THE NATIONAL CANCER PROGRAM

M A N AG I N G T H E N AT I O N ’ S R E S E A R C H P O RT F O L I O

AN ANNUAL PLAN AND BUDGET PROPOSAL FOR FISCAL YEAR 2013

National Cancer Institute

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES

National Institutes of Health
Contents

1 Foreword

4 Provocative Questions

8 Center for Cancer Genomics

16 Introduction to Cancer Profiles

18 Pancreatic Ductal Adenocarcinoma

22 Colorectal Cancer

26 B-Cell Lymphoma

30 Renal Cell (Kidney) Cancer

34 GI Stromal Cancer 

39 Research Focus: Comorbidities

42 Research Focus: Circulating Tumor Cells

44 Research Focus: Reducing Cancer Health Disparities

50 The Frederick National Laboratory for Cancer Research

61 Small Business Innovation Research, Small BusinessTechnology Transfer (SBIR, STTR)

 66 NCI Center for Global Health

72 NCI-Designated Cancer Centers 

83 Glossary of Terms

84 Budget 
NATIONAL CANCER INSTITUTE | 1

FOREWORD

MANAGING THE NATION’S RESEARCH PORTFOLIO

The National Cancer Program

T

his year marks the 75th anniversary of the founding of the 

National Cancer Institute, the first so-called “categorical 

institute” of what has become the National Institutes of 

Health, with its 27 Institutes and Centers. Over the years, 

the Congress and the public have generously supported the 

NCI—and the NIH generally—with sustained budgetary increases. 

This was especially true for the NCI during the rapid expansion of its 

budget following the National Cancer Act of 1971 and for the NIH, 

including the NCI, during the 5-year doubling of its budget, launched 

in 1998. Both of these eras of rapid growth were remarkably fruitful. 

The first launched the pursuit of cancer genes and the molecular 

basis of oncogenesis, laying the foundation for the transformation 

of clinical oncology that is now occurring. The latter accelerated the 

completion of the human genome project that now guides the study 

and control of all diseases, including cancers. Since 2003, however, 

the budgets of the NCI and the NIH have grown minimally, with their 

buying power shrinking by about 20 percent as 

a consequence of inflation. 

This decade-long hiatus in financial growth has come, ironically, 

at a time of unmatched promise in the oncological sciences and at 

a time when the world of cancer research has expanded in talent, 

facilities, and ideas. Progress in molecular biology, especially in 

the deciphering of cancer genomes and the probing of the signaling 

pathways that govern normal and malignant cell growth, has 

transformed our ability to understand the broken parts of a cancer 

cell; to develop new and more precise therapeutic strategies; to 

begin to reformulate diagnostic categories; and to imagine screening 

for and prevention of some cancers in more powerful ways. In 

just the past few years, NCI-supported science has delivered a 

remarkable collection of genetic information about several types 

of cancers, a number of new targeted therapies for various cancers, 

compelling examples of successful immunologically basedtherapies, persuasive evidence that radiographic screening can 

reduce lung cancer mortality, and many new observations about the 

genesis of cancer cells, their development, their behavior, and their 

microenvironment. 

This decade-long hiatus in financial growth has come, ironically, at a time of 

unmatched promise in the oncological sciences and at a time when the world of cancer 

research has expanded in talent, facilities, and ideas.
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One of the goals of this annual report is to summarize some of these 

findings and their practical consequences, so that the NCI’s many 

supporters and beneficiaries can better appreciate the significance 

of the NCI and the argument for the enhanced support that we 

request in the “by-pass budget.” We provide this summary in two 

ways: by describing some of the NCI’s broad research programs that 

address a wide range of cancers and their underlying biological 

properties and by discussing several specific types of cancers (five 

this year) that exemplify the various strategies and the variable rates 

of progress on the different diseases that we are working to control. 

The latter disease-specific presentations also help to acquaint the 

report’s readers with some important fundamental principles: first, 

that different types of cancers are often united by common themes, 

but also characterized by inherent differences in epidemiological 

factors, molecular mechanisms, and clinical features; and second, 

that studies of each cancer type are strongly influenced by work on 

other types of cancer. These notions have implications with respect 

to the way we use the public funds we receive from Congress. We 

must, and we do, balance our knowledge about the public health 

burden of each cancer type against a consistent historical message: 

The sources of our greatest advances are difficult to predict and 

often emerge from unexpected places. So scientific opportunity, the 

richness of experimental ideas, and the talent of investigators must 

be taken into account, along with the toll taken by individual cancer 

types, if we are to spend our funds wisely and earn public trust, 

especially at a time of fiscal restraint.

When the National Cancer Act was signed in 1971, the NCI Director 

was deemed to be the leader of the National Cancer Program, the 

totality of the nation’s efforts to combat cancer. We now recognize 

that efforts to control cancer and its effects—through science, 

medicine, and social programs—are now so vast, conducted by so 

many people, and funded by so many organizations that leadership 

in any strict sense is not possible. Still, the NCI and its Director have 

enormous potential to lead the nation’s efforts through the NCI’s 

“convening power”—the ability to bring people together from all 

sectors working on cancer and to think cooperatively about how to 

solve our most difficult problems. 

In that spirit, the NCI makes frequent use of its many wellestablished external committees—the National Cancer Advisory 

Board, the Board of Scientific Advisors, the Clinical and 

Translational Advisory Committee, the Director’s Consumer 

Liaison Group, and others—to discuss new programs and obstacles 

to progress. In addition, especially over the past 2 years, the NCI 

has been convening a large number of workshops and creating new 

advisory groups to seek broad counsel on a variety of important 

topics. Most numerous among these have been the Provocative 
NATIONAL CANCER INSTITUTE | 3

Questions workshops, designed to solicit ideas from a diversity of 

scientists and clinicians about important research opportunities 

that have been comparatively neglected (see p. 4). Other gatherings 

have been convened to explore ways to accelerate the improvements 

in medical practice, best called “precision medicine,” in the era of 

genetically informed cancer care that we are now entering (see p. 13). 

The NCI also has new means for obtaining specialized advice about 

critical components of its scientific program: the National Frederick 

Advisory Committee for oversight of the Frederick National 

Laboratory for Cancer Research (see p. 50) and outside advisors for 

the National Cancer Informatics Program, (see p. 78) and for two 

new centers at the NCI: the Center for Cancer Genomics (see p. 8) 

and the Center for Global Health (see p. 66). Still other discussion 

groups have been assembled to consider the pending reorganization 

of the NCI’s Clinical Trials Cooperative Groups and the increasing 

recognition of the centrality of “team science” in cancer research.

Such group events inevitably illustrate the strength, size, and 

diversity of the organizations that share the NCI’s goals and work 

with us in various ways to reach those goals. Those organizations 

include private pharmaceutical and biotechnology firms; scientific 

and medical societies; disease advocacy organizations and other 

voluntary groups; state-based research programs; and a variety of 

research institutions, universities, and medical schools, especially 

the NCI-designated cancer centers. 

Connected by financial ties that may be loose or tight, these 

organizations are joined solidly to the NCI by a fierce determination 

to make progress against the complex set of diseases that we group 

together as cancer. In many ways, the interactions between these 

groups—convened, organized, and led by the NCI—constitute the 

backbone of the National Cancer Program. This report inevitably 

focuses on the specific contributions that the NCI makes to this 

complex national effort; our achievements constitute a reliable 

barometer of the National Cancer Program’s progress and promise. 

For that reason, the NCI offers this report as an account of how the 

entire nation is faring in its efforts to control a world-wide scourge.

Harold Varmus, M.D.

Director, NCI
Provocative Questions

IF YOU DO NOT KNOW HOW TO ASK THE RIGHT QUESTION, YOU DISCOVER NOTHING. 

— W. Edwards Deming,

 American statistician and expert on innovation

One of the ways NCI exercises its leadership of the National Cancer Program is by helping define 

for the research community the most important research questions that will lead to the greatest 

advances against cancer. Readers of last year’s report will recall that NCI launched in late 2010 

a Provocative Questions initiative to identify important but non-obvious questions, the answers 

to which will surely drive progress against cancer. Since then, the Provocative Questions 

website has listed more than 100 questions and has been visited by more than 35,000 scientists 

worldwide. NCI issued a request for applications that focused on a selected list of 

24 questions. More than 750 applications were reviewed by panels assembled by NCI, and 

56 applications totaling just under $21.5 million were funded.
NATIONAL CANCER INSTITUTE | 5

 Colorectal cancer cell.

D

uring the past year and a half, recognizing that most good 

research begins with a good question, NCI has brought 

together diverse groups of researchers—many who have 

never met before—to propose, craft, and debate what 

they consider to be critical questions in cancer research. 

Questions that are outside the usual sphere of focus and that could 

lead to important discoveries are the basis for NCI’s Provocative 

Questions initiative.

NCI launched the initiative late in 2010, seeking to go beyond the 

questions that are self-evident or that have been studied for many 

years. We asked investigators to propose intriguing questions that 

need attention but might not otherwise get it or that have stumped 

us in the past but may be answered by new technologies. The 

initiative, which elicited a strong and exciting response from the 

research community, has recently funded its first 56 investigators. 

Seventeen workshops included clinical and translational 

investigators, basic scientists, behavioral researchers, 

epidemiologists, evolutionary biologists, drug developers, 

communications experts, and more. In every workshop, new and 

thought-provoking questions emerged. Researchers showed great 

enthusiasm for helping to set the agenda.

To extend this exercise well beyond the relatively small number 

of people who could be invited to the workshops, NCI created an 

interactive website (provocativequestions.nci.nih.gov). Visitors 

to the website had the opportunity to learn more about the 

Provocative Questions initiative, review the recommendations 

of workshops already conducted, 

propose additional questions, 

and comment on questions 

proposed at workshops or on 

the website. 

From the hundreds of questions 

that were submitted during 

workshops and online, 24 were 

chosen for solicitation of grant 

applications. These questions 

build on specific advances in 

our understanding of cancer 

and cancer control, they address 

broad issues in the biology of 
6 | NATIONAL CANCER INSTITUTE

cancer that have proven difficult to resolve, and they take into 

consideration the likelihood of progress in the foreseeable future. 

Answers to these questions could help to overcome obstacles to the 

control of cancer.

To initiate research focused on these 24 questions, NCI issued a 

request for applications and received more than 750 applications 

that were reviewed by panels assembled by NCI. Fifty-six 

applications totaling just under $21.5 million were funded. 

Because the Provocative Questions exercise intends to focus our 

attention largely on understudied areas, study sections were asked 

to judge the relative value of applications by considering the power 

of the ideas proposed to answer the questions, rather than by 

evaluating preliminary data or the reputation of an applicant. 

The initiative does not replace NCI’s longtime and essential 

emphasis on funding investigator-initiated research, but rather 

it represents a compromise between investigator-initiated 

projects and NCI-directed programs.

Pr o v o c at i v e Qu e s t i o n s

Why don’t more people alter behaviors known to 

increase the risk of cancers?

Certain modifiable behaviors, such as tobacco use, ultraviolet light 

exposure, and sexual behaviors, are linked to increased risk of some 

cancers. By understanding basic mechanisms of executive control, 

emotion, and motivation, we might be better able to understand 

why people fail to alter behavioral patterns, and then be able to help 

them reduce their resistance to change. Recent advances in behavioral 

and neurological studies can help advance understanding of whether 

defects—in the delivery of messages or in the efforts to change 

behavior—affect an individual’s ability to avoid risky behavior. 

Reductions in behavior that increase risk would have an enormous 

impact on the incidence of cancer.
NATIONAL CANCER INSTITUTE | 7

Scanning electron micrograph of human cancer cells.

Pr o v o c at i v e Qu e s t i o n s

Given the appearance of resistance in response to 

cell-killing therapies, can we extend survival by using 

approaches that keep tumors static?

One of the most disappointing features of the development of new, 

targeted therapeutics is how routinely drug resistance emerges. 

Evolutionary theory may provide answers to that conundrum. Strong 

selection, one theory suggests, will always result in the emergence 

of resistant populations, as long as some portion of the stressed 

population can adjust to the selective pressure. Similar theories 

suggest that lessening the selective pressure to a level that merely 

holds the population in check may succeed for extended periods of 

time. Developing and using drugs that are not solely designed to kill 

cells may help establish a balance that results in tumor stasis, rather 

than strong selection for drug resistance. Ultimately, this may not 

produce a cure for a particular cancer but rather a method to treat 

cancer as a chronic disease. There may be situations in which living 

longer with a non-regressing tumor is preferable to rapid tumor 

regression followed by an almost certain drug-resistant relapse.

Reflecting the involvement of experts from many disciplines, 

the Provocative Questions cover numerous areas. For example: 

How does obesity contribute to the incidence and mortality of 

cancer? Why do some commonly used drugs, such as aspirin, 

appear to reduce the risk of cancer? How do changes in RNA 

processing contribute to tumor development? How do some 

neurological diseases, such as Parkinson’s disease, reduce the 

incidence of some cancers? The boxes below contain detailed 

descriptions of several of the Provocative Questions. 

The Provocative Questions initiative is an experiment in its 

own right, one that asks several questions about the research 

process. The first clear result is that the research community has 

responded. Soon we will know whether the questions will incite 

“provocative results.” There’s more to learn, of course. How do we 

best use good questions to paint the landscape of what we know 

and what we want to know about cancer? Will interesting answers 

lead to sustained research programs that expand the pursuit of 

additional answers?

NCI plans to expand the list of questions through additional 

workshops and the website, to invite applications in response 

to the RFA annually for at least another 2 years, and to consider 

whether to expand the initiative in the more distant future.
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Center for Cancer Genomics

Pursuing the genetic foundations of many cancers is a vital component of NCI’s current 

research, and such genetic and genomic studies comprise a great proportion of the institute’s 

research portfolio. Our principal task in the years ahead—for NCI and for the entire cancer 

research enterprise—will be managing huge volumes of data; standardizing how tissue 

samples are collected, sequenced, and analyzed; and encouraging donations of tissue 

samples from patients.

T

he discoveries of genetic conditions associated with cancer, 

along with the molecular abnormalities identified in 

tumors, are now beginning to drive improvements 

in cancer screening, diagnosis, and care. By 

studying the structure and function of entire 

genomes sampled from humans and other organisms, as well 

as studying the molecular make-up of individual patients’ 

tumor cells, researchers have already pointed to many 

genes involved in cancer that are informing drug 

development, knowledge of biologic function, and DNAbased diagnostics. These findings all lead toward “precision 

medicine,” an approach in which diagnoses are refined and 

treatments are custom-tailored based on the molecular 

make-up of an individual tumor. For some cancers, 

including leukemias and lung and breast carcinomas, 

targeted treatments developed based on these findings are 

already helping patients. 

