state-of-the-art prostate
cancer models in mice. However, to encourage additional ideas and
diverse approaches for mice, as well as other animals, we would plan to
fund administrative supplements for individual grants to support
development and validation of prostate models in other animals in
addition to mice. The supplement program may be extended to include
Cancer Center core grants and SPORES.

Using Transplantation Technologies in Model Development

There is a transplantation technology whose implementation could have an
immediate impact on deriving prostate cancer models. This technology
became apparent when mice were developed lacking specific genes
implicated in human prostate cancer, so called knock-out mice, and these
mice died during embryogenesis. Verification of the function of these
genes in prostate cancer will be delayed until strategies can be
developed and applied. In order to further this research, we would plan
to institute a research collaboration activity that consists of the
three or four laboratories capable of implementing the transplantation
technology research:

-   Rescue of the prostate gland precursor structure from late-stage
    embryonic-lethal knock-out embryos, and transplantation into normal
    male mice of the same genetic background.

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-   Use of the "rescued" prostate glands that do develop prostate cancer
    to derive a resource of permanent cell lines representative of the
    earliest stages of prostate cancer initiation and progression.

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-   Analysis of progressive gene expression changes from different
    stages (e.g., tumor development).

    Creating Models to Study Prostate Epithelium and Underlying Stroma

The creation and refinement of models to study the interaction of
prostate epithelium with its underlying stroma, and with endothelial,
neuroendothelial, and immune cells is an important but difficult area to
address. Equally challenging is derivation of models to study
interaction of prostate tumor cells with the cellular components of the
tissue to which prostate cancer usually metastasizes including the lymph
nodes, lung, liver, and bone. NCI would plan to release a Program
Announcement for phased innovative (R21/R33 and SBIR/STTR) awards to
encourage development of a variety of cellular, multi-cellular, or
mathematical models of normal prostate development that can be extended
to understand prostate cancer etiology and progression.

The NCI has already announced administrative supplements to NCI-funded
Research Project (R01) and Program Project (P01) grants to assist with
unanticipated costs associated with the development and validation of
mouse models of human prostate cancer. In addition, NCI-funded
investigators whose research involves investigations of mouse models and
who require supplemental support to take advantage of new opportunities
afforded by these cancer models may submit a request detailing the basis
for the needed supplement. Application submission deadlines for these
supplements were April 15 and June 1.

### Strategies & Plans: Cancer Genome Anatomy Project

Goal:

Identify genes and characterize novel genetically derived biomarkers
that are differentially expressed or suppressed in the progression and
metastasis of prostate cancer.

Initiative:

Over the past two years, the Tumor Gene Index component of the Cancer
Genome Anatomy Project (CGAP) has pursued the discovery and cataloging
of genes expressed during prostate cancer development. These studies,
focused on normal, pre-cancerous and cancerous epithelial cells, as well
as whole tumors, have resulted in the identification of over 8800 genes
expressed in the prostate including 734 newly discovered genes. This
progress has been remarkable and builds a platform for prostate cancer
research studies ranging from prevention to early detection, to
therapeutic strategies. Based on the current results, there is now an
even greater opportunity to build genomic technology and information
infrastructure and apply these resources in basic and clinical cancer
research.

## National Institute of Diabetes and Digestive & Kidney Diseases

The NIDDK is firmly committed to play an important role in a broad NIH
approach to the problem of prostate cancer. Particular research
strengths of this Institute are in the basic biology of the prostate,
the mechanisms of androgen action, clinical studies of benign disease of
the prostate, and epidemiology of urologic disorders. These strengths
provide a compelling base for major expansion, and position us to attack
critical questions as part of a broad NIH approach to this major health
problem. Our efforts are intended to integrate with and to complement
the NCI plans. We will work to ensure continued integration of our
programs with those of the NCI and other NIH institutes with active
programs in this area. One important forum for coordination is the
Urology Subcommittee of the Kidney and Urology and Hematology
Interagency Coordinating Committee, chaired by the NIDDK.

#### Program Planning Process

Our planning process for development of prostate cancer programs has
been undertaken with advice from the NIDDK Advisory Council. In March
1998, we convened an International Symposium on Prostate Growth, which
resulted in the identification of a number of priorities for new
research directions. To ensure continued external advice the Institute
has convened a special Ad Hoc Prostate Planning Group to provide
overview of existing programs and ongoing input into the development of
new programs. The Institute leadership meets regularly with members of
the urology community, particularly the leadership of the American
Urological Association, American Foundation for Urological Disease and
the Society for Basic Urological Research, as well as leaders in the
field of endocrine research, and actively solicits the advice and input
of these societies. Our planning process has also been carefully
integrated with planning activities undertaken by NCI. A number of
members of our investigative communities participated in the NCI
Progress Review on Prostate Cancer, and the priority items in this plan
are areas also identified as important in the Report of the Prostate
Cancer Progress Review Group.

#### Directions 

The discoveries that will lead to improved therapy and ultimately
prevention and cure need to be sought through a number of avenues:

-   Prostate cancer typically develops in the setting of underlying
    benign prostatic disease. We need to understand more about the
    processes that cause growth of the prostate with age -- and what
    this growth process has to do with malignant change.

-   The outcome of cancer depends not just on the behavior of the tumor
    cell -- but also on the normal surrounding cells that are not
    themselves cancerous. We need to know more about the normal prostate
    cells -- and the genes they express -- in order to identify new
    targets for disease intervention. We also need to know more about
    the interactions between prostate cancer cells and bone, to
    understand the determinants of metastasis.