Arul Chinnaiyan, M.D., 

Ph.D., and colleague at 

the University of Michigan 

Medical School, explore the 

practical aspects of genomic 

sequencing in clinical 

practice. 

Microtubes containing purple 

solutions of DNA lying on 

top of an autoradiogram. The 

bands on the autoradiogram 

represent the sequences of 

genetic code of these DNA 

samples (right).

Recognizing the power of genomics, NCI recently established 

a Center for Cancer Genomics, with the mission of developing 

and applying genome science to better diagnose and treat cancer 

patients. NCI is supporting research to identify the genetic drivers 

of cancer, to advance adoption of precise tumor diagnosis and 

treatment, to prepare patients and their doctors for the changes 

in medical care influenced by genomics, and to protect privacy 

without blocking progress in cancer treatment or research. 

The center was headed during its first year by renowned geneticist 

Barbara Wold, Ph.D., from the California Institute of Technology 

(Caltech). During her leave from Caltech (she joined NCI in 

September 2011), Wold worked to build the new organization. 

The center’s flagship program, The Cancer Genome Atlas (TCGA), 

10 | NATIONAL CANCER INSTITUTE

is a joint initiative of NCI and the National Human Genome Research 

Institute (NHGRI). TCGA is currently collecting and analyzing thousands 

of samples—as many as several hundred for each of more than 20 

different cancers—to identify genetic and epigenetic features that drive 

the initiation and progression of cancer. The center will incorporate many 

other NCI-sponsored genomics initiatives, such as the Therapeutically 

Applicable Research to Generate Effective Treatments (TARGET) program, 

which aims to identify useful genetic markers in childhood cancers; the 

Cancer Genetic Markers of Susceptibility (CGEMS) project, a collaboration 

with NCI’s Division of Cancer Epidemiology and Genetics to use genomewide association studies to identify inherited genetic susceptibility to 

prostate, breast, pancreatic, lung, and 

bladder cancers; and the Cancer Target 

Discovery and Development (CTD2) 

Network, which aims to bridge the 

gap between the enormous volumes of 

data generated by the comprehensive 

molecular characterization of various 

cancer types and the ability to use 

these data to develop human cancer 

therapeutics.

Barbara Wold, Ph.D.

The Center for Cancer Genomics 

promotes opportunities to work with 

other agencies and with community 

physicians to usher in a modern era of 

prevention, diagnosis, and treatment 

based on the study of genomes, gene 

expression, proteomics, and other 

technologies. Right now, NCI is 

working with the cancer research community to ask: What are the key 

scientific opportunities? What is the best and speediest path to the clinic? 

Where are the bottlenecks in discovery, trial design, and standard 

of care? How can we best exploit the genomic sequencing of tumors 

in clinical practice to drive further discovery?

Discoveries based on genomics will lead to molecular diagnostics and 

drug development. In turn, clinical data from application of these 

new findings will be fed back into the system for continued discovery. 

“Complete understanding of cancer will come,” Wold said, “if we can 

harness data obtained in the clinic from patients and use it to inform and 

improve diagnosis and treatment in a cyclic way.”
NATIONAL CANCER INSTITUTE | 11

New thinking about the classification of lung cancers

Squamous cell

 

40%

 15%

Small cell 

5% 4%

Adeno- Large cell carcinoma 23% 

3% 2% 2% 2% 1.5% 1% 1% 1%

NO MUT

T

ON 

-RAS

C3A 

ALK 

AK

K

EGFR 

TP53

HER2

BRAF 

IDH1 

TI

N-RAS 

A

PIK

CTNNB1

IN THESE GENES

MUTATION FREQUENCY IN LUNG ADENOCARCINOMA ROS1

For decades, lung cancers have been categorized into four types based on the size and appearance of the 

malignant cells seen under a microscope. But genomic studies suggest that these types of lung cancers, such 

as adenocarcinoma, may be classified — and in some cases treated more effectively — by identifying the 

mutations present in patients’ cancer cells. Source: Levi Garraway, Dana-Farber Cancer Institute.

Cancer Genomics Research: The Cancer Genome Atlas 

Begun as a pilot project by NCI and NHGRI in 2006, The Cancer 

Genome Atlas (TCGA) established a research infrastructure and focused 

initially on the genomic characterization of three cancers: glioblastoma 

multiforme, ovarian cancer, and lung cancer. As one of the NIH’s signature 

programs under the American Recovery and Reinvestment Act, NCI and 

NHGRI expanded TCGA to characterize 20 cancer types in detail by 2014. 

By November 2011, TCGA had collected tissue samples (tumor tissue 

as well as normal tissue) from patients with most of those 20 cancers. 

A number have reached their 500-sample goal, and others are rapidly 

heading toward it. At the time of this writing, about a quarter of TCGA’s 

findings have been published, another quarter are being analyzed, and the 

remaining half are still in the data-collection stage.

In June 2011, TCGA researchers published as an open-access article—that 

is, a peer-reviewed article posted online and accessible to everyone, free 

of charge—the largest cancer genome study to date: an analysis of genome 

changes in ovarian cancer. They reported sequencing the whole exome 
12 | NATIONAL CANCER INSTITUTE

(examining all the protein-coding regions of the genome) on an unprecedented 

316 ovarian tumors. The study confirmed that mutations in a single gene, 

TP53—a tumor protein involved in cell cycle arrest, apoptosis, senescence, and 

DNA repair—are present in more than 96 percent of the tumors. TCGA also 

identified a multitude of less-frequent mutations in other genes.

NCI and NHGRI are now using the capacity that has been built for these 

large efforts to sequence genomes of rare tumors that were not the original 

focus of TCGA or TARGET. Fewer samples, perhaps 50 rather than several 

hundred, will be sequenced. Through the NCI Center to Reduce Cancer 

Health Disparities, NCI is also working to obtain more samples from minority 

populations (see p. 44). 

Meanwhile, researchers are starting to introduce complex molecular 

diagnostics into clinical trials and the care of individual patients. In a recent 

pilot test of so-called clinical sequencing, Arul Chinnaiyan, M.D., Ph.D., 

and colleagues at the University of Michigan Medical School, explored 

the practical aspects of genomic sequencing in clinical practice as part of 

a study funded by NCI and the Prostate Cancer Foundation. For an initial 

two patients—one with metastatic colorectal cancer and one with metastatic 

melanoma—they used a combination of sequencing technologies to identify 

and cross-validate classes of mutations and other genetic abnormalities that 

were common in these cancers. Moreover, they completed this project in less 

than a month and at a cost of just $3,500. Now the University of Michigan 

researchers are setting up clinical protocols to match patients’ genetic 

changes to clinical trials to demonstrate patient benefits.

High-Quality Tissue Samples

In operating rooms around the country, tissue collected from patients is 

usually preserved in formaldehyde at room temperature and then embedded 

in paraffin. Later, it can be sliced for microscopic examination. These 

formaldehyde-fixed, paraffin-embedded (FFPE) samples are widely available, 

but the tissue is often not of high enough quality for genomic studies. 

“Forty years ago, cancer was a black box. We had essentially no 

understanding of how cancer cells differ from normal cells. Today we have a 

remarkably deep understanding of this process. Investment in basic research 

has paid off significantly, with effective new drugs based entirely on these 

discoveries. But this is just the beginning. I predict that over the next few 

decades we’ll see many more examples of currently difficult-to-control cancers 

coming under control, based on our sophisticated understanding of the inner 

workings of cancer cells, as well as powerful new technologies. It is important 

to point out that 40 years is a blink in time when one considers a disease 

that’s affected humanity since its beginnings,” said Tyler Jacks, Ph.D., cancer 

researcher and director of the Koch Institute for Integrative Cancer Research 

at MIT. 
NATIONAL CANCER INSTITUTE | 13

Precision Medicine 

In November 2011, the National Academy of Sciences 

(NAS) released an important report, Toward Precision 

Medicine: Building a Knowledge Network for Biomedical 

Research and a New Taxonomy of Disease. The committee 

wrote that “realizing the full promise of precision 

medicine, whose goal is to provide the best available care 

for each individual, requires that researchers and healthcare providers have access to very large sets of health and 

disease-related data linked to individual patients.”

That’s a lofty goal that requires much better integration 

of research and data from patient visits and patient care 

than exists today. The idea is to get information directly 

from patient populations treated at community settings—

patients not enrolled in clinical trials—and feed it into the 

knowledge network used by researchers and clinicians.

To speed improvements in the control of disease, the 

committee called for a knowledge network that contains—

and more importantly, integrates—all disease-relevant 

information, akin to a biomedical Google. Clinical care 

has improved for certain cancers because of genetic 

knowledge, but the pace could be faster. There is an 

abundance of disease-relevant data, but it’s not always 

carefully collected or made available in a usable form. 

The NAS committee envisioned marrying insights from 

basic and clinical research with data from patient care 

settings to enable discovery and lead to what they refer 

to as “precision medicine.” 

Charles Sawyers, M.D., chair of the Human Oncology and 

Pathogenesis Program at Memorial Sloan-Kettering Cancer 

Center, and Tom Misteli, Ph.D., a senior investigator at 

NCI’s Center for Cancer Research who studies genome 

organization, were part of the NAS committee. Both 

described how a knowledge network would advance 

their work. Sawyers said he would like to see the clinical 

infrastructure adopt genomic profiling on a more routine 

basis to characterize tumors arising in all patients, 

especially the relatively small proportion of patients who 

are involved in clinical trials. It should become part of the 

baseline characterization of a cancer patient, he said, like 

getting a complete blood count or chemistry panel. 

Basic scientists like Misteli could use the knowledge 

network as a new discovery tool. “A knowledge network—

an interface between patient data and basic research—

would allow us to mine the data in an unbiased way to 

develop hypotheses and answer 

important questions,” Misteli 

explained.

Protecting Privacy while 

Supporting Research

Obtaining and sharing data from 

patients will require an evolution 

in patient privacy rules. “If 

properly informed,” Sawyers 

said, “more patients are willing 

to share the data that emerge 

from studies of their tissues. 

The opportunities for benefits 

today are much more obviously tangible, so it’s time for a 

rethinking of privacy rules.” With key legislation in place, 

particularly the Genetic Information Nondiscrimination 

Act, which prohibits discrimination in health insurance 

and employment based on genetic information, there is 

an opportunity to modify the strictness of current privacy 

rules. 

“We need to get national consensus on patient consents,” 

said NAS committee member Isaac Kohane, M.D., Ph.D., 

the director of Children’s Hospital Informatics Program 

and Henderson Professor of Pediatrics and Health 

Sciences and Technology at Harvard Medical School. 

“Advocacy groups are very much in favor of sharing 

patient data for research. There are mechanisms that we 

can implement to allow patients to opt in or opt out of 

data sharing.”

Kohane directs a unit called Informatics for Integrating 

Biology and the Bedside, an NIH-funded National 

Center for Biomedical Computing site based at Partners 

HealthCare System in Boston. The center’s studies have 

shown that health care systems can be used to conduct 

genomic research and discovery research using the 

informational byproducts and the biological products of 

health care delivery. It also works to include minorities, 

who are often underrepresented in cohort studies but are 

frequent users of local, community-based medical centers. 

The NAS committee recommended pilot projects to 

establish large databases over years or decades, to be 

mined by all interested parties in an open-source way. 

“Pilots should be done at point of care,” Sawyers said. 

“That should be the new model for learning in the future.”
14 | NATIONAL CANCER INSTITUTE

A histology technician in 

the NCI Department of 

Laboratory Pathology cuts 

paraffin blocks of tumor 

tissue into slices 3 to 4 

microns deep.

Rigorous genomic studies like TCGA need the highest quality tissue samples 

available. Consequently, researchers have been limited to using tumor 

samples that were plunged directly into liquid nitrogen in the operating room 

before storage. This method offers high-quality samples, but it is costly and 

difficult to implement at a broad community level. Recently, however, new 

technology is making possible the comprehensive analysis of FFPE samples. 

Paul Mickey Williams, Ph.D., at NCI’s Frederick National Laboratory for 

Cancer Research, compared gene expression profiling of tumor samples from 

patients with diffuse large B-cell lymphoma that were preserved via FFPE 

with those preserved via the rapid freezing method. Using material from 45 

patients, he was able to accurately amplify and sequence RNA from both 

samples with 97.7 percent accuracy. 

“If we are moving into a world of new and powerful diagnostic tests, we need 

to be certain that every patient has a specimen that is going to be of adequate 

quality,” Williams said. 
NATIONAL CANCER INSTITUTE | 15

Old Specimens through a New Lens

Historically, tumor samples have been preserved in formalin and encased 

in paraffin wax blocks, a process called FFPE (“formalin-fixed and paraffin 

embedded”) that rendered them worthless for genomic study by then 

existng methods. But advances in technology have overcome this barrier 

and may soon open vast libraries of older samples to genomic scrutiny. 

Researchers from the Huntsman Cancer Institute at the University of Utah 

recently used this new approach to analyze changes in the genome of Ewing 

sarcoma tumors, many of which were collected a decade or more earlier and 

preserved in paraffin. Ewing sarcoma is a rare cancer that strikes children, 

teenagers, and young adults; only 300 to 400 cases are diagnosed in the 

United States each year. 

“The rarity of Ewing sarcoma poses a problem for cancer research,” said 

Huntsman’s Joshua Schiffman, M.D. “Because there are so few cases, it has 

been difficult in the past to find enough tissue samples to conduct valid 

studies of the genetics and biology of this disease.” Further complicating 

matters, most of the samples scientists have access to have been FFPE 

preserved.

“FFPE has been the standard technique for preserving pathology samples for 

decades,” said Schiffman. “But until recently, genomics technology has not 

been available to make use of the huge resource these samples represent.” 

Using the new tool, however, the Hunstman team analyzed 40 FFPE 

samples of primary tumors from Ewing sarcoma patients who 

were treated at Primary Children’s Medical Center in Salt Lake 

City during the past 12 years. “This doesn’t sound like a 

large sample, but for this rare cancer, it reflects 10 percent 

of all cases diagnosed in a given year, so the quantity is 

significant,” he added.

The researchers recently published their findings about the 

genome of Ewing sarcoma in Cancer Genetics, where they 

reported finding a previously unknown sarcoma subtype, 

genetic factors related to long-term survival, and identification 

of a genetic change between the primary and metastatic stages 

of the disease that could lead to better, more targeted treatment for 

patients who have Ewing sarcoma.

 “Our results will have to be validated with a larger number of samples, 

but this gives us the tool to do that on clinically archived samples,” said 

Schiffman. “Clearly, learning more about FFPE-preserved tumor samples 

with these genomic factors will be essential to finding new treatments that 

will improve overall survival among all Ewing sarcoma patients.” 
16 | NATIONAL CANCER INSTITUTE

Introduction to Cancer Profiles

The disease we call cancer is, in actuality, a collection of diseases, 

each of which poses a different set of questions for the researchers 

who search for causes, mechanisms, and commonalities that will 

inform better prevention, detection, diagnosis, and treatment. The 

pages that follow present profiles of five cancers, which represent a 

small slice of NCI’s extensive research portfolio. For some of these 

cancers, we’re able to tell a story of important and recent progress in 

controlling them. Other cancers we profile remain resilient and difficult 

to treat, despite our research efforts, but our growing understanding 

of the basic cancer biology in these cancers offers promise for effective 

intervention.

For the vast majority of cancers, it takes years—often decades—for the 

complement of mutations necessary to drive the disease to occur. This 

is why three-quarters of all cancers in the United States are diagnosed 

in people who are 55 years of age or older. For some cancers, such as 

colorectal cancer, many of the molecular steps that silently accumulate 

during the cancer’s quiescent stages have been identified, and 
NATIONAL CANCER INSTITUTE | 17

improved screening methods—which offer the best control for colorectal 

cancer—have been developed. For renal cancer, studies of highly 

affected families have provided insight into the genetic underpinnings 

of not only inherited forms of the disease but also of sporadic, or noninherited, forms. Comprehensive genomic analysis is also facilitating 

classification of diseases such as B-cell lymphoma, which should inform 

research and lead to individualized treatments. For some cancers, 

such as those of the pancreas, a better understanding of the tumor 

microenvironment and host factors may help achieve the improvements 

in patient outcomes that have been elusive to date. Targeted therapies, 

such as imatinib (Gleevec®) in gastrointestinal stromal tumors, 

illustrate the potential power of therapies directed at genetic targets.

NCI is committed to answering the most pressing questions for each 

cancer type and continuing to pursue fundamental knowledge about the 

inner workings of cancer cells, building upon past discoveries, so that 

we can eventually control cancers of all types. 
18 | NATIONAL CANCER INSTITUTE

Pancreatic Ductal Adenocarcinoma

Because pancreatic cancer is often diagnosed at a late 

stage, surgical removal of the tumor or the organ is often 

difficult, if not impossible. Pancreatic ductal adenocarcinoma, 

or PDAC, is by far the most common type of pancreatic 

malignancy. PDAC is distinct from other cancers due to the 

biological barrier the tumor builds around itself. Patients 

whose disease is caught at an early stage have a better 

chance of long-term survival, but the pancreas emits few 

known clues to signal that the carcinogenic process has 

begun, so there are currently no early detection tests. For 

more than 30 years, NCI-supported laboratory scientists 

have been studying a gene called KRAS, the genetic driver of 

pancreatic cancer initiation and progression. However, at this 

time, no therapeutic solutions to KRAS mutations have been 

developed. Pancreatic cancer is the fourth leading cancer 

killer in the United States. Overall, just 6 percent of patients 

survive 5 years after diagnosis. In 2012, it is estimated that 

there will be 43,920 new diagnoses of pancreatic cancer and 

37,390 deaths will be attributed to it. Further identifying risk 

factors and genetic changes, achieving greater understanding 

of the metastatic process, and developing better methods 

of early detection and treatment offer the means of better 

controlling PDAC.

Pancreatic cancer cell. Colored scanning electron micrograph (SEM) 

of a pancreatic cancer cell.

The pancreas contains two types 

of tissue that have distinct jobs. 

Pancreatic endocrine tissue, 

which gives rise to pancreatic 

neuroendocrine tumors, is 

responsible for making hormones, 

such as insulin, that help regulate 

blood sugar levels. Pancreatic 

exocrine tissue produces enzymes 

that aid in digestion. Pancreatic 

ductal adenocarcinoma, or 

PDAC, arises in exocrine tissue, 

specifically in the cells comprising 

the ducts that carry pancreatic 

digestive enzymes to the small 

intestine. PDAC accounts for more 

than 90 percent of all pancreatic 

cancers. It is these tumors, which 

are most often fatal, that are the 

focus of this profile.

Mouse Models Help Reveal 

Tumor Defense

In 2003, Sunil Hingorani, M.D., 

Ph.D., and colleagues at the 

University of Pennsylvania, with 

funding from NCI’s Mouse Models 

of Human Cancer Consortium, 

engineered a mouse model of 

human PDAC and were able to 

watch the disease unfold step 

by step. Similar to PDAC tumors 

in humans, the tumors in these 

mice are surrounded by a dense 

cellular matrix, or stroma, that 

forms a shield around the tumor 

mass, like the shell around 

a walnut. This shell causes 

increased fluid pressure within 

the tumor microenvironment 

that compresses existing blood 

vessels, thereby limiting the blood 

supply to the tumor. Consequently, 

when a chemotherapy drug is 

administered, the restricted blood 

flow prevents sufficient amounts 

of the drug from reaching the 

tumor.

The precise mechanisms that 

cause this restricted blood flow 

are not fully understood. However, 

mouse models are proving to 

be an invaluable tool in the 
NATIONAL CANCER INSTITUTE | 19

search for answers to this question 

and questions about many types 

of human cancer, as well as in 

devising new therapeutic options 

for patients. In 2009, Kenneth Olive, 

Ph.D., and others at the Cambridge 

Research Institute in London used 

mouse models of human PDAC 

to show that an experimental 

drug that inhibits an intracellular 

signaling pathway linked to several 

cancers (known to researchers as 

the “Hedgehog” pathway) caused 

regression of the stromal barrier 

surrounding pancreatic tumors, 

subsequently leading to the 

expansion of tumor blood vessels. 

The reopening of the vasculature 

permitted increased delivery of the 

chemotherapy drug gemcitabine to 

the tumors, resulting in inhibition 

of tumor growth. This discovery 

suggests that inefficient drug 

delivery may be one reason that 

pancreatic tumors do not respond 

well to chemotherapy. 

Hedgehog pathway inhibitors have 

since been tested in clinical trials 

of pancreatic cancer, with mixed 

results, but other approaches to 

breaking down the stromal barrier 

are also being investigated. Two 

teams—one led by Hingorani at the 

Fred Hutchinson Cancer Research 

Center in Seattle, and the other led 

by David Tuveson, M.D., Ph.D., then 

at the Cambridge Research Institute 

in the United Kingdom—recently 

reported that an enzyme called 

PEGPH20, which targets a molecule 

called hyaluronan, improves 

delivery of the drug gemcitabine 

to mouse pancreatic tumors. 

Hyaluronan, or hyaluronic acid 

(HA), is a complex sugar that occurs 

naturally in the body and is a major 

component of the stromal matrix 

surrounding pancreatic tumors. 

Like the Hedgehog inhibitors, 

PEGPH20 caused alterations to 

the stroma and vasculature of 

mouse PDAC, permitting high 

concentrations of gemcitabine to 

spread throughout the tumors. The 

result was a significant increase in 

the survival time of mice treated 

with gemcitabine plus PEGPH20 

compared with mice treated with 

gemcitabine alone. An early-phase 

clinical trial is under way to test 

the combination of PEGPH20 

and gemcitabine in people with 

metastatic pancreatic cancer. 

Risk Factors

To learn more about the role of 

inherited genes in predisposing 

people to pancreatic cancer, the 

NCI-supported Pancreatic Cancer 

Cohort Consortium conducted two 

genome-wide association studies. 

These types of studies, which 

involve the rapid scanning of 

DNA markers across the complete 

genomes of many people, seek 

to identify genetic variations 

associated with a particular disease. 

The researchers discovered four 

novel regions in the genome that are 

associated with risk for pancreatic 

adenocarcinoma, and they are now 

investigating these associations by 

examining the functions of genes in 

the four regions. 

As with many other cancers, 

lifestyle and comorbid conditions 

may play a role in pancreatic cancer. 

Until recently, however, only two 

factors were known to increase 

pancreatic cancer risk: cigarette 

smoking and diabetes. Studies by 

researchers, including investigators 

in NCI’s Division of Cancer 

Epidemiology and Genetics, have 

now revealed that several additional 

factors may increase pancreatic 

cancer risk, including intake of 

foods high in fat (particularly from 

processed and animal sources), 

heavy alcohol use, being overweight 

or obese in young adulthood, and 

older age. (The link between obesity 

and cancer is being addressed 

in NCI’s Provocative Questions 

initiative, page 4.) Approximately 

one-quarter of pancreatic cancers 

are attributable to an “unhealthy 

lifestyle,” according to the findings. 

New efforts are under way to clarify 

the mechanisms underlying these 

associations. 

Research on many cancer risk 

factors, including diet, stress, 

inflammation, and environmental 

exposures, will be significantly 

enabled by a new experimental 

population research resource. 

Uncovering New Drivers of 

Pancreatic Cancer through 

Rapid Autopsy

Past analyses of malignant 

pancreatic tumors have revealed 

that virtually all of them harbor 

mutations in the KRAS gene. 

Other commonly mutated genes 

have been known for some time to 

include the tumor suppressors p16, 

p53, and SMAD4. More recently, 

researchers have begun trying to 

uncover the mechanisms of PDAC 

metastasis. As part of this effort, 

Christine Iacabuzio-Donahue, 

M.D., Bert Vogelstein, M.D., and 

their colleagues at Johns Hopkins 

University studied samples of 

primary tumor tissue and metastatic 

tissue from the lungs, liver, and 

other organs of patients who had 

undergone a procedure known 

as rapid autopsy. 

In rapid autopsy, which represents 

a new approach in pancreatic 

cancer research, tissue is collected 

within a few hours of a patient’s 

death. Because DNA, RNA, and 

other molecules within cells begin 

to degrade shortly after death, 

rapid autopsy allows researchers 

to collect tissue samples that will 

yield clearer insights into the 

biological processes that contribute 

to pancreatic cancer and other 

diseases. 
20 | NATIONAL CANCER INSTITUTE

The Johns Hopkins University team 

sequenced every gene in rapid 

autopsy specimens from seven 

patients to compare the genetic 

mutations in metastatic lesions 

versus the primary tumor. Some 

of the mutations they found were 

present in most or all of the primary 

tumor cells, suggesting that they 

occurred before the development 

of metastasis. However, in each 

patient, a set of progressor 

mutations was also identified. 

Progressor mutations are genetic 

changes that are present in one or 

more of metastases examined, as 

well as in pockets of cells within 

the primary tumor. Overall, the 

Hopkins team’s data indicate that 

cells within the primary tumor, 

which all descended from a 

single cell, accumulate additional 

mutations over time, giving rise 

to subpopulations of cells, some 

of which are able to leave the 

pancreas and take root in other 

parts of the body. Further analysis 

of the affected genes should help 

elucidate the cellular pathways 

that contribute to pancreatic cancer 

progression and metastasis.

Rapid autopsy programs have now 

been established at the Sidney 

Kimmel Comprehensive Cancer 

Center at Johns Hopkins University 

and the University of Nebraska 

Medical Center’s Eppley Institute 

for Research in Cancer and Allied 

Diseases. To date, these two centers 

have conducted more than 100 

rapid autopsies of patients with 

pancreatic cancer who died despite 

aggressive treatment. 

In addition, there is growing 

evidence that the tumor 

microenvironment plays an 

important role in conferring drug 

resistance and in tumor recurrence. 

The NCI Tumor Microenvironment 

Network (TMEN) consortium is 

addressing this important area of 

research with multiple human 

cancers, including PDAC, using 

tissues from rapid autopsy to 

delineate the mechanism of tumor 

stroma-conferred resistance. 

Detection is Key

The American Cancer of the 

Pancreas Screening (CAPS) 

Consortium, established by Marcia 

Canto, M.D., at Johns Hopkins 

University and researchers at 

four other U.S. institutions, is 

developing approaches to detect 

and selectively treat asymptomatic 

high-grade precancerous lesions 

of the pancreas, which are more 

likely to respond to treatment than 

advanced pancreatic tumors. NCI 

and the Lustgarten Foundation, 

a nonprofit organization focused 

on advancing pancreatic cancer 

research, funded a recently 

completed CAPS study. The CAPS 

team used three common imaging 

modalities—computed tomography 

(CT), magnetic resonance imaging 

(MRI), and endoscopic ultrasound 

(EUS)—to screen individuals at high 

risk of developing pancreatic cancer 

because of a strong family history 

of the disease or the presence of 

a predisposing genetic mutation, 

such as a BRCA2, p16/CDKN2A, or 

STK11 gene mutation. 

About 42 percent of the symptomfree CAPS study participants 

were found to have at least one 

pancreatic mass, and many had 

multiple lesions. Most of the masses 

were small cysts that warranted 

only continued monitoring, but 

a small number of participants 

were found to have noninvasive 

high-grade lesions, which were 

subsequently removed surgically. 

The results of the study revealed 

that MRI and EUS are better than 

CT for detecting pancreatic lesions. 

However, more research is needed 

to better identify individuals for 

whom this kind of screening is 

appropriate and to guide decisions 

about next steps when lesions are 

found, since many lesions may 

pose no threat to the patient. CAPS 

researchers are continuing to address 

these issues in another clinical trial 

that is already under way and in a 

planned international collaboration 

involving researchers from 10 

countries on four continents.

Although imaging may offer 

visual clues about the presence 

of pancreatic cancer and its 

precursors, biomarkers may 

provide different or complementary 

information for early detection. 

With funding support from the NCI 

Mouse Models of Human Cancers 

Consortium and the institute’s Early 

Detection Research Network, Samir 

Hanash, M.D., Ph.D., and others 

at the Fred Hutchinson Cancer 

Research Center joined forces with 

investigators at Harvard Medical 

School and the University of 

Michigan to conduct an in-depth 

analysis of the proteins in the 

plasma of a genetically engineered 

mouse model of pancreatic cancer. 

Based on samples from mice with 

early-stage disease, similar to the 

PDAC precursors detected in the 

CAPS study, the team identified a 

panel of five biomarkers that were 

elevated in diseased mice compared 

with their healthy counterparts. 

The team is now studying whether 

the candidate biomarkers, when 
 NATIONAL CANCER INSTITUTE |

Light micrograph of a section through 

an adenocarcinoma of the ducts of a 

human pancreas. 

measured in blood samples taken 

from individuals at high risk of 

cancer, are able to distinguish 

those who would subsequently be 

diagnosed with pancreatic cancer 

from those who would not. 