-   Developmental biology is proving to be an important source of clues
    about disease. We need to understand the developmental program for
    formation of the prostate and the lineage of the cells that make up
    the gland.

-   What is the action of androgen, the genes it controls and the
    mechanisms by which the hormone turns genes on and off? These are
    critical basic questions broadly anticipated to yield the basis for
    new therapeutic approaches.

-   We know too little about the variation in susceptibility of
    different populations to the disease of the prostate. Careful
    monitoring of epidemiological trends in the burden of benign and
    malignant prostate disease is an important priority. Particularly,
    the enhanced susceptibility of certain racial groups to prostate
    cancer -- and the relative protection of other groups -- are
    phenomena that we need to understand.

-   Better strategies to prevent the two feared complications of surgery
    on the prostate -- urinary incontinence and impotence -- are needed
    urgently. Although new surgical approaches for both benign prostatic
    hypertrophy and prostate cancer have reduced the rate of these
    complications, further progress is needed.

-   Prostate cancer is a hormone responsive tumor and the major forms of
    treatment of advanced prostate cancer involve pharmacologic blockade
    of the gonadatrophin release or antagonism of the androgen receptor.
    There are new and emerging opportunities to improve these
    approaches.

#### Five Year Prostate Research Plan

The NIDDK plans to expand substantially efforts in prostate research in
1999. Particular consideration will be given to full-funding of
competing research project grants in the Institute's Urology and
Endocrinology programs in areas that include:

-   Characterization of the cellular and molecular events that occur
    during prostate development;

-   Characterization\--using array methods\--of the patterns of gene
    expression in the prostate throughout the male life cycle, and
    during hyperplasia;

-   Targeted development of additional tools for study of prostate
    biology, such as identification of promoter sequences that dictate
    cell specific expression;

-   Expansion of support for development of surrogate markers,
    particularly characterization of proteins secreted by prostate
    tissues;

-   Expanded epidemiologic studies of prostate disorders in minority
    populations;

-   Identification of regulatory elements in androgen-regulated genes;

-   Elucidation of the mechanism of transactivation by ligand-bound
    androgen receptors;

-   Characterization of the growth factors critical for normal prostate
    tissue maturation and growth, and their contributions to tumor
    growth; and

-   Detailed studies of steroid metabolism in the prostate, centering on
    conversion of testosterone to dihydrotestosterone.

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-   The Institute's George O'Brien Kidney and Urology Centers devoted to
    urology research, and one or two of the Kidney Centers with
    particular strength in genitourinary development, are being invited
    to prepare proposals for programs of pilot and feasibility projects
    in prostate biology.

-   The NIDDK also is supporting a study entitled "Chronic Prostatitis
    Collaborative Clinical Research Studies." This will be the first
    large, multicenter study designed to gather well-defined, detailed
    clinical information on the condition and then use that base to test
    and evaluate new treatment strategies in the future. The study will
    document symptoms, possible risk factors, medical histories and
    treatments; test blood, prostate fluid, semen and urine; and explore
    possible relationships between chronic prostatitis, urethral and
    bladder inflammation and other chronic pelvic pain disorders.

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-   One of the NIDDK's existing George O'Brien Centers specializing in
    Urology is competing for renewal in 1999. The competition has
    resulted in receipt of five applications, which have not yet
    undergone review and received scores. If the proposals are
    excellent, the Institute may consider funding a second center beyond
    the one serving as a replacement.

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-   Expansion of the Institute's urology epidemiology program is
    underway. An epidemiologist has just been recruited, and the NIDDK's
    epidemiology support contract will be doubled in size. Further
    expansion will continue in 2000, if it is deemed to be appropriate.
    A related effort to establish under contract a national database for
    clinical urology is expected to be awarded in 2000, and will be
    about one-half related to the prostate research.

-   Funds may be used to fund research project grants beyond the payline
    for new prostate projects in the Urology and Endocrinology Programs.
    Also, NIDDK staff are planning a special meeting of outside experts
    to discuss the most promising ongoing research projects that could
    benefit from supplementation. NCI staff are being invited to join in
    this meeting, together with prostate research leaders of their
    choice. There has also been a proposal for supplements to the
    clinical trial on Medical Treatment of Prostatic Symptoms to allow
    application of array methods to assess correlations in patterns of
    gene expression in tissue specimens with clinical outcomes in
    patients; this proposal will be further evaluated for possible
    funding in 1999 or 2000.

***Training and manpower in investigative urology:*** The NIDDK plays a
special role in fostering and supporting research training and manpower
in investigative urology--both of clinical and basic investigators.
Strengthened recruitment of investigators to study prostate cancer and
enhanced support for career development are critical for the development
of a national program on prostate cancer.

***O'Brien Urology Centers:*** The NIDDK currently supports five George
O'Brien Urology Research Centers. Some prostate cancer related work is
performed in all of these centers, and three have a particular focus on
the biology of the prostate.

-   The focus of the Center at the University of Washington is on
    prostate cancer, including how prostate cancer spreads to tissues
    beyond the prostate gland, the mechanisms that control the
    expression of prostate-specific antigen (PSA), development of
    research methods for gene therapy of prostate cancer, and
    interference with tumor progression, which may lead to treatments
    for prostate cancer.

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-   The Center at the Sloan-Kettering Institute for Cancer Research is
    investigating regulatory mechanisms of prostate tumor progression,
    specifically the cellular changes that are associated with the
    progression of disease from normal to premalignant conditions.