Another team at the University of 

Nebraska Medical Center’s Eppley 

Institute for Research in Cancer and 

Allied Diseases has been working 

to develop a test that harnesses 

the body’s immune response to 

pancreatic cancer cells to aid in 

detection and diagnosis. In a recent 

study, the Eppley team looked at 

all of the genes expressed in 

peripheral blood mononuclear 

cells (immune cells including 

monocytes, T lymphocytes, 

B lymphocytes, and natural 

killer cells) from 26 patients 

with pancreatic cancer and 33 

healthy control subjects. They 

found a number of genes that were 

expressed at different levels in 

the two groups and identified a 

“predictor set” of eight genes that 

was able to distinguish between 

those with pancreatic cancer and 

those without the disease with 

considerable accuracy. Moreover, 

there is some evidence that 

premalignant pancreatic lesions 

also induce immune system 

changes, suggesting that it might be 

possible to exploit these changes 

to detect noninvasive pancreatic 

lesions before they become invasive 

cancers. 

To be useful, early detection 

methods for pancreatic cancer 

should be able—at a minimum—

to identify disease before it has 

metastasized outside the pancreas. 

However, scientists still do not 

understand the process by which 

tumor cells leave the pancreas 

and take root in other places in 

the body. The Johns Hopkins 

team that sequenced DNA from 

primary tumors and metastases 

used mathematical modeling 

and clinical histories to estimate 

how long it took for the identified 

mutations to accumulate. They 

concluded that, on average, it took 

more than 11 years for a “mature” 

tumor to form after the occurrence 

of the first cancer-related mutation 

in a pancreatic cell, and that it took 

an additional 6 years before cells 

from the primary tumor gave rise 

to a metastatic lesion at another 

location. A follow-up modeling 

study involving a larger number of 

rapid autopsy patients illustrated 

the heterogeneity of the metastatic 

process: Some patients with tumors 

smaller than 1 centimeter in size 

will have metastases while a small 

percentage of patients with larger 

tumors will be metastasis-free. The 

possibility of early metastases was 

demonstrated in the laboratory of 

Ben Stanger, M.D., Ph.D., at the 

Abramson Cancer Center of the 

University of Pennsylvania, where 

pancreatic tumor cells were found 

to enter the bloodstream of a mouse 

model of pancreatic cancer even 

before an overt tumor could be 

found in the pancreas. 

Innovative Funding Strategies

NCI is working with a group 

of organizations, including the 

Pancreatic Cancer Action Network, 

the Lustgarten Foundation, and 

the National Pancreas Foundation, 

to explore cooperative strategies 

for funding pancreatic cancer 

research. These funding strategies 

would allow meritorious grant 

applications to be passed from one 

organization to another for funding 

support.

Each organization continues to 

support branches of research most 

vital to its goals, such as improved 

mouse models of pancreatic cancer. 

These models allow researchers 

in many institutions to study how 

cancer arises via a constellation of 

mutations that are known from the 

analysis of tumors. Mouse models 

also provide researchers with a 

common platform for drug testing 

at many of the NCI-designated 

cancer centers. In addition, 

the Lustgarten Foundation is 

completing a pancreatic cancer 

biomarkers initiative aimed at 

identifying substances in the blood, 

body fluids, or tissue that signal 

a risk of cancer or its presence at 

very early stages. The Lustgarten 

Foundation also identified and 

funded research groups working 

to develop antibodies to the 

biomarkers identified through the 

initiative, with the stipulation that 

all antibodies would be deposited 

with the NCI Early Detection 

Research Network and made freely 

available to the cancer research 

community.

21
22 | NATIONAL CANCER INSTITUTE

Colorectal Cancer

Colorectal cancer originates in the mucosal tissue that lines the 

inside of the colon and rectum. It is thought that most cases of 

colorectal cancer develop progressively from small abnormal 

growths called polyps. Ninety percent of colorectal polyps are 

classified as hyperplastic polyps, growths that generally do 

not become cancerous. The remaining 10 percent of colorectal 

polyps are classified as adenomatous polyps, or adenomas, and 

research has shown that these lesions give rise to virtually all 

cases of colorectal cancer. Because there is evidence that it takes 

approximately 10 years for an adenomatous polyp less than 

1 centimeter in size to transform into an invasive colorectal tumor, 

most of these polyps should be detectable by screening—and 

removed—before they can become cancerous. Therefore, regular 

screening, especially with flexible sigmoidoscopy or colonoscopy, 

is probably the single most important tool in the medical toolbox 

for colorectal cancer, since finding and removing precancerous 

polyps and early cancers is the best way to reduce morbidity and 

mortality from this disease. Over the years, clinical implementation 

of these insights has already saved tens of thousands of lives, with 

a reduction in colorectal cancer deaths by approximately 3 percent 

per year from 1999 through 2008—a decrease of around 30 percent. 

Still, in 2012 it is estimated that more than 143,000 Americans will 

be diagnosed with colorectal cancer and more than 51,000 will 

die from the disease.

Colon cancer. Colored X-ray showing cancer (green) of the colon. The colon, together with the 

much smaller rectum, forms the large intestine.

The first step in virtually 

all colorectal cancers is the 

runaway proliferation of cells in 

the mucosal epithelium of the 

colon or rectum that begins with 

mutation of a tumor suppressor 

gene. Such mutations are rarely 

hereditary and most are believed 

to be related to lifestyle factors, 

including diet, although a family 

history of colorectal cancer is a 

risk factor for the disease. 

This excessive cell proliferation 

can almost always be traced 

back to problems in the Wnt 

signaling pathway, a network 

of proteins that plays a role 

in embryonic development, 

cell differentiation, and many 

other critical cellular processes. 

Alterations or aberrations in 

this pathway are also linked to 

the initiation and progression 

of many kinds of cancer, as 

tumorigenesis is a likely result 

when the Wnt pathway goes 

awry. 

One way the Wnt signaling 

pathway has been implicated 

in colon and rectal cancers is 

through mutation of the tumor 

suppressor gene APC. This 

gene normally suppresses Wnt 

signaling, and thus suppresses 

tumorigenesis. After mutation 

of one copy of APC, however, 

silencing of the cell’s other 

copy by a second molecular 

event is sufficient to allow for 

uncontrolled cell proliferation, 

leading to the formation of an 

early adenoma. Progression from 

an early adenoma to invasive 

carcinoma is thought to involve 

the acquisition of additional 

mutations in other genes. 

To date, scientists have 

identified a number of mutations 

that contribute to the initiation 

and progression of colorectal 

cancer. In addition to APC, in 
NATIONAL CANCER INSTITUTE | 23

those cases in which APC is not 

mutated, other genes mutated in 

colorectal cancer include KRAS, 

PIK3CA, TP53, SMAD4, PTEN, 

BRAF, and FBXW7. Moreover, 

mutations in genes involved in DNA 

repair (mismatch repair genes), such 

as MSH2, MLH1, MSH6, and PMS2, 

have been associated with one of 

the well-known types of inherited 

predisposition to the development 

of colorectal cancer. The discovery 

of these genes and the way they 

work represents a milestone in 

cancer research and understanding. 

Many of these same genes have been 

shown to play a role in other tumor 

types, such as those of the breast, 

pancreas, brain, stomach, lung, and 

prostate. 

Researchers supported through 

NCI’s Integrated Cancer Biology 

Program and using data generated 

through The Cancer Genome Atlas 

project (see p. 11) are beginning to 

explore how the complex interplay 

of known genetic alterations, both 

driver and passenger mutations, 

interact during the development 

of colorectal cancer. Using 

sophisticated computational tools, 

these approaches will help uncover 

new targets for diagnosis and 

intervention.

These are not simply intellectual 

triumphs. They have important 

implications for reducing the 

morbidity and mortality from 

colorectal cancer. Through 

molecular, epidemiologic, and 

mathematical studies of colorectal 

cancer, we now know that it takes 

an average of 30 years for a patient 

to die following the molecular 

event—often a mutation in the 

APC gene—that initiated his or her 

tumor. The final stage, metastasis, 

begins an average of 27 years after 

the initial event. Importantly, up 

until the metastatic stage, virtually 

all colorectal tumors, whether 

benign or malignant, can be cured 

by surgery alone, without the need 

for any additional therapy. Put 

another way, a death from colorectal 

cancer today will most likely occur 

because the cancer or its precursor 

adenoma was not detected during 

the preceding 27 years. 

Hereditary Forms of 

Colorectal Cancer

Although hereditary forms of the 

disease account for only about 

10 percent of the total number of 

colorectal cancers diagnosed in the 

United States, the affected families 

are often decimated by cancer, with 

parents, siblings, and extended 

relatives developing the disease at 

an early age, often in the prime of 

life (30s and 40s) and sometimes 

even younger. However, these 

cases have also offered some of the 

best clues about the initiation and 

progression of colorectal cancer. 

Many hereditary colorectal cancer 

syndromes have been recognized for 

decades, but the molecular basis for 

them was unknown. Scientists now 

know the genomic basis for every 

one of these syndromes. Familial 

Adenomatous Polyposis, Hereditary 

Non-Polyposis Colorectal Cancer 

(HNPCC, or Lynch syndrome), 

Attenuated Polyposis, Peutz-Jeghers 

syndrome, Juvenile Polyposis 

Syndrome, and others are each 

caused by a hereditary mutation in 

one or more genes. 

These discoveries have completely 

changed the management of disease 

in families with these syndromes. 

Tests for detecting the relevant 

mutations are now commercially 

available, and members of these 

families can determine in childhood 

whether they have inherited a 

mutated gene or not. Those who 

have only normal copies of the 

genes can be reassured that their 

colorectal cancer risk is no higher 

than average. Conversely, those 

who have inherited a mutated 

gene may undergo surveillance for 

colorectal polyps or tumors earlier 

and more frequently and have 

lesions removed when they are still 

benign. Some patients may require 

removal of some or all of the colon. 

With appropriate genetic counseling 

and surveillance measures, most 

patients with hereditary colorectal 

cancer syndromes can have life 

expectancies similar to those of the 

general population. 

DNA Mismatch Repair

HNPCC, or Lynch syndrome, 

is the most common form of 

inherited colorectal cancer and is 

characterized by defects in a DNA 

repair mechanism called mismatch 

repair (MMR). The defects are 

caused by hereditary, or germline 

(affecting every cell in the body), 

mutations in the MMR genes 

MLH1, MSH2, MSH6, and PMS2. 

These genes encode proteins that 

act as proofreaders that identify 

and correct errors that naturally 

occur when cells replicate their 

DNA content during cell division. 

When mutations inactivate both 

copies of an MMR gene, other 

mutations start accumulating 

throughout the genome because 

cells are now unable to properly 

repair “mismatches” that occur 

during DNA replication. Some of 

the mutations that would have 

been repaired under normal 

circumstances can now potentially 

contribute to the development of 

cancer. In addition, MMR proteins 

are thought to play a role in other 

processes that help suppress 

carcinogenesis: DNA damage 

surveillance and the prevention 

of recombination between two 

non-identical DNA sequences. 

Proper MMR function is vital to 

cellular health and function. People 

with Lynch syndrome have an 

increased risk of developing not 

only colorectal cancer, but also 

endometrial, ovarian, stomach, 

liver, urinary tract, brain, and skin 

cancers.
24 | NATIONAL CANCER INSTITUTE

Because the cell’s replication 

machinery makes mistakes more 

frequently on repetitive sequences, 

MMR-defective cells often display 

variability in the length of DNA 

segments known as microsatellites, 

which are comprised of short (two 

to six bases), tandemly repeated 

sequences. This variability in 

microsatellite DNA length is called 

microsatellite instability. Genes 

that contain microsatellites in their 

coding regions have an increased 

risk of mutation. Compared to cells 

with a normal MMR system, cancer 

cells with a defective MMR system 

are more prone to acquiring and 

retaining new mutations in cancerassociated genes, such as TGFβRII, TCF4, IGF2R, and BAX. It is 

estimated that MMR-defective cells 

have mutation rates 100 to 1,000 

times higher than normal cells.

MMR defects occur in approximately 

15 percent of non-hereditary 

colorectal tumors, as well as 

in some other cancers, such as 

endometrial cancer and gastric 

cancer. The mechanism of how 

these defects arise is different: 

MMR genes are silenced through an 

epigenetic mechanism called DNA 

methylation, rather than genetic 

mutation, as in patients with 

Lynch syndrome. 

Therapy

The prognosis for patients with 

metastatic colorectal cancer has 

improved significantly in the past 

decade. Surgery is curative for most 

patients during the first stage of the 

disease. Additional improvement 

has been realized, in part, because 

of the unprecedented way in which 

these cancers can and have been 

studied as they grow—the same 

techniques that make them good 

targets for prevention make them 

easy to study in patients. But 

progress also has come through 

painstaking research into the 

best conventional chemotherapy 

drug combinations, advances in 

imaging and radiotherapy, and 

the development of new antibody 

therapies such as cetuximab and 

panitumumab, which both target a 

protein called the epidermal growth 

factor receptor. As a result, more 

than 50 percent of patients with 

metastatic colorectal cancer can 

expect to live longer than 5 years, 

far longer than expected in the past. 

More Effective Screening

The practical implications of this 

knowledge are clear: One important 

way to reduce the suffering and 

death from colorectal cancer is 

to detect it before it occurs or 

metastasizes. Recent studies show 

that the removal of polyps helps 

reduce colorectal cancer deaths by 

up to 50 percent. Increasing the 

prevalence of colorectal cancer 

screening might result in an even 

greater reduction in the future.

There are several effective 

screening options. Colonoscopy 

is a procedure in which a flexible 

tube with a tiny camera (called an 

endoscope) is inserted through the 

rectum and allows visualization 

of the entire colon. If a polyp is 

found, it can be removed during 

the procedure. Sigmoidoscopy 

also uses a flexible endoscope and 

allows polyp removal during the 

procedure, but less of the colon is 

visualized than with colonoscopy. 

Fecal occult blood tests check for 

blood in stool specimens. NCI is 

also funding a study of “virtual 

colonoscopies,” which allow the 

detection of polyps without the 

insertion of tubes into the colon 

or rigorous bowel preparation 

procedures. Additionally, NCIfunded investigators are engaged in 

developing blood-based and stoolbased tests that can detect abnormal 

genes or other biomarkers that could 

improve early detection. 

Public health specialists will have 

to determine the optimal ways to 

ensure compliance with evidencebased screening guidelines in 

appropriate populations, as well 

as to ensure greater uptake of 

preventive measures, such as diet 

and lifestyle changes. 
 NATIONAL CANCER INSTITUTE | 25

NCI’s Cancer Genome Atlas Yields Insights Into Colorectal Cancers

The Cancer Genome Atlas project 

this summer provided the most 

recent elucidation of just how 

critical the new era of genomically 

informed medicine will be for colon 

and rectal cancers. (See related 

story on TCGA on p. 11.)

Initially, the TCGA Research 

Network studied colon tumors as 

if they were distinct from rectal 

tumors. However, according to 

TCGA’s large-scale genetic analysis 

of colon and rectal cancer tissue 

specimens, the pattern of genomic 

alterations in colon and rectal 

tissues is the same, regardless of 

anatomic location or origin within 

the colon or the rectum. Therefore, 

these two cancer types can be 

grouped as one. 