-   The Center at The University of Texas Southwestern Medical School is
    examining several aspects of benign and malignant prostate growth,
    including the genetic alterations involved in prostate cancer, and
    the expression of male hormones in benign and malignant prostates.

In the current funding year, supplementary pilot and feasibility funds
are being made available to these centers to develop new directions for
work related to prostate cancer. Expansion of support for these centers
in future fiscal years would be anticipated.

#### Targeted Areas of Scientific Emphasis

The following topic areas, all traditionally areas of strength in NIDDK,
present opportunities for particular emphasis and expansion in this
five-year plan. Each of these research avenues is described more fully
in the following sections of this five-year Professional Judgment
Report:

-   Clinical studies of the transition from benign to malignant prostate
    disease;

-   Cell and developmental biology of the normal prostate gland;

-   Androgen action, steroid hormone interacting proteins;

-   Epidemiology of prostate disease in minority populations;

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-   Post-prostate-surgery urinary incontinence and impotence.

#### Prospective clinical studies of the transition between benign prostatic hyperplasia and prostate cancer

Goals:

-   Define the effect of various strategies to treat benign prostatic
    hyperplasia on the incidence of prostate cancer;

-   Develop pathological criteria for sub-categorization of benign
    prostatic hyperplasia; examine correlations between molecular
    markers and pathological characteristics; establish the relative
    risk of prostate cancer associated with each sub-type;

-   Examine prospectively the prognosis of prostatic intraepithelial
    neoplasia (PIN);

-   Improve the accuracy of the diagnosis of early prostate cancer;

-   Test the predictive value of potential surrogate markers of prostate
    cancer;

-   Undertake systematic assessment of the patterns of gene expression
    in the prostate gland to define new molecular markers associated
    with enhanced susceptibility to prostate cancer and to define new
    molecular markers associated with the transition to malignant
    disease.

-   Elucidate further the detailed mechanisms of gonadotropin, androgen,
    and growth factor action on the prostate.

Implementation:

The NIDDK supports an extensive investigative program on treatment of
benign disease of the prostate, especially, benign prostatic
hyperplasia, BPH. A keystone of this program is an important clinical
trial, the Medical Therapy of Prostate Symptoms (MTOPS), currently in
its third year. MTOPS assesses the effect of two different
pharmacological agents on the prevention of progression of symptomatic
BPH and correlates those clinical effects with molecular and genetic
actions on prostate biopsy tissue from participants in the study.

The study supports 19 clinical centers and has an enrollment of
approximately 1,000 patients. It was developed with the principal goal
of prospective, randomized evaluation of medical therapy for prostate
symptoms, but has enormous potential for prospective evaluation of
cancer risk. Patients are very carefully characterized and closely
followed, with regular studies including stored plasma samples and
repeat biopsies. All patients have undergone regular ultra-sound imaging
using state of the art quantitative techniques.

Over the next ten years, a substantial portion of these patients are
expected to develop prostate cancer. This cohort provides an
extraordinary and very cost effective opportunity for studies to address
the goals enumerated previously. We would plan to expand this cohort,
and make it the basis for a major prospective epidemiology study with
the goals listed above.

The following specific steps would be needed to fully implement this
initiative:

-   Expand funding of MTOPS centers to expand the patient base and
    ensure the epidemiological expertise to achieve the goals listed
    previously;

-   Establish support for micro-array technology development and
    application of micro-array methods to stored patient biopsies;

-   Solicit investigator-initiated adjunctive studies utilizing the
    MTOPS patient population to evaluate surrogate markers and new
    diagnostic approaches.

-   Initiate clinical studies to determine the effectiveness of new
    prevention strategies.

#### Cell biology and developmental biology of the prostate gland

Goals:

-   Define the cellular characteristics of the epithelial cells, stromal
    cells, endothelial cells, neuroepithelial cells and inflammatory
    cells that make up the prostate;

-   Define the specific interactions between these cells;

-   Develop a complete characterization of the biological processes in
    the prostate during its development, maturation and transition from
    normal to hyperplastic to malignant states;

-   Encourage investigation that utilizes these insights to define new
    therapeutic targets.

Implementation:

The NIDDK program in prostate biology and prostate growth provides a
strong starting basis to build expanded investigation in these areas.
Our advisory groups consistently recommend strong investment in the
basic biology of the prostate gland as the best long-term strategy to
identify breakthroughs in therapy, prevention and diagnosis of prostate
cancer. Funding for this program in 1998 was approximately \$5.0
million. Substantial expansion in each of the next fiscal years would be
strongly justified scientifically by the scientific opportunities
available in this area.

Most of the work on these topics is and will likely continue to be
undertaken through investigator-initiated grants. Recently a program
announcement, cosponsored with the NCI, was issued to stimulate
submissions in these areas. A specific solicitation, focused on
development of the prostate gland, is planned for 2000. Further steps to
encourage investigation in these areas would include regular workshops
and development of targeted research initiatives.

#### Mechanisms of androgen action 

Goals:

-   Define the potential roles of androgen and critical other steroid
    hormones in prostate growth, tissue interactions and development;

-   Define the structure of androgen nuclear receptors;

-   Define the interacting proteins and the ligand-metabolizing enzymes
    in the prostate.

Implementation:

This important topic was identified as the number one priority in the
Prostate Cancer Review Report by Subgroup A, Biology, Progression and
Metastasis. It is widely recognized that the transition from androgen
dependence to androgen independence is an absolutely critical event in
the natural history of prostate cancer, and that this biological event
often determines the patient prognosis. It is therefore critical that we
develop a precise understanding of the process of androgen regulation of
gene transcription.

As was recognized in the Prostate Cancer Review Group Report, this is an
area traditionally supported by NIDDK, largely through
investigator-initiated grants. Program initiatives over the next five
years would undertake to encourage submissions in this area and to
encourage investigators to examine these issues in prostate models. In
addition, we would explore targeted strategies to expand translational
and industry investment in these areas.

#### Epidemiology of prostate disease, especially in minority men

Goals:

-   Define which segments of the U.S. population have enhanced or
    reduced susceptibility to benign prostatic hypertrophy and
    prostatitis, and the relationship between altered risk of benign
    disease and altered risk of prostate cancer;

-   Identify genetic and environmental factors associated with enhanced
    or reduced cancer risk, particularly in minority men.

Implementation:

Studies of prostate cancer have established that African American men
are at increased risk, and suggest reduced risk in Americans with Asian
backgrounds. There is less data on the relative risk for these
populations of benign disease, or on the association between benign
disease and cancer risk. In 1999, the NIDDK issued a Request for
Proposals to establish a prospective epidemiology database of urologic
disease. This study will use existing databases to examine a variety of
associations and to obtain important descriptive parameters of urologic
disease in the United States. This program will provide the
infrastructure to address the issues defined above.

#### Complications of Surgery on the Prostate

Goals:

-   Define strategies to reduce the incidence of urinary incontinence
    and impotence after surgery

-   Develop new therapies and investigate efficacy of established
    therapies for these two surgical complications.

Implementation:

Better strategies are urgently needed to prevent the two feared
complications of surgery on the prostate\--urinary incontinence and
impotence. Although new surgical approaches for both benign prostatic
hypertrophy and prostate cancer have reduced the rate of these
complications, further research is needed. Clinical and basic
investigation in these two areas is a traditional strength of the
programs supported by NIDDK. Creation of a clinical trials consortium to
evaluate surgical outcome prospectively and rigorously, and to test new
therapies would be encouraged in this area. A pilot phase would occur in
2000, with full implementation in 2001.

#### Training and Manpower Issues 

Our advisory groups consistently identify a shortage of trained,
experienced investigators in urology as an impediment to development of
strong research in this area. The NIDDK has a strong program of support
for training and career development in urology, but anticipates a need
for substantial strengthening of this investment.

Programs would be developed to target the following needs:

-   Training of investigators with expertise in both clinical urology
    and in the design and implementation of clinical trials;

-   Recruitment of Ph.D. investigators from a variety of basic science
    disciplines to study of prostate cancer;

-   Development of careers of Ph.D. investigators.

Existing NIH training mechanisms, including the recently initiated
awards for training of clinical investigators and mid-career
investigators (K23 and K24), provide valuable approaches to these
problems. NIDDK has also in the past utilized mechanisms of co-funding
with non-profit foundations, for example NIH-AFUD fellowships, of
training programs that would continue.

#### O'Brien Urology Centers 

The NIDDK currently supports five George O'Brien Urology Research
Centers. Some prostate cancer related work is performed in all of these
centers, and three have a particular focus on the biology of the
prostate.

Centers with a particular focus on prostate are as follows:

The Center at the University of Washington focuses on prostate cancer.
This includes how prostate cancer spreads to tissues beyond the prostate
gland, the mechanisms that control the expression of prostate-specific
antigen (PSA), development of research methods for gene therapy of
prostate cancer, and interference with tumor progression, which may lead
to treatments for prostate cancer.

The Center at the Sloan-Kettering Institute for Cancer Research is
investigating regulatory mechanisms of prostate tumor progression,
specifically the cellular changes that are associated with the
progression of disease from normal to premalignant conditions.

The Center at The University of Texas Southwestern Medical School is
examining several aspects of benign and malignant prostate growth,
including the genetic alterations involved in prostate cancer, and the
expression of male hormones in benign and malignant prostates.

In the current funding year, supplementary pilot and feasibility funds
are being made available to these centers to develop new directions for
work related to prostate cancer. Expansion of support for these centers
in future fiscal years would be anticipated.

## National Human Genome Research Institute 

#### Genetic Factors -- Hereditary Cancer

The intramural research program of the NHGRI continues to focus
significant effort on the identification of genes important in
hereditary susceptibility to prostate cancer as well as genes involved
in sporadic cases and disease progression. In the past, genetic
contributions to most common diseases were virtually impossible to sort
out. NHGRI intramural studies of prostate cancer provide a compelling
example of how research tools developed by the Human Genome Project are
bringing clarity to such scientifically murky health problems. Because
prostate cancer clusters in some families, especially when the onset is
early, researchers have suspected the disorder has a strong genetic
component. That suspicion was borne out two years ago when an
international team of researchers, led by scientists at the NHGRI and
Johns Hopkins, located a region on chromosome 1 that appears to contain
a gene variation (HPC1) that predisposes men to prostate cancer. This
was the first proof that prostate cancer risk is controlled by specific
genes.