Other findings from the TCGA 

colorectal study point to additional 

treatment options. There is a 

known association between the 

aggressiveness of colorectal 

tumors and the phenomenon 

of hypermutation, in which 

the rate of genetic mutation is 

abnormally high because normal 

DNA repair mechanisms are 

disrupted. In the TCGA study, 16 

percent of the specimens were 

found to be hypermutated. Threefourths of these cases exhibited 

microsatellite instability, which 

often is an indicator of better 

prognosis. Microsatellites are 

repetitive sections of DNA in the 

genome. If mutations occur in the 

genes responsible for maintaining 

those regions of the genome, the 

microsatellites may become longer 

or shorter. 

The investigators observed that 24 

genes were mutated in a significant 

number of the 224 colorectal 

cancer specimens examined. In 

addition to genes found through 

prior research efforts (e.g., APC, 

ARID1A, FAM123B/WTX, TP53, 

SMAD4, PIK3CA, and KRAS), 

the scientists identified three 

other genes (ARID1A, SOX9, and 

FAM123B/WTX) as potential drivers 

of this cancer when mutated. It is 

only through a study of this scale 

that these three genes could be 

implicated in this disease.

The research network also 

identified the genes ERBB2 and 

IGF2 as mutated or overexpressed 

in colorectal cancer and, therefore, 

as potential drug targets. These 

genes are involved in regulating 

cell proliferation and were 

observed to be frequently 

overexpressed in colorectal tumors. 

This finding points to a potential 

drug therapy strategy in which 

inhibition of the products of these 

genes would slow progression of 

the cancer.

A key part of this study was the 

analysis of signaling pathways. 

Among their many functions, 

signaling pathways control gene 

activity during cell development 

and regulate the interactions 

between cells as they form 

organs or tissues. Among other 

findings, the TCGA Research 

Network identified new mutations 

in the Wnt pathway, which is 

altered in more than 95 percent 

of colorectal cancers. According 

to the researchers, this finding 

will improve development of Wnt 

signaling inhibitors, which show 

initial promise as a class of drugs 

that could benefit colorectal cancer 

patients. 

In addition to examining the 

Wnt pathway, the investigators 

identified RTK/RAS and AKT-PI3K 

as pathways that are altered in 

a substantial set of colorectal 

tumors, which therefore may show 

promise for developing targeted 

therapies for colorectal cancer. 

Because of these findings, drug 

developers may now be able to 

narrow their scope of investigation 

with an expectation of producing 

more focused therapeutic 

approaches.
26 | NATIONAL CANCER INSTITUTE

B-Cell Lymphoma

Lymphomas are cancers that arise from lymphoid cells, which 

are part of the immune system. The World Health Organization 

currently recognizes about 70 different types of lymphoma and 

divides them into four major groups: mature B-cell neoplasms, 

mature T-cell and natural killer cell neoplasms, Hodgkin 

lymphoma, and immunodeficiency-associated lymphoproliferative 

disorders. Although Hodgkin lymphoma is a B-cell malignancy, 

it is characterized by an abnormal type of cell known as the 

Reed-Sternberg cell, which is not found in other types of B-cell 

lymphoma. Collectively, lymphomas represent about 5 percent of 

all cancers diagnosed in the United States. In 2012, it is estimated 

that 79,000 Americans will be diagnosed with lymphoma and 20,100 

will die from the disease. Although lymphoma incidence rates have 

been stable over the past decade, lymphoma death rates have been 

declining steadily. These declines in mortality can be attributed 

to improvements in treatment. Today, the 5-year relative survival 

rate for all patients diagnosed with lymphoma is approximately 

71 percent; for patients diagnosed with Hodgkin lymphoma, it’s 

about 85 percent. Indeed, Hodgkin lymphoma is now considered 

one of the most curable forms of cancer. Treatments for lymphoma 

include surgery, watchful waiting, chemotherapy, radiation therapy, 

and targeted therapy. The choice of treatment depends on the type 

and grade of the lymphoma, the stage of the disease, and the age 

and general health of the patient. 

FDG-PET/CT fusion image of the body, frontal section, showing B-cell (type B) nonHodgkin lymphoma with abdominal lymph node localization and splenic involvement. 

©Centre Jean Perrin

The cells that give rise to 

lymphomas are the progeny, or 

offspring, of blood stem cells, 

which are multipotent cells that 

divide to produce myeloid cells 

and lymphoid cells. Myeloid cells 

include red blood cells and white 

blood cells known as granulocytes 

(eosinophils, neutrophils, and 

basophils). Lymphoid cells 

include T cells, B cells, and 

natural killer cells. Lymphoma is 

a disease of lymphoid cells, with 

B-cell cancers representing up 

to 80 percent of all lymphomas 

diagnosed in adults. This profile 

focuses on a B-cell lymphoma 

known as diffuse large B-cell 

lymphoma, or DLBCL.

Not Just a Single Disease

B cells are an integral part of the 

adaptive immune system, which 

is also known as the specific 

immune system. This part of the 

immune system is activated in 

response to invading pathogens, 

such as bacteria and viruses, and 

it has the ability to remember 

previous contacts with foreign 

invaders, mounting stronger 

responses to them each time they 

are encountered. A portion of 

activated B cells will develop into 

antibody-producing plasma cells. 

Others will become “memory 

cells” that can be activated in 

response to future attacks.

Over the past decade, Louis M. 

Staudt, M.D., Ph.D., chief of NCI’s 

Molecular Biology of Lymphoid 

Malignancies Section, has been 

a leader in the effort to classify 

B-cell lymphomas based on 

their molecular underpinnings. 

He and his colleagues study 

gene mutations linked to cancer 

development and changes in 

gene activity that are associated 

with particular tumor types. 

Using DNA microarrays and gene 

expression profiling, Staudt and 

his colleagues have identified new 

forms of B-cell lymphoma that 
NATIONAL CANCER INSTITUTE | 27

are indistinguishable by diagnostic 

methods currently in widespread 

use. For example, they found 

that DLBCL, which oncologists 

previously thought was the most 

common type of lymphoma, is 

actually three distinct diseases—

germinal center B-cell-like (GCB) 

DLBCL, activated B-cell-like (ABC) 

DLBCL, and primary mediastinal 

B-cell lymphoma—each of which 

responds differently to therapy. 

For example, genetic analyses 

performed by Staudt and his 

colleagues revealed that mutation 

of a gene called MYD88 in ABC 

DLBCL tumors can lead to chronic 

activation of a signaling pathway 

known as the nuclear factor kappa 

B (NF-kB) pathway, which promotes 

cancer cell survival. “We found that 

if you can interrupt this survival 

pathway,” Staudt said, “you can kill 

the lymphoma cells.” 

Moreover, Staudt and his colleagues 

identified mutations in two 

additional genes in ABC DLBCL 

tumors that appear to contribute to 

lymphoma development: CD79 and 

CARD11. Now, they are looking for 

drugs that counteract the effects of 

these three mutations.

“We understand many of these 

cancers, from a biological 

perspective, much better than we 

did a decade ago,” said Wyndham 

Wilson, M.D., Ph.D., head of NCI’s 

Lymphoma Therapeutics Section. 

“And what’s important is that the 

biological understanding leads to 

new targets for drugs.”

Drugs for Every Tumor

Basic scientific research can lead 

to unexpected discoveries, and 

discoveries applied to the treatment 

of one type of cancer can often be 

applied to another. This storyline is 

playing out in B-cell lymphoma, as 

Staudt and Wilson are successfully 

applying a strategy that had first 

been applied to treat multiple 

myeloma, a cancer of bone marrow 

cells.

Wyndham Wilson, M.D., Ph.D., (left)

and Louis M. Staudt, M.D., Ph.D., of the 

National Cancer Institute.
28 | NATIONAL CANCER INSTITUTE

Decades of sustained funding 

by NCI and other NIH institutes 

have provided a clear picture 

of how proteins are normally 

broken down, or degraded, 

inside cells in structures called

proteasomes. This understanding 

ultimately led to the 

development, and FDA approval 

in 2003 for certain other cancers, 

of the drug bortezomib (Velcade), 

which blocks the degradation of 

numerous proteins, including 

many that regulate the cell cycle 

and cell death (apoptosis).

Staudt and colleagues found that 

bortezomib inhibits the NF-kB 

signaling pathway, which is 

chronically activated in most 

cases of ABC DLBCL, whether 

due to MYD88 gene mutation 

or another mechanism. This 

knowledge led Staudt and 

Wilson to begin testing the drug, 

in combination with standard 

chemotherapy, in patients 

with B-cell lymphoma. They 

found that the bortezomib–

chemotherapy combination 

produced complete or partial 

remissions in 10 of the 12 ABC 

DLBCL patients they tested. 

This subtype of DLBCL has 

historically been very difficult to 

treat. Bortezomib in combination 

with standard chemotherapy 

to treat patients with DLBCL is 

now being tested in a large-scale, 

international phase 3 clinical 

trial. 

“This is a baby step,” Staudt said. 

“Bortezomib works, but it affects 

many pathways within cells and 

causes side effects that limit its 

use. We want to find something 

that has a more targeted role in 

the cell and is more tolerated by 

patients.”

skln surface

Burkitt lymphoma, shown 

in the lower portion of the 

frame, beneath the skln.

One such promising agent is 

a drug called ibrutinib, which 

inhibits a signaling protein 

inside B cells called Bruton’s 

tyrosine kinase, or BTK. Ibrutinib 

was first found to be active 

against chronic lymphocytic 

leukemia, and it was approved 

for this use by the FDA in March 

2012. Research by Staudt, 

Wilson, and their collaborators 

has demonstrated that chronic 

activation of a protein called the 

B-cell receptor on the surface 

of B cells is another pathogenic 

mechanism in ABC DLBCL. 

Signals from activated B-cell 

receptors are received by BTK, 

which, in turn, relays them to 

NF-kB, which ultimately acts 

to promote cell survival. “BTK 

is a critical link between the 

cell surface and signaling in the 

nucleus,” said Staudt, whose 

team is in the very early stages 

of studying that link. 

One patient that Staudt treated 

with ibrutinib had such a large 

tumor in her abdomen that she 

couldn’t eat. The tumor had 

not responded to conventional 

chemotherapy. Nevertheless, 

after 1 week on ibrutinib, taken 

orally each day, she no longer 

felt any discomfort and imaging 

confirmed that the tumor had 

shrunk. She was able to eat 

again and returned home. 

Another patient had ABC DLBCL 

that had responded twice to 

chemotherapy but eventually 

recurred each time. Her tumor 

had a mutation in the B-cell 

receptor, suggesting that the 

receptor might be chronically 

“on,” delivering signals that 

could be blocked by ibrutinib. 

She began to feel better within 

the first week of treatment, 

and, by 8 weeks, her cancer 

was in complete remission. 

She remained cancer-free 15 

months later, taking only this one 
 NATIONAL CANCER INSTITUTE | 29

drug daily. Although these are 

exceptional cases, they point to 

future promise from drugs that 

target similar signaling pathways.

Unlike conventional 

chemotherapy, treatment with 

ibrutinib causes minimal side 

effects, if any. Ongoing studies 

of this drug are assessing the 

frequency and the duration 

of the tumor responses. The 

methods that Staudt identified 

to assign lymphomas to the ABC 

molecular subtype are allowing 

his team to determine which 

tumors will respond to this BTK 

inhibitor—a textbook example of 

precision medicine.

Other researchers are also 

trying to discern the molecular 

features of DLBCL. For example, 

Todd Golub, M.D., of the Broad 

Institute of MIT and Harvard has 

sequenced the protein-coding 

regions of the genomes of tumor 

samples from 55 patients with 

DLBCL and paired samples of 

normal tissue, and he identified 

a number of new mutations 

not previously associated with 

DLBCL. The newly identified 

mutations will provide further 

insights into the development of 

DLBCL, as well as new targets for 

drug development. 

Although the sophisticated tools 

required to do these analyses are 

available at NCI’s laboratories 

in Maryland, they are not 

yet available at most clinics 

around the country. By bringing 

these advanced technologies 

to patients around the world, 

doctors will be able to diagnose 

lymphoma types based on their 

gene expression patterns. 

Staudt is leading an NCI 

initiative to develop easy and 

inexpensive ways for doctors 

to analyze B-cell lymphoma 

samples genetically. “This will 

allow our knowledge of which 

treatments work against which 

genetic mutations to have a 

more widespread impact,” he 

said. The Lymphoma-Leukemia 

Molecular Profiling Project 

involves researchers from around 

the United States, Canada, and 

Europe. They have developed 

a DNA microarray, called a 

“lymphochip,” that defines 

gene expression profiles to 

distinguish lymphoma subtypes. 

“We have all this knowledge 

now,” Staudt said. “But this has 

not yet penetrated the broader 

community. That’s our next 

goal.”

Circulating tumor cells captured 

from a sample of whole blood.

[Image courtesy of S. Stott; © Science/AAAS]
30 | NATIONAL CANCER INSTITUTE

Renal Cell (Kidney) Cancer

The most common type of kidney cancer is renal cell carcinoma 

(RCC), which arises in the renal parenchyma (the part of the 

kidney that makes urine). RCC accounts for more than 90 percent 

of kidney cancers. Nearly three-quarters of RCCs are classified 

as clear cell carcinomas because of their pale appearance when 

examined under a microscope. The other major type of RCC is 

called papillary carcinoma. In addition to RCC, other cancers that 

occur in the kidney are transitional cell carcinomas of the renal 

pelvis (the part of the kidney where urine collects and drains to 

the ureters and the bladder), sarcomas, and Wilms tumors, a 

rare type that occurs almost exclusively in children. Cigarette 

smoking, obesity, and hypertension appear to contribute to the risk 

of RCC. In addition, mutations in more than 15 genes have been 

associated with RCC, both in the inherited and sporadic forms, 

but they provide only a partial picture of the complex processes 

of this disease. Kidney cancer incidence has increased steadily 

over the past several decades, a rise attributed in part to increased 

detection of early-stage disease. Moreover, kidney cancer mortality 

rates have improved little in the past 20 years. This year in the 

United States, it is estimated that more than 64,000 people will be 

diagnosed with kidney cancer and about 13,000 will die from it. 

Greater understanding, gleaned from laboratory research on the 

molecular underpinnings of RCC, has yielded new strategies for 

its treatment, including the first generation of molecularly targeted 

therapies, many of which deplete tumor cells of nutrients and 

oxygen by blocking the growth of blood vessels.

Renal carcinoma of the right kidney, shown on an intravenous pyelogram, or IVP.

Credit: BSIP / Science Source

Current understanding of the 

molecular genetics of RCC 

stems largely from studies 

of families with inherited 

predispositions for the disease. 