Less than six months ago, studying over 300 families, each with many
affected men, the same team of researchers found a second site, on the X
chromosome (HPCX), that also appears to contribute to the development of
prostate cancer. These discoveries pinpoint the neighborhood in which
two prostate cancer susceptibility genes must lie. In a "house to house"
search of those chromosomal regions, NHGRI investigators now are working
vigorously to identify the precise genes and the misspellings on both
chromosomes that correlate with risk of prostate cancer. In this way,
Human Genome Project tools are allowing scientists to develop a
comprehensive understanding of the causes of prostate cancer. Improved
understanding of the molecular causes of prostate cancer will lead to
better abilities to predict which men are at highest risk, which can
allow them to be carefully watched for early signs of prostate cancer.
In the longer term, better understanding of this disease will expand
potential areas for new therapies and provide a fundamentally new
paradigm for sorting out the hereditary, environmental, and
socio-economic bases of human illness.

#### Genetic Factors -- African American Men

While prostate cancer is common among all U.S. males, it is especially
common among African-American men. African American men are 35 percent
more likely than their white male counterparts to develop the disease
and more than twice as likely to die from it. Researchers based at NHGRI
and Howard University, supported by funds provided from the NIH Office
of Research on Minority Health, are heading a nationwide study that
applies the full force of genome technologies to attempt to explain the
causes of this apparent disparity. Are men of African descent inherently
more susceptible to prostate cancer, and what role do other
community-based factors play? The Howard-NHGRI study is being carried
out primarily by black scientists and doctors located in seven study
centers around the country. So far, 31 large African-American families
with several affected men have volunteered medical histories and blood
samples that will be used to zero in on prostate cancer-related gene
alterations on chromosomes 1, X, and others. In the next few years,
these studies will bring a much broader understanding of this very
common disorder, and ideally suggest new ways to intervene, treat, or
even prevent it.

#### Genetic Changes -- Prostate Cancer Cells

While hereditary factors are heavy contributors to the development of
prostate cancer for some men, most prostate cancer results from changes
in the genetic material of individual cells that occur throughout life.
Using the techniques of modern genomics, NHGRI investigators are seeking
to define the genetic changes in cells that lead to the initiation and
progression of prostate cancer.

Several developing technologies now are being used to gain insight into
the human cell and to transform the study of human genetics. Much of it
is borrowed from the computer chip industry and the devices are often
called \"DNA chips.\" In most experiments in the past investigators have
looked at one gene at a time. Yet humans are thought to have tens of
thousands of genes, and they work in concert or committees (scientists
call these pathways) to get things accomplished. Ultimately, to really
understand the behavior of the human organism, and what goes wrong when
a disease occurs, what we would really like to be able to do is look at
the behavior of all the genes in a single experiment. That might finally
provide a true picture of what\'s going on inside the body.

Work emanating in part from the NHGRI\'s intramural research program has
developed robotic tools to touch the surface of a microscope slide and
leave behind a microscopic drop of fluid. Each drop contains millions of
strands of DNA-copies of a single gene. The current model is capable of
creating an array of 15,000 tiny drops on each of the slides. Each spot
is a detector or specific assay reagent. The strands of DNA in it are
like tiny pieces of Velcro that stick only to the products of one
particular gene. When researchers pour the contents of a cell over that
slide, the spots that pick up evidence of active genes can be made to
glow. The thousands of glowing dots provide a landscape of active genes
that could suggest how tumor cells work or how a cell responds to
disease.

This approach is now being used to look at the changes in gene
expression that occur as prostate tissue progresses from normal
epithelium, to a pre-malignant state called "pin," to a low grade
malignancy, to a higher grade malignancy, to a malignancy which is no
longer hormonally responsive. In each state of progression, certain
genes are turned on and off in a particular tumor, representing the
pathways of control of cell growth that are contributing to the
malignant state. Each of these changes represents a crucial clue to the
pathogenesis of prostate cancer, and can suggest new ways of treating or
preventing the disease.

Of course not every prostate cancer follows the same set of steps; when
a pattern of abnormal gene expression is observed in a particular tumor,
it is critical to determine whether this is a common or rare event. To
explore this question, NHGRI investigators have developed the "Tissue
Chip" \-- hundreds of different tissue samples, derived from normal or
malignant tissue, are arrayed on to a microscope slide using robotic
technology. Using this chip, the over expression of a particular
candidate prostate cancer gene can be assessed in one experiment in a
very large number of tumors, and an analysis which would have taken many
months in the past can be done in one day. In this way one can identify
the major culprits in prostate cancer, and focus new interventions on
these common themes.

#### Future Directions -- NHGRI Prostate Cancer Research

Over the next five years, NHGRI investigators aim to identify all of the
common contributing genes to hereditary susceptibility - besides HPC1
and HPCX, there is strong evidence pointing to another region of another
chromosome, and other regions also contain hints of hereditary factors.
As the precise genes are identified, clinical studies would be
undertaken to offer genetic testing to men from high risk families, to
identify those at greatest risk for life-threatening disease and design
a program of surveillance to identify their cancers early enough to
achieve cure. In addition, using the chip technology, the common changes
in gene expression that contribute to various steps in malignant
transformation would be cataloged, and used to derive new hypotheses
about the molecular steps involved in prostate cancer. These would in
turn suggest new and more powerful ways to treat or prevent the disease.

## National Center for Research Resources 

Through its support of multidisciplinary research infrastructure, the
National Center for Research Resources (NCRR) is uniquely positioned to
provide complementary research support in partnership with other
institutes or Centers to address clinical and basic research needs for
prostate cancer research. The NCRR can provide the infrastructure
support for clinical trials and other related clinical studies, the
development of animal models, development of new technologies and
instrumentation, including imaging technologies. This support would
facilitate interdisciplinary collaborations across NIH components and
would advance efforts to develop more sensitive and specific screening
technologies and more effective therapeutic interventions.

## National Institute of Environmental Health Sciences

Prostate cancer is a disease of enormous public health importance; it is
the most frequently diagnosed cancer in American men. However, little is
understood about its pathogenesis. Effective prevention will depend on
research into how genetic predisposition and environmental exposures the
risk of prostate cancer. The National Institute of Environmental Health
Sciences (NIEHS) is spearheading this approach to understanding
gene-environment interactions in prostate cancer development, with the
help of several key initiatives.

***Environmental Genome Project:*** Human diseases, such as prostate
cancer, are generally the consequence of both genetic susceptibility and
environmental exposure. The tools of molecular genetics provide new
opportunities to understand the genetic basis for individual differences
in susceptibility to environmental exposure. The NIEHS is expanding its
research program on genetic susceptibility to environmentally-associated
diseases through a new Environmental Genome Project. Over the next five
years, the Environmental Genome Project would systematically identify
the allelic variants of disease susceptibility genes in the U.S.
population, develop a central database of known polymorphisms for these
genes, and foster population‑based studies of gene-environment
interaction in disease etiology. By identifying those genes and allelic
variants that affect individual response to environmental toxins, we can
better predict health risks and develop environmental policies to
protect the most vulnerable subgroups of the population from such
diseases such as prostate cancer.

The NIEHS Environmental Genome Project would be a broad, multi‑center
effort to identify systematically in the U.S. population the alleles of
environmental disease susceptibility genes. Susceptibility genes will be
chosen through a peer‑reviewed process and are expected to include five
broad gene classes: genes controlling the distribution and metabolism of
toxicants; genes for the DNA repair pathways; genes for the cell cycle
control system; cell death/differentiation genes; and, genes for signal
transduction systems controlling expression of the genes in the other
classes. This effort would result in the systematic identification of
the polymorphisms of these genes found in the U.S. population. A central
database of the polymorphisms would be made available. This database
will support both functional studies of alleles and population‑based
studies of disease risk.

***Exposure Assessment Initiative:*** The NIEHS and the Centers for
Disease Control and Prevention are collaborating on improving the
exposure assessment of a particular group of environmental
exposures‑‑the environmental endocrine disruptors which could contribute
substantially to the understanding of how environmental chemicals may
promote or induce prostate cancer. This collaboration will strengthen
the science base for risk assessments by quantifying the amount of a
given chemical or a chemical structural class in the human body as a
consequence of exposure from daily living. In the case of environmental
endocrine disruptors, we know that there are scores of environmental
chemicals that possess hormonal activity, including pesticides,
industrial byproducts, health care products and compounds arising from
the manufacture and use of plastics and detergents. In addition, there
are numerous plant and fungal products that also possess hormonal
activity and are known to produce health effects when people are exposed
to them insufficient quantities. Unfortunately, we know very little
about the human body burden of these chemicals and this lack of
knowledge creates much of the controversy over their impact on human
health. This information is needed before we can make a more
science‑based evaluation of whether these environmental agents are
producing effects on hormonally sensitive diseases such as prostate
cancer.

***cDNA Microarray Analysis of Gene Expression:*** cDNA microarrays are
tools that can be used to analyze changes in genome‑wide patterns of
gene expression. This technology may revolutionize the way toxicological
problems are investigated. Given that exposures to different classes of
toxicant result in distinct patterns of altered gene expression,
microarray technology can be used to categorize and classify these
effects through the direct comparison of gene expression patterns in
control versus treated samples on the same cDNA microarray. In defined
model systems, treatment with known agents, dioxin‑like compounds, or
estrogenic chemicals may provide a gene expression \"signature\" on a
microarray which represents the cellular response to these agents. These
same systems can then be treated with unknown, suspect agents to
determine if one or more of these standard signatures is elicited. This
approach will also help elucidate an agent\'s mechanism of action and
may also be used to detect changes in exposed human populations. It is
also likely that new molecular targets of toxicant action will be
identified, and that these new targets may be good candidates for
analysis in the Environmental Genome Project.

The NIEHS is in the process of establishing cDNA microarray technology
in a collaborative research effort with the National Human Genome
Research Institute. Custom cDNA arrays or \"chips\" are being developed
that comprise human cDNA clone subarrays oriented toward detection of
the expression of genes involved in responses to toxic insult. The goals
of the project are to use gene expression methodologies to: 1) identify
toxicants on the basis of tissue specific patterns of gene expression
(molecular signature); 2) elucidate mechanisms of action of
environmental agents through the identification of gene expression
networks; 3) use toxicant‑induced gene expression as a biomarker to
assess human exposure; 4) extrapolate effects of toxicants from one
species to another; 5) study the interactions of mixtures of chemicals;
and 6) examine the effects of low dose exposures versus high dose
exposures. In addition, gene expression profiles are likely to be
excellent surrogate markers of safety and efficacy for use in clinical
trials, which face a similar \"bottleneck\" effect to that identified
for toxicology studies. Future resources in the area of prostate cancer
could be applied, in part, to the NIEHS effort to develop cDNA
microarray technology for the elucidation of prostate‑specific patterns
of gene expression resulting of exposure to low level environmental
toxicants either singly or in mixtures. Funds would also be targeted to
identify gene expression networks that may lead to the induction and/or
progression of prostate cancer.