Over the past two decades, 

five forms of familial RCC 

have been identified, each 

associated with specific genetic 

mutations. The most common of 

these familial disorders is von 

Hippel-Lindau (VHL) syndrome, 

which increases risk for tumors 

of the eye, pancreas, brain, 

and kidneys. Studies of VHL 

families showed that virtually 

all members carry mutations in 

a gene on chromosome 3. The 

gene, which is also called VHL, 

was identified by researchers in 

the NCI intramural program in 

1993, and its protein product 

acts as a tumor suppressor. 

When VHL is inactivated, cells 

behave as though they lack 

sufficient oxygen and nutrients. 

As a result, the cells ramp up a 

number of survival pathways, 

including those that promote 

the growth and recruitment of 

new blood vessels—a classic 

tumor characteristic. As with 

most other mutated genes 

identified in inherited kidney 

cancer, VHL is mutated in 

sporadic kidney cancers, too. 

(Sporadic kidney cancers arise 

in patients who do not have 

an inherited predisposition.) 

A recent study estimated that 

in more than 90 percent of 

sporadic clear cell RCCs, VHL

is inactivated by mutation or 

other changes that reduce its 

expression.

In total, mutations in more 

than 15 genes have been 

associated with inherited and/

or sporadic RCC. However, 

the genes identified to date, 

although important, provide 

only a partial picture of the 

complex processes that lead to 

RCC. This point is illustrated 
NATIONAL CANCER INSTITUTE | 31

by the findings of NCI-funded 

geneticist Kimryn Rathmell, M.D., 

Ph.D., who leads a research team 

at the University of North Carolina 

at Chapel Hill and uses a variety 

of models to study RCC. Rathmell 

engineered mice with mutations in 

VHL but found that the mice did not 

develop RCC until she treated them 

with a drug that causes additional 

random mutations throughout the 

genome. These results suggest that, 

although the loss of VHL function 

is an important event, other stillunknown mutations or aberrations 

also play a role. 

Angiogenesis

Over the past decade, several 

targeted therapies have been 

developed and approved for the 

treatment of RCC. Some interfere 

with pathways that are altered 

when VHL is mutated, including 

pathways involved in increased 

blood vessel formation. The strategy 

is to block the growth of these 

blood vessels and kill tumor cells 

by depleting them of nutrients and 

oxygen. 

When tumors grow to 

approximately 2 cubic millimeters 

in size, about the size of a raindrop, 

they start to form their own network 

of blood vessels by inducing the 

outgrowth of sprouts from preexisting blood vessels in a process 

known as angiogenesis. Tumors 

depend on this new blood vessel 

network to supply the oxygen and 

nutrients necessary for survival, 

growth, and spread. 

In a healthy person, the growth of 

new blood vessels is kept in check 

by a balance of proangiogenic and 

antiangiogenic chemical signals. But 

tumor cells—together with cells in 

the tumor’s immediate surroundings, 

or microenvironment—release an 

abundance of proangiogenic signals, 

upsetting the normal balance. These 

signals coax cells called endothelial 

cells to migrate and develop into 

new blood vessels for the tumor. 

Unlike normal blood vessels, 

tumor blood vessels are frequently 

disorganized, uneven in size and 

shape, and leaky.

Genomic Research. The Cancer 

Genome Atlas project (see p. 11) 

holds promise to help generate 

additional information about the 

genetic patterns that characterize 

RCC. As part of this effort, 500 

RCC tumors (both clear cell and 

papillary carcinomas) are undergoing 

comprehensive genomic analysis. 

The findings, it is hoped, will help 

define subgroups of clear cell and 

papillary RCC, which should better 

guide research and treatment of 

these diseases. 

Over the past two decades, a 

number of natural and synthetic 

agents have been discovered to 

block angiogenesis and thereby slow 

or stop tumor growth and spread. 

The FDA has approved several 

drugs that inhibit angiogenesis for 

the treatment of cancer, including 

breast, colon, lung, kidney, 

liver, and brain cancer, as well 

as neuroendocrine tumors and 

gastrointestinal stromal tumors. 

Kimryn Rathmell, M.D., Ph.D.

University of North Carolina at 

Chapel Hill.
32 | NATIONAL CANCER INSTITUTE

Unfortunately, most patients 

experience only a temporary 

benefit from currently available 

angiogenesis inhibitors. Over 

time, tumors become resistant 

to this treatment and start 

growing or spreading again. One 

strategy to decrease resistance 

to antiangiogenic inhibitors is 

to target multiple pathways at 

the same time, using a single 

inhibitor or a combination of 

inhibitors. Clinical trials are 

currently testing combinations 

of antiangiogenic therapy and 

other treatments that target 

blood vessels, such as tumor 

vascular-disrupting agents 

that target already established 

tumor blood vessel networks. 

Angiogenesis inhibitors, like 

most cancer therapies, are not 

without side effects. In addition 

to testing new angiogenesis 

inhibitors and combinations of 

treatments, efforts are under way 

to reduce toxicities associated 

with angiogenesis inhibitors, 

such as bleeding, hypertension, 

and blood clots that may lead to 

a stroke or heart attack. 

Other Clinical Approaches

“We need a new approach 

to go after the heart of these 

cancers,” said W. Marston 

Linehan, M.D., chief of NCI’s 

Urologic Oncology Branch. 

Linehan noted that all of the 

genes identified in familial RCC, 

including VHL, are involved 

in cellular metabolism: They 

are responsible for monitoring 

and responding to changes in 

available energy, nutrients, iron, 

and oxygen. It may be possible 

to improve on or complement 

current RCC treatment strategies 

by targeting the metabolic 

defects that occur in this disease. 

Linehan’s laboratory has found 

that the diabetes drug metformin, 

which alters how cells respond 

to energy needs, can have a 

profound effect on RCC cells 

in tissue culture. Whether this 

finding will lead to a treatment 

strategy to help patients with 

RCC remains to be seen. 

Jeffrey Sosman, M.D., at 

Vanderbilt-Ingram Cancer Center 

in Nashville, is among scientists 

trying another approach to stop 

RCC: coaxing the body’s immune 

system into attacking cancer 

cells more effectively. It is an 

approach that is being explored 

in many types of cancer, and 

one drug that enables enhanced 

immune responses against 

cancer, ipilimumab (Yervoy), 

has already been approved 

as a treatment for advanced 

melanoma. A new drug, called 

MDX-1106, works in a way 

similar to that of ipilimumab. 

MDX-1106 is an antibody that 

binds to and blocks the activity 

of a protein on immune cells 

called PD1. PD1’s job is to keep 

immune responses in check, 

preventing runaway responses 

that might damage the body’s 

normal tissues. But there is 

evidence that tumors can take 

advantage of PD1 and prevent 

immune cells from fighting RCC 

and other cancers. In an initial 

clinical trial of MDX-1106, it 

shrank tumors in a quarter of 

patients. The drug is now being 

tested in large-scale international 

clinical trials. 

Jeffrey Sosman, M.D.,

Vanderbilt-Ingram 

Cancer Center.
 NATIONAL CANCER INSTITUTE | 33

Judah Folkman, “Grandfather” of Angiogenesis

The scientist most responsible for 

the field of angiogenesis research 

was the late Judah Folkman, 

M.D., of Harvard University. As 

a young Navy doctor, Folkman 

studied blood vessel growth at 

the National Naval Medical Center. 

It was during his Navy career 

that he invented an implantable 

device that allowed the timed 

release of fertility drugs, and he 

donated it patent-free to the World 

Population Council. This is the 

device now known as Norplant, 

and it marked Folkman’s first 

legacy in the biomedical research 

community. 

In 1971, after returning to his 

alma mater, Harvard, he used 

his familiarity with the vascular 

system to postulate, in a landmark 

New England Journal of Medicine 

article, that all cancerous tumors 

depend on the initiation and 

maintenance of a new vascular 

supply to support their rapid 

growth and development. If this 

blood supply could be cut off, he 

proposed, the tumor would wither 

and die. 

Initially disregarded by many 

cancer researchers, his views 

on angiogenesis have become 

mainstream orthodoxy, leading 

to the use of angiogenesisblocking drugs as a mainstay 

of therapy for many kinds of 

cancers. The list includes such 

drugs as bevacizumab (Avastin), 

sorafenib (Nexavar), sunitinib 

(Sutent), pazopanid (Votrient), 

and everolimus (Afinitor), some 

of which were already known to 

affect cancer cell signaling and 

growth, as well as vascularization. 

More than 50 angiogenesis 

inhibitors have entered clinical 

trials for cancers as wideranging, morphologically, as lung 

cancer, prostate cancer, breast 

cancer, and liver cancer. While 

antiangiogenesis therapy hasn’t 

proven to be quite the “silver 

bullet” Folkman predicted it would 

be, it remains one of the most 

effective approaches to controlling 

cancer.

Progression of angiogenesis. This is a physiological process involving the growth of new blood vessels from pre-existing vessels, occurring in 

the transition of tumors from a dormant state to a malignant state.
34 | NATIONAL CANCER INSTITUTE

GI Stromal Cancer

Gastrointestinal stromal tumors (GISTs) are uncommon tumors 

that form in the wall of the gastrointestinal tract from cells known 

as ICCs, or interstitial cells of Cajal. ICCs are sometimes called 

gastrointestinal pacemaker cells because they help transmit 

signals from the autonomic nervous system to the smooth muscles 

of the gastrointestinal wall, stimulating waves of contraction 

(peristalsis) that help propel food and waste products through the 

digestive system. GIST can begin anywhere in the gastrointestinal 

tract; 60 percent of tumors originate in the stomach, and another 

30 percent in the small intestine. Other sites of origin include the 

esophagus, colon, rectum, and anus. GIST affects about 4,000 

to 5,000 people in the United States each year. GIST treatment in 

adults has been greatly improved by the development of several 

highly effective targeted therapies. In children, however, the story 

is very different.

Three-dimensional computed tomographic reconstruction scan of the small intestine 

showing a gastrointestinal stromal tumor (GIST), seen as a red spot in the jejunum. 

Until the 1990s, any sarcoma 

that developed in the walls of the 

gastrointestinal tract was called a 

gastrointestinal sarcoma. With the 

emergence of technologies that 

allowed researchers to classify 

tumors based on their molecular 

characteristics, it became clear 

that these tumors are not all the 

same. Among the subgroups that 

emerged was GIST. 

In 1998, Seiichi Hirota, M.D., 

Ph.D., of Osaka University 

Medical School in Japan found 

that the tumor DNA from five 

of six tested GIST patients had 

a mutation in a gene called KIT.

Since then, other researchers have 

determined that approximately 

85 percent of all GISTs have a KIT

mutation and that 5 to 8 percent 

have a mutation in another gene 

called platelet-derived growth 

factor receptor alpha (PDGFRA). 

The discovery of KIT mutations, 

which are not found in other 

gastrointestinal tumors, offered 

an easy way to genetically 

distinguish most GISTs, and it led 

to the development of targeted 

treatments for the disease. 

Both KIT and PDGFRA encode 

cell-surface receptor proteins. 

The portion of each molecule 

that sits on the cell surface acts 

as a receptor for specific growth 

factors; the portion of each 

protein that is located inside the 

cell has tyrosine kinase enzyme 

activity. When the appropriate 

growth factors bind to these 

receptors, the tyrosine kinase 

portions become activated and 

start transmitting signals to the 

cell nucleus, thereby promoting

cell proliferation and survival. 

The mutations identified in KIT

and PDGFRA in GIST lead to the 

production of receptor proteins 

that are activated all of the time—

that is, the tyrosine kinases are 

continuously transmitting signals 

that promote cell proliferation 
NATIONAL CANCER INSTITUTE | 35

and survival, even in the absence 

of growth factors.

Tyrosine kinases are enzymes 

that transfer a phosphate group 

from a molecule called adenosine 

triphosphate, or ATP, to specific 

proteins. As a result, proteins that 

receive these phosphate groups, 

which are linked to tyrosine 

amino acids in the proteins, are 

either turned “on” or turned 

“off.” Cells use tyrosine kinases—

both those that are part of cellsurface receptor proteins and 

those that are located exclusively 

inside cells—to control many 

vital functions, including the cell 

cycle, metabolism, proliferation, 

differentiation, and survival. 

Altogether, 90 tyrosine kinases 

have been identified in human 

cells, and activating mutations in 

a number of these kinases have 

been shown to play a role in 

human cancer.

George Demitri, M.D., (left) of the 

Dana-Farber Cancer Institute and 

Jonathan A. Fletcher, M.D., of the 

Brigham and Women’s Hospital.

Another example of tyrosine 

kinase activation in human cancer 

involves a protein called ABL, 

which is an intracellular tyrosine 

kinase. Constitutive activation of 

this kinase is the cause of chronic 

myelogenous leukemia (CML). 

In CML, part of the gene that 

encodes ABL becomes joined with 

part of another gene called BCR,

producing a fused gene known 

as BCR-ABL. The product of this 

fused gene is a protein, BCR-ABL, 

in which the ABL tyrosine kinase 

is constitutively active. Once this 

was discovered, researchers began 

searching for a drug that would 

block the activity of the BCRABL tyrosine kinase. This search 

ultimately led the development of 

a drug called imatinib (Gleevec), 

which is highly effective in the 

treatment of CML. In 2001, the 

FDA approved imatinib for the 

treatment of CML. Even before that 

approval, however, researchers 

were trying to determine whether 

imatinib could block the activity 

of other tyrosine kinases. In 2000, 

laboratory scientists demonstrated 

that imatinib could also block 

the activity of KIT and PDGFRA. 

Shortly thereafter, North American 

and European research teams 

launched a series of clinical trials to 

determine whether imatinib would 

work against GIST. 

“We hoped that it would yield 

just some benefit,” said George 

Demetri, M.D., an oncologist at the 

Dana-Farber Cancer Institute in 

Boston. “We had no idea just how 

incredibly beneficial it would end 

up being.” 

Although fewer than 5 percent of 

GIST patients benefit from standard 

chemotherapy, more than 50 

percent responded to imatinib in 

the original study. Some patients 

from the initial trial of imatinib 

are still in remission more than a 

decade later, said Demetri. In 2002, 

the FDA approved imatinib for 

GIST patients whose tumors have 

mutations in KIT, and it has rapidly 

become the standard of care for 

metastatic GIST. However, some 

patients develop resistance to this 

drug and have to turn to secondline treatments as their tumors 

accumulate new gene mutations. A 

second-line drug, sunitinib (Sutent), 

which also targets the KIT protein, 

has been approved for patients 

who develop resistance to imatinib. 

The duration of the clinical benefit 

from sunitinib depends on the 

mutations in the patient’s GIST and 

its metastases. Approximately 20 

percent of patients taking sunitinib 

have stable disease for 2 years or 

longer. 
36 | NATIONAL CANCER INSTITUTE

“But, we’re still not curing 

anyone,” noted Demetri. Patients 

must remain on treatment 

or their tumor will begin to 

grow again. Demetri recently 

discovered that cells in the 

area around GISTs produce 

signaling molecules that keep 

the tumor alive during treatment 

with imatinib. Blocking these 

signals, he said, could make the 

tumor cells die. He has already 

identified some of the molecules, 

and now he is piecing together 

their functions and learning how 

to block them. 

Compared with many other 

cancers, GIST appears to have 

a relatively stable genome, and 

only a small number of driving 

genetic mutations have been 

found in these tumors thus far. 

For this reason, GIST is being 

used to explore general questions 

about cancer development and 

metastasis in the hope that the 

knowledge gained can be applied 

to other cancer types. By studying 

GIST biology, researchers may 

learn more about how tumors of 

all types grow and spread. 

For example, studies of early 

GIST might reveal what makes 

a cancer aggressive. Some small 

GISTs grow very slowly, even 

though they appear to have the 

same driving genetic changes 

as those that grow rapidly. 

Researchers in Japan have found 

millimeter-sized GISTs in the 

gastrointestinal tracts of around 

40 percent of people who died 

from other causes. “There are 

these tiny GIST freckles,” said 

Demetri, “but they never turn 

into larger tumors, even though 

they have the same driving 

mutations.” This study in Japan 

suggests that other events—

perhaps additional mutations 

or changes in the tumor 

microenvironment—are required 

to turn these GIST tumors into 

aggressively growing cancers. 

Lee Helman, M.D., 

National Cancer Institute.

Pediatric GIST: A Very 

Different Disease 

Pediatric GIST is very rare, 

even by rare cancer standards, 

representing only 1 to 2 percent 

of all GIST cases (approximately 

60 cases per year in the United 

States). It is also very different 

from its adult counterpart. 

Whereas 85 percent of GISTs in 

adults harbor mutations in one 

of two genes, KIT or PDGFRA,

the opposite is true in children 

with GIST—85 percent have no 

detectable mutation in either 

gene. The events that trigger 

these pediatric tumors are 

unknown, and the tumors do not 

respond to imatinib or sunitinib, 

the drugs that have made such a 

difference for adults with GIST. 

For children and youth who 

develop GIST, NCI and the 

Eunice Kennedy Shriver National 

Institute of Child Health and 

Human Development have 

partnered with members of 

GIST Support International and 

the LifeRaft Group to organize 

a consortium of pediatric GIST 

researchers to field a program 
 NATIONAL CANCER INSTITUTE | 37

at the NIH Clinical Research 

Center aimed at designing 

innovative treatment 

protocols. Within the past 4 

years, 60 to 80 patients with 

pediatric GIST have been 

evaluated at NIH, explains 

Lee Helman, M.D., from NCI’s 

Pediatric Oncology Branch. 

Su Young Kim, M.D., Ph.D., 

formerly an NCI postdoctoral 

fellow, led the clinical team 

in Helman’s lab, which 

includes geneticists, medical 

oncologists, pediatric 

oncologists, pediatric 

surgeons, nutritionists, and 

pain specialists. The research 

team has learned about 

the clinical and molecular 

features of this disease, which 

distinguish it from GIST 

in adults. They found that 

the disease is usually slowgrowing in children, occurs 

overwhelmingly in girls, 

and almost always occurs in 

the stomach, whereas adult 

GIST occurs equally in both 

genders and occurs often in 

the small intestine as well as 

in the stomach. In addition, 

in contrast with adult GIST, 

pediatric GIST often presents 

as multifocal disease, meaning 

that there are multiple, 

distinct tumor foci within the 

affected anatomic region. 

Pediatric GIST can arise in the 

context of a hereditary cancer 

syndrome called the CarneyStratakis syndrome. This 

syndrome predisposes affected 

individuals to GIST and to 

paraganglioma, a rare tumor of 

the peripheral nervous system 

(nerves outside of the brain 

and spinal cord). CarneyStratakis syndrome is caused 

by an inherited mutation 

in a gene that produces a 

protein called succinate 

dehydrogenase (SDH), 

which is involved in cellular 

respiration. Last year, a DanaFarber research team led by 

pediatric oncologist Katherine 

Janeway, M.D., reported that five 

of 34 patients (15 percent) with 

so-called wild-type GIST (no 

KIT or PDGFRA mutations) who 

were 22 years of age or younger 

and who had no personal or 

family history of paraganglioma 

(that is, they were not affected 

by Carney-Stratakis syndrome) 

had tumors with an SDH gene 

mutation. This finding suggested 

that SDH mutations might 

play a role not only in GISTs 

associated with Carney-Stratakis 

syndrome but also in nonhereditary forms of the disease. 

Janeway and her team then 

showed that all pediatric GISTs 

tested, including those with and 

without SDH gene mutations, 

lacked expression of the SDH 

protein. They are now looking 

for mutations in other genes or 

epigenetic changes—alterations 

that affect gene expression but 

do not involve changes to the 

Pediatric oncologist 

Katherine Janeway, M.D.,

Dana-Farber Cancer 

Institute.

DNA sequence of genes—to 

explain the absence of SDH 

protein in pediatric GISTs. A 

deficiency in SDH protein leads 

to the accumulation of succinate 

in cells and subsequent 

increased production of vascular 

endothelial growth factor and 

insulin-like growth factor 1 

receptor. Drugs that target these 

molecules may help GIST 

patients who have an SDH 

deficiency.

The patients described in 

Janeway’s study attended the 

NIH GIST clinic, and the genetic 

testing of their tumors took place 

there. 

“We are now beginning to define 

the disease more by molecular 

drivers, which is always a good 

thing,” Helman said. Identifying 

molecules or changes that drive 

tumor development is the first 

step in developing new targeted 

therapies.
38 | NATIONAL CANCER INSTITUTE

Research Focus

In this section we provide a snapshot of three important research areas 

that affect many types of cancers. In the first section, on comorbidities, 

we discuss our growing understanding of the ways that health 

conditions such as heart disease, diabetes, and obesity complicate 

the treatment of many cancers. In the next section, on circulating 

tumor cells, we highlight a new approach to understanding how 

tumors metastasize. In the third section, on reducing cancer 

health disparities, we show how NCI is working to understand and 

address the disproportionate burden of cancer among various racial 

and ethnic groups.
 NATIONAL CANCER INSTITUTE | 39

Research Focus: 

Comorbidities

S

ixty percent of cancer patients and survivors are age 65 

or older. With age comes increased risk for other health 

conditions such as heart disease, diabetes, and dementia. 

Growing rates of obesity and physical inactivity, 

problems pervasive in the U.S. population, also increase 

the risk for many chronic conditions. Based on National Health 

Interview Survey data, among cancer patients age 65 and older, 36 

percent reported at least one additional illness—referred to as a 

comorbidity—and 16 percent reported two or more comorbidities. 

When people with cancer have one or more comorbidities, what is 

the impact on the care that they receive? And, in turn, how does 

their cancer treatment affect their other conditions? 

Older age, comorbidities, and functional limitations should 

not automatically deprive a patient of treatment. Often, 

older patients can tolerate chemotherapy as well as 

younger patients. For example, postoperative, or adjuvant, 

chemotherapy for colorectal cancer in patients age 70 and 

older is as effective as it is in younger patients, and harmful 

side effects can be reduced if certain drugs (oxaliplatin, 

for example) are avoided. But questions exist as to which 

treatments and which comorbidities interact. For example, 

how do heart disease drugs interact with cancer drugs when 

both may affect cardiac function? And many people with diabetes 

have peripheral neuropathy, nerve damage that causes numbness or 

pain in the hands and feet. But some chemotherapy drugs have the 

same side effects. Do the two together make the condition worse? 

Many of these questions need to be explored. And most importantly, 

can we remediate some of the age-associated comorbidities so older 

patients with cancer can derive the full benefits of cancer treatment?

Comorbidities affect a patient’s ability to participate in clinical 

research, as well, according to Julia Rowland, Ph.D., director of 

NCI’s Office of Cancer Survivorship. Older patients are more likely 

than younger ones to be excluded from treatment studies because 

they have other chronic health problems. For example, individuals 

with a history of diabetes or heart disease often have changes 

in their kidney, liver, or heart function tests that require their 
40 | NATIONAL CANCER INSTITUTE

exclusion from drug trials. This means that most treatments, as 

they move through clinical testing, are not tested in patients with 

comorbidities. So, although we have a growing population of older 

patients who will need to be treated for cancer, we don’t have the data to 

know what is safe and effective for them, Rowland explained. To address 

these questions, NCI has funded several new grants that specifically 

consider comorbidities in cancer patients.

Siran Koroukian, Ph.D., at Case Western Reserve University School 

of Medicine, has been studying comorbidities among elderly cancer 

patients in Ohio. With funding through the NIH Clinical and Translational 

Science Awards program, her group has linked data from the Ohio 

Cancer Incidence Surveillance System with Medicare data and the 

home health care Outcome and Assessment Information Set to explore 

the prevalence and impact of multimorbidity, defined as having one or 

more comorbidities, functional limitations, or geriatric syndromes. As 

many as 88 percent of Ohio residents with breast, prostate, or colorectal 

cancer who were admitted to home health care in the 30-day window 

after cancer diagnosis had one of the multimorbidity conditions or some 

combination of the three. The most common comorbid conditions were 

hypertension, cardiovascular disease, diabetes, and arthritis. 

In a 2011 NCI-funded study, Koroukian’s group examined the effects of 

multimorbidity on treatment and survival outcomes in older patients 

with local and regional breast or colorectal cancer. Patients with 

multimorbidity were less likely to receive standard therapy and more 

likely to experience poor survival outcomes. What remains unclear is the 

degree to which these poorer outcomes resulted from the patients’ poor 

general health or from their inability to tolerate standard therapy. 

Preparing for a Boom in Older Cancer Survivors

In the not-too-distant future, the United States can expect a sizable 

increase in the number of older citizens who have survived cancer. 

Although some believe that the term “survivor” refers to someone who 

has been “cured,” NCI defines a survivor as anyone who is living with 

“Now that we are moving toward molecularly targeted therapeutics, 

our two big questions are: How do we apply this modern science to treatments in 

clinical trials, and then how do we export what we learn at the cancer center to 

benefit the patients in our region? That is our biggest challenge. We’ll need regional 

networks, partners who treat patients within communities—including minority 

communities—who can provide tumor samples so we can do molecular analyses and 

determine whether a patient is best suited for standard therapy or targeted therapy. 

We need to have minority patients in genomics studies now to answer questions in 

the most scientifically sound way,” said Max Wicha, M.D., cancer researcher and 

founding director of the University of Michigan Comprehensive Cancer Center. 
NATIONAL CANCER INSTITUTE | 41

Estimated Number of Persons Alive in the U.S. Diagnosed with Cancer on January 1, 

2008 by Current Age

40-64 years of age

65 + years of age 

20-39 years of age 

≤ 19 years of age 

 Source: SEER Cancer Statistics Review, 1975–2008.

a cancer diagnosis, regardless of the present status of his or her cancer. 

In a 2011 study, NCI investigators predicted a 42 percent increase in the 

number of cancer survivors 65 years of age and older—from about 

8 million to more than 11 million—between 2010 and 2020. 

The study, led by Rowland, is the first in a planned series of annual 

reports on the booming—and aging—population of cancer survivors in the 

United States. 

“We often think of cancer survivors as young people,” Rowland said. 

“But the reality is that most are older adults.” Among all cancer types, 60 

percent of survivors are age 65 and older (see pie chart). For colorectal 

cancer, 73 percent of survivors are in that older age range. 

Although clinicians are doing a better job at diagnosing cancer and a 

better job of controlling disease, their patients, who are living longer, 

often suffer adverse effects from treatment, some of which are longterm or delayed. “None of our treatments is benign. To realize the goal 

of reducing the national burden of cancer, we need to focus research 

on this older survivor population in addition to the younger survivor 

population,” Rowland said. 

Cancer care does not end once treatment of the disease is completed. It 

also includes consideration of the effects of survivors’ health behaviors 

and medical follow-up care on cancer-related morbidity and mortality. 

People are now living longer, but many struggle with quality-of-life 

issues. Attending to these issues, including comorbidities, will be 

important. “We really don’t know some of the interactions between 

cancer and other chronic problems in the older survivor population,” 

says Rowland. “Nor do we fully appreciate the impact of cancer and its 

treatment on the processes of aging.” In the coming years, the Office of 

Cancer Survivorship plans to focus attention on the rapidly expanding 

population of older survivors. 
42 | NATIONAL CANCER INSTITUTE

Research Focus: 

Circulating Tumor Cells 

C

ancer is most treatable when it is contained, before it has 

a chance to spread to distant parts of the body. Metastasis 

is often the beginning of cancer’s deadly path. Metastatic 

tumors can spring from a very small number of cells that 

break off from a primary, or original, tumor and find their 

way to distant sites in the body. At those sites, the metastatic cells 

can advance quickly or stay dormant for years. Finding the most 

dangerous of these metastatic cells will be a crucial element in 

preventing and combating advanced cancer.

When a patient has cancer, a small number of cancer cells can shed 

from the primary tumor and enter the bloodstream. The presence 

of these circulating tumor cells (CTCs) displays one of the routes 

by which some cancers spread to distant parts of the body. It also 

offers the possibility of developing blood tests that can diagnose 

cancer, guide treatment, predict whether the tumor will spread, 

and follow the course of a disease. The possibilities are vast, but 

they depend on an understanding of the biology of CTCs that 

science has not yet achieved.

Daniel Haber, M.D., Ph.D., of Harvard Medical School and the 

Massachusetts General Hospital, is among several NCI-funded 

scientists who are trying to get at the root of what CTCs are and 

how they can be used in the clinic. Their results, for now, are 

limited by the technology that detects CTCs. Current techniques for 

separating CTCs from blood cells often yield too few tumor cells to 

do complete analysis of their properties. 

The platform that is most widely used is the Veridex CellSearch 

system. When magnetic nanoparticles carrying antibodies specific 

for a protein found on cancer cells are mixed with a small sample 

of a patient’s blood, the antibodies attach to CTCs. A magnet is 

used to pull the nanoparticle–antibody–CTC complexes out of the 

blood, the cells are stained, and then they are analyzed under a 

microscope to ensure that they are truly tumor cells—which are 

shaped differently from normal blood cells—and to count them. 
NATIONAL CANCER INSTITUTE | 43

“Right now we know that if you have circulating tumor cells that are 

detectable in the blood, then you have a worse cancer than if we can’t 

detect cells,” says Haber. “But until we can get to the genetics of these 

cells, we’re not taking full advantage of this technology.”