***New Models for Prostate Cancer Research:*** There is a lack of
appropriate animal models for prostate cancer. NIEHS researchers are
working with a new mouse model called TRAMP (Transgenic Adenocarcinoma
of the Mouse Prostate). These mice develop prostate cancer by six months
of age. A colony has been established, and the first study will be to
characterize the pathogenesis of lesion development and related
parameters in target tissues. Researchers are also interested in the
modulation of IGF‑I and in determining how this affects the pathogenesis
and development of the prostate cancer in the TRAMP model.

***Environmental Family Cohort:*** Some of the most significant public
health findings have arisen from large, long‑term cohort studies. The
two prime advantages of any cohort study are that careful exposure
information can be collected before disease occurs, and many different
disease outcomes can be addressed in a single setting. Previous cohorts
established to study such factors as diet and risk of cancer and other
diseases collected little information on environmental exposures and
have not been selected to maximize the possibility of exposure. The
NIEHS is studying the feasibility of establishing a cohort of people who
live in areas with a high burden of exposure to environmental pollutants
(e.g., parts of Louisiana, New Jersey, or Los Angeles). Special efforts
would be made to enroll persons from different ethnic minorities. Over
time, the health problems, including prostate cancer, that develop in
this cohort would provide rich opportunities for specific studies.
Studies of prostate cancer and other specific diseases in this cohort
would permit testing of candidate susceptibility genes as part of the
Environmental Genome Project.

***Vitamin D Receptor Polymorphisms and Prostate Cancer Risk:*** NIEHS
researchers have demonstrated an association between a polymorphism in
exon 9 of the vitamin D receptor (VDR) and increased prostate cancer
risk. Prostate cancer cases and controls are currently being analyzed
for VDR polymorphisms. The goal is to characterize the association of
genetic polymorphisms in the VDR and the development of prostate cancer
that has previously been described. Opportunities exist to accelerate
this project as well as enable the NIEHS to extend it to additional
polymorphisms using results from the Environmental Genome Project.

***Genetic Susceptibility and the Environment in Prostate Cancer
Risk:*** The research on genetic susceptibility tests the hypothesis
that commonly inherited allelic variants of certain genes, in
conjunction with environmental exposures, affect a person\'s risk of
developing disease. The primary focus of this work has been on bladder
cancer, although recently we have expanded to include studies of
prostate. NIEHS researchers have obtained DNA samples with linked
epidemiologic information with which to extend earlier findings of an
association between a polymorphism in the 3\'UTR of the vitamin D
receptor gene and prostate cancer risk. Genotyping has been completed
and data analysis is to begin. In addition, researchers have genotyped
prostate cancer cases and controls for a polymorphism in CYP17, a gene
involved in androgen metabolism, and are starting data analysis.
Opportunities exist to accelerate this project as well as enable the
NIEHS to extend it using results from the Environmental Genome Project.

***Metastasis Suppressor Gene for Prostatic Cancer:*** Progression of
cancer to the metastatic state involves multiple cellular and genetic
changes, including the loss of metastasis suppressor functions and the
activation of oncogenes. NIEHS researchers cloned a gene, termed KAI1,
that can suppress the metastatic ability of a rat prostatic cancer cell
line. KAI1 is highly expressed in normal prostate and breast epithelial
cells but is dramatically lower in cancer cell lines derived from
metastatic tumors. Primary and metastatic tumor specimens have been
collected from prostate, colon, breast, and ovarian tumors to
investigate whether KAI1 expression can be used to predict the
metastatic ability of primary cancers. Current work involves the
characterization of the regulation of KAI1 function and an examination
of the role of KAI1 in cell‑cell aggregation, adhesion, and invasion.
This work is expected to result in a model that would allow the
development of KAI1 gene therapy protocols. Opportunities exist to
accelerate and extend this project. For example, a possible metastasis
suppressor gene has been identified on chromosome 8p; this gene would be
cloned and characterized.

## National Institute on Aging

#### Prostate Cancer Research Plan

The NIA singled out prostate cancer as one of the first extramural
research initiatives developed by its Cancer Section, newly created in
1996, in the NIA Geriatrics Program. According to the NCI SEER Program,
prostate cancer is a disease of older men, with 77 percent of all
prostate cancer cases and 92 percent of prostate cancer mortality
occurring in the 65+ age group. Prostate cancer also has the highest
incidence of any malignancy for white and black men 65 years and older,
1186.5 and 1593.7 per 100,000 population, respectively. In addition,
age-adjusted mortality rates are more than twice as high for African
Americans as for white Americans. Guided by these facts, the NIA issued
a Program Announcement, \"Aging, Race, and Ethnicity in Prostate
Cancer\" (PA-97-019) in the NIH Guide to Grants and Contracts (Volume
25, Number 44). This PA encourages the extramural research community to
take advantage of recently acquired scientific knowledge and expertise
developed in biology, gerontology, oncology, urology, and other
disciplines and professions, as well as to apply these resources to
aging-relevant research questions on prostate cancer for aging males of
different races and minority backgrounds. The clinical component of this
PA encourages studies on determinants of age- and race-associated
differences in prostate cancer detection, treatment, and survival. Other
major components of the PA solicit studies on the etiology and risk
factors that affect the rate of increase with age in prostate cancer and
on developing new methods and testing improved methods to identify high
risk older white and African American men and low risk men of different
racial and ethnic origins.

The NIA's intramural program has used its unique resource, the Baltimore
Longitudinal Study of Aging (BLSA), to investigate the longitudinal
trends in prostate specific antigen (PSA). The BLSA investigates how
these trends influence the utility of this measure in detecting prostate
cancer, in prospectively identifying men at high risk for the disease,
and in determining the prognostic and diagnostic value of the free/total
ratio of PSA. NIA investigators have also examined the linkage between
longitudinal testosterone levels, insulin-like growth factors (IGF-I and
IGF-II, and IGF binding protein-3), and prostate cancer risk.

Research from the BLSA continues to study the time course for the
development of prostate cancer and markers useful in early diagnosis.
The goal is to define which groups of men should be tested, how long and
how often they should be tested to maximize the identification of
treatable prostate cancer while minimizing the costs of evaluation. This
work has shown that the rate of change in prostate specific antigen over
time, known as *PSA velocity*, improves the specificity of PSA. This
means that knowing how fast PSA levels change over time allows
identification of men at higher risk for the development of prostate
cancer. In these studies, 70 percent of men ultimately diagnosed with
prostate cancer had a PSA velocity exceeding 0.75 ng/ml per year. Less
than five percent of men without prostate cancer have a rate of change
in PSA exceeding 0.75 ng/ml per year. These data have now been confirmed
in large prospective screening trials. Investigators have also shown
that a PSA screening frequency of two years is not likely to miss a
curable prostate cancer when the initial PSA level is less than two
ng/ml, thus reducing the required frequency for PSA screening in many
men.

Recently, free/total PSA ratio has become available for clinical use.
Low ratios have been shown to be associated with prostate cancers.
Studies of men in the BLSA have now shown that the free/total PSA ratio
was abnormally low 10 years prior to diagnosis in the cohort of subjects
who ultimately were diagnosed with prostate cancer. Therefore, by using
the PSA free/total ratio it is possible to identify men at risk even
when total PSA values are within normal limits as was the case in the
BLSA cohort. Further correlations of these data show that the percentage
of free prostate-specific antigen in sera predicts aggressiveness of
prostate cancer before diagnosis. These findings can improve the ability
to screen men for this disease and make it possible to identify men who
are at higher risk of developing an aggressive cancer. By knowing early
that a cancer is present, and by knowing its aggressiveness, men and
their physicians can better plan appropriate therapeutic strategies.

NIA and Johns Hopkins University School of Medicine investigators have
used the BLSA cohort to examine the role of hormones in promoting
prostate cancer as well as the potential use of hormone measurements as
potential markers of prostate cancer risk. These studies have employed a
\"retro-prospective\" study design, using stored samples from the BLSA
collection taken as much as 15 years before men developed clinical
evidence of prostate cancer and comparing them with samples from
age-matched men followed for similar periods of time with no diagnosis
of prostate cancer. To date, these studies have provided evidence that
serum testosterone levels, whether measured as total or biologically
available fraction, do not predict subsequent development of prostate
cancer.

Previous studies evaluating the roles of circulating insulin-like growth
factors (IGF-I and IGF-II) and their major plasma binding protein, IGF
binding protein-3 (IGFBP-3), have suggested that lower than average
levels of IGF-I and high levels of IGF-II may each be independently
associated with a reduced risk of prostate cancer, while the apparent
protective effect of IGFBP-3 was not statistically significant. In
contrast, recent NIA intramural studies have shown that once levels of
PSA are known, determinations of IGF-I, IGF-II, and/or IGFBP-3 add no
useful predictive information for identifying patients at high risk for
prostate disease in groups of longitudinally-followed middle aged and
older men. Further studies are planned to investigate the role of
longitudinal changes in growth factors and sex steroids in predicting
prostate cancer risk.

## National Institute of Nursing Research

#### Care of Men with Prostate Cancer: 

NINR has identified opportunities for expanding its biobehavioral and
psychosocial research on prostate cancer to include:

-   managing symptoms following treatment (e.g., urinary incontinence
    and pain);

-   nursing interventions to improve quality of life, including sexual
    role and function;

-   decision--making associated with treatment options (e.g. watchful
    waiting vs. surgery);

-   decision--making associated with screening for prostate cancer.

These studies would provide important knowledge to improve
decision‑making, management of symptoms, and quality of life for men
with prostate cancer.

## National Institute of Mental Health 

NIMH supports research on the interactions of stress and emotions with
life-threatening illnesses such as cancer. A primary focus of
NIMH-supported research related to prostate cancer is characterization
of the stress of with having prostate cancer and undergoing a radical
prostatectomy. This research examines psychological, physiological, and
quality-of-life changes associated with the surgery and short- and
long-term recovery; it also examines dispositional and environmental
factors that might serve to predict response to surgery and long-term
recovery. An objective of this research is to develop a pre-surgical
stress management approach that will reduce the negative impact of
prostatectomy on patients. Other NIMH research explores the genetic
basis of familial prostate cancer.

## National Institute of Deafness and Other Communication Disorders 

Mammalian bombesin receptors are expressed by some prostate tumor cells,
and can mediate a bombesin‑dependent growth stimulatory response in some
prostate carcinoma cell lines. In this project, the structure, function,
and regulation of three mammalian bombesin receptor subtypes is defined
at the molecular level. Recent studies have: 1 ) identified structural
determinants essential for binding both agonist and antagonists; 2)
established that agonist-mediated receptor phosphorylation occurs within
seconds after ligand binding, and attenuates receptor signaling and
interaction with cognate GTP-binding proteins; and 3) created mouse
models unable to express two of the known mammalian bombesin receptors,
both of which show abnormalities in weight control and/or satiety. A
more complete understanding of bombesin receptor function would
hopefully facilitate the development of therapeutic strategies that
utilize bombesin receptors as therapeutic targets in the diagnosis and
treatment of human prostate cancer.