The FDA has approved the Veridex CellSearch system to test blood 

samples for the presence CTCs in patients with metastatic breast cancer, 

metastatic colorectal cancer, and metastatic prostate cancer, and some 

cancer centers are using it to predict disease outcomes. Tracking the 

numbers of CTCs before and after chemotherapy can be used to predict 

survival time and recurrence rates among patients. But the test is based 

only on numbers of CTCs rather than the genetics or other qualities of the 

cells. 

“The problem with the existing method is that it fixes the cells in 

order to separate them, so they’re dead,” says Robert Kinders, Ph.D., 

head of the Pharmacodynamics Assay Development Laboratory at the 

Frederick National Laboratory for Cancer Research. Kinders is leading a 

collaboration between NCI and industry to create a new platform, tailored 

to NCI’s research needs, that can pull live CTCs from blood (see related 

story p. 63). 

Daniel Haber, M.D., Ph.D., (left) 

and Mehmet Toner, Ph.D., of the 

Massachusetts General Hospital 

Cancer Center and the Harvard 

Medical School.
44 | NATIONAL CANCER INSTITUTE

Research Focus: 

Reducing Cancer Health Disparities 

A

troubling truth about cancer is that its burden is not 

shared equally among Americans. African American 

men, for example, are twice as likely as their white 

counterparts to die of prostate cancer. While Hispanics 

have lower rates of incidence and death from all 

cancers combined when compared with non-Hispanic whites, 

they are more likely to develop certain cancers, including 

cancers of the stomach, cervix, or liver. NCI is pursuing 

research on many fronts to understand and address these 

disparities—whether due to genetic or other biological factors, 

influenced by diet or lifestyle, or perhaps most tragically, 

as a result of poorer access to preventive care, screening, 

and high-quality treatment. 

Overcoming cancer health disparities among subsets of 

our citizens is a moral and ethical obligation, as well as a 

scientific challenge. Through its Center to Reduce Cancer 

Health Disparities (CRCHD), NCI supports research to identify 

and understand the factors that contribute to disparities in the 

incidence and mortality of cancer, and to develop and disseminate 

appropriate interventions that are culturally relevant. Much of this 

work, described on the following pages, occurs within a network of 

community-based partnerships that NCI has established across the 

nation.

Along with its portfolio of community-based clinical research and 

training programs and in conjunction with other NCI activities, 

CRCHD supports basic research that reveals a complex picture of 

the roots of cancer disparities. Genetic and other biological factors 

contribute to differences in cancer incidence and outcomes among 

U.S. population groups.

To gather more information about the molecular basis of cancer, 

for example, the Center for Cancer Genomics is expanding the 

participation of racially and ethnically diverse and underserved 

populations in programs such as The Cancer Genome Atlas (TCGA, 

see p. 11), the Therapeutically Applicable Research to Generate 

Effective Treatments initiative, and other genetic studies (see p. 8). 
NATIONAL CANCER INSTITUTE | 45

To increase the rate of collection of high-quality biospecimens from 

under-represented groups, NCI is launching The National Biospecimen 

Awareness and Collection Campaign. The ultimate goal of this campaign 

is to develop and advance our ability to diagnose, treat, and prevent 

cancer among all people, as well as reduce cancer disparities among 

specific population groups. Breast and prostate cancer will be the initial 

priorities of the joint effort with TCGA, although tissue samples of all 

cancer types are being acquired. 

Complementary activities are under way in NCI’s Geographic Management 

of Cancer Health Disparities Program and Biospecimen/Biobanking 

Geographic Management Program to develop culturally relevant patient 

education modules on biospecimens and biorepositories, which will 

expand on patient education materials developed in recent years by 

collaborations between the Cancer Information Service and Community 

Networks Programs across the nation. 

Additional efforts focus on the influence of comorbidities (see p. 39), 

such as diabetes and obesity, on cancer health disparities. NCI also funds 

programs to increase the number of investigators who undertake cancer 

health disparities research, as well as the number of researchers from 

under-represented backgrounds who pursue cancer research in general. 

Community Networks Program Centers

CRCHD also supports community-based participatory research, education, 

and training to reduce the cancer burden in minority and underserved 

communities. Leaders from several of these centers recently co-authored 

a paper that provides examples to primary care physicians of ways to 

enhance life after cancer in diverse populations. 

Several NCI grantees study cancer prevention in American Indian 

communities. Jeffrey Henderson, M.D., M.P.H.—a Lakota, enrolled in 

the Cheyenne River Sioux Tribe—founded the Black Hills Center for 

American Indian Health in Rapid City, South Dakota. As part of the 

Regional Native American Community Network Program, Henderson is 

studying lifestyle and behavioral risk factors, such as tobacco use, that 

are associated with cancer—particularly lung cancer—among Native 

Americans. 

A team led by Stevens Smith, Ph.D., and Leah Arndt, Ph.D., at the 

University of Wisconsin, is nearing completion of a 3-year smoking 

cessation study of American Indians. The goal of the Menominee Smoking 

Cessation trial—the first tribal-sponsored clinical trial in the nation—

is to test a culturally tailored treatment versus standard treatment in 

adult American Indian smokers at the Menominee Tribal Clinic. 

The research team collaborated with the Spirit of Eagles, an NCIsupported Community Network Program (CNP) that works to improve 
46 | NATIONAL CANCER INSTITUTE

Bringing Genomics to Native Americans

Just 10 years ago, Phyllis Pettit Nassi—enrolled in the 

Otoe-Missouri Tribe and a member of the Cherokee 

Nation—couldn’t even use the word “cancer” among 

Native American populations. Traditional cultural 

beliefs held that if you speak of illnesses or negative 

happenings, you bring them to the listener. She set 

out to increase awareness, demystify cancer, and 

remove the fear of the word itself. 

“Today, we can talk about cancer,” said 

Pettit Nassi, who is manager of special 

populations at Huntsman Cancer 

Institute in Salt Lake City. She spends 

most of her time on the road, traveling 

across Utah and 17 other states, including 

Idaho, New Mexico, Montana, Arizona, 

Wyoming, and Alaska. Her goal is to help 

Native American populations understand 

the importance of early detection for cancer 

and participation in research. She accepted 

NCI’s charge to increase tribal participation 

in clinical trials. After much consulting with 

interested tribes, she has increased clinical 

trial participation from zero to 12 people this 

past year.

She has most recently added genomics to the 

important topics she discusses. “I decided this year 

that we need to leap forward,” said Pettit Nassi, who 

is a member of NCI’s Director’s Consumer Liaison 

Group. Since July 2011, she has spoken to more than 

50,000 tribal members in small group meetings or 

while staffing a booth at Native American events. 

“In these conversations, I mention genomics and 

share my belief that our tribal members and our 

health care providers must begin to get information 

on personalized medicine and genetically targeted 

therapies,” she said. “It’s so very important that 

we don’t get left behind.”

In January, Pettit Nassi traveled to the Confederated 

Tribes of the Goshute Reservation in remote 

Ibapah, Utah. This tribe and many others, 

she said, are ready to learn about genomics, 

precision medicine, and genetically targeted 

therapies. “This small, rural, underserved 

tribal nation is poised to accept and participate 

in studies that will benefit their tribal members 

if given the chance, resources, and support to do 

so,” she said. 

Pettit Nassi, Huntsman Cancer 

Institute.
NATIONAL CANCER INSTITUTE | 47

A Bridge Within the Hispanic Community

People of Hispanic origin form the largest ethnic or 

racial minority—48 million people—in the United 

States. Forty-five percent of New Mexico’s population 

is Hispanic. 

Monica Toquinto grew up in New Mexico and wanted 

to give back to her Mexican-American community. 

She became an outreach worker with the University 

of New Mexico Cancer Center (UNM). The importance 

of her work hit home recently, when her mother was 

diagnosed with cancer. 

“Everybody has the right to the right information 

about cancer,” Toquinto said. “And we all deserve the 

best treatment.” She knew many Hispanic people who 

lacked basic information about cancer. “I didn’t know 

anything about cancer. I thought it was the end, but 

it’s not,” she said. At the cancer center’s outreach 

training, she learned that when people are diagnosed 

early, they have a better chance of surviving cancer. 

She learned that people need to take an active role 

in maintaining their health, and not wait 2 to 5 years 

to see a doctor. Now she shares that message, in 

English and Spanish, with communities throughout 

New Mexico, sometimes driving 4 hours to reach rural 

communities of 500 that have no access to services. 

She works as a patient navigator for people who don’t 

know where to start. “Our job is to let them know the 

first step and the last step,” she explained. “We get 

them to the right place right away.” 

Monica Toquinto (center) with Michelle Suina (left) and Maria Otera,

University of New Mexico Cancer Center.

UNM’s outreach programs go where the people are. 

For example, through a partnership with the Mexican 

Consulate, called Ventanilla de Salud (Window of 

Health), UMN holds “Cancer 101” education sessions 

in the consulate’s waiting room. While more than 

100 people wait for their documents or information, 

they attend sessions on cancer, risk reduction, and 

screening. Through the consulate, outreach workers 

see 15,000 people each year and handle 300 to 400 

referrals. For each referral, the outreach staff members 

follow up to make sure the person connects with the 

health care system. Word of mouth leads to many more 

referrals throughout the year.
48 | NATIONAL CANCER INSTITUTE

cancer control in Native American and Alaska Native populations, to 

establish a successful partnership with the Menominee Tribe. The study 

also includes qualitative analyses of participant interviews to inform 

future improvements in treatment.

At CNP-Appalachia, researchers went to a new setting, food pantries, with 

tested and validated educational materials about breast cancer screening 

from the American Cancer Society’s Tell-A-Friend program. In 18 rural 

food pantries throughout Indiana County, Pennsylvania, the researchers 

used the program’s three-contact approach of information dissemination, 

one-on-one education, and phone calls. Researchers distributed 

promotional flyers in food bags, volunteers visited each pantry to educate 

and answer questions, and health workers called every woman who 

expressed interest to provide information on scheduling a mammogram. 

Of the 379 women contacted, 302 were eligible on the basis of age; of 

those, 52 percent were in need of a screening mammogram. Eighty-seven 

percent of those women subsequently received mammograms; three of 

those women were diagnosed with breast cancer and entered treatment. 

The project led to a 28 percent increase in breast cancer screening among 

underserved residents of Indiana County during the intervention year, 

demonstrating the effectiveness of this community-based approach in 

boosting screening rates. 

Church-Facilitated Initiative to Promote Health in Appalachia

The Appalachia Community Cancer Network, an NCI-supported CNP, 

is partnering with churches across the Appalachian region of Kentucky, 

Ohio, Pennsylvania, Virginia, and West Virginia to implement the 

Faith-based Initiative to Promote Health in Appalachia project. This 

initiative will utilize the strengths of the faith-based community to 

promote health and raise awareness about cancer prevention and early 

detection. The project, which was launched in September 2011 and 

will continue through August 2015, involves 20 churches across the 

five states. Participants at 10 of the churches (chosen at random) were 

invited to participate in a program that addresses physical activity and 

healthy food choices, while participants in the other 10 churches received 

education on cancer screening. In addition to measuring the effects of 

these interventions, the researchers will try to determine whether using 

churches to deliver these programs results in durable effects among the 

participants. Toward the end of the study period, the churches will switch 

programs, so the 10 that received the physical activity and healthy food 

choices program will also receive the screening program, and vice-versa. 

All participating churches will have the opportunity to participate in 

both programs.

The project led to a 28 percent increase in breast cancer screening among underserved 

residents of Indiana County during the intervention year. 
NATIONAL CANCER INSTITUTE | 49

Overall Cancer Incidence and Death Rates 

All Sites

Racial/Ethnic Group Incidence Death

All 465.2 178.7

African American/Black 489.5 216.4

Hispanic/Latino 353.7 146.3

American Indian/Alaska Native 328.9 156.2

White 471.7 177.6

Statistics are for 2005–2009, age-adjusted to the 2000 U.S. standard million population, and represent the number 

of new cases of invasive cancer and deaths per year per 100,000 men and women. 

 Native Americans:

•	 American Indians and Alaska Natives continue to have the poorest 5-year survival rates, 

among all racial and ethnic groups, for all cancers combined.

•	 Cancer is the second leading cause of death among Native Americans over age 45.

 Hispanics:

•		 For all cancers combined, and for the most common cancers (prostate, female breast, 

colorectal, and lung), age-adjusted incidence and death rates are lower among Hispanics 

than among non-Hispanic whites. 

•	 Cancers for which rates are higher in Hispanics than in other racial or ethnic groups include 

those of the stomach, cervix, liver, and gallbladder, and acute lymphocytic leukemia.

•	 Although Hispanics have lower incidence and death rates than non-Hispanic whites for the 

most common cancers, they are more likely to be diagnosed with a more advanced stage of 

disease.

•	 Statistics reported for Hispanics overall may mask wide variations in the cancer burden for 

specific populations according to country of origin.

African Americans:

•	 African American/black men have the highest incidence rate for prostate cancer in the 

United States and are more than twice as likely as white men to die of the disease.

•	 In the United States, white women have the highest incidence rate for breast cancer, 

although African American/black women are most likely to die from the disease.

•	 African American/black men and women have the highest incidence and death rates for 

both colorectal and lung cancers.
50 | NATIONAL CANCER INSTITUTE

The Frederick National Laboratory 

for Cancer Research

The Frederick National Laboratory for Cancer Research (FNLCR) was established in 1971 

under the National Cancer Act to provide rapid response capabilities and one-of-a-kind 

resources for the biomedical research community. Its scientists develop technologies and 

perform studies to support NCI’s mission, as well as the work of other NIH institutes. Like 

Los Alamos, Brookhaven, Sandia Labs, and others, it is a Federally Funded Research and 

Development Center (FFRDC), using this special contract with SAIC-Frederick, Inc., to cut 

red tape and bring public and private partners to the table swiftly to undertake difficult 

medical research. Changes in how NCI and the biomedical community conduct and support 

research, however, and the kind of research that characterizes contemporary science, have 

created an opportunity to re-envision the role of a national laboratory devoted to cancer 

research. For this purpose, NCI recently established an advisory committee to help identify 

new projects and emerging needs that might benefit from the processes and resources 

available at Frederick. The committee, chaired by Zach W. Hall, Ph.D., former executive vice 

chancellor for research at the University of California, San Francisco, requested at its first 

meeting that NCI develop a strategic plan for FNLCR designed to achieve the full potential of 

the capabilities made possible through its designation as an FFRDC. 
NATIONAL CANCER INSTITUTE | 51

In the 1980s, early in the HIV/AIDS epidemic, medical progress reached 

a critical technological impasse: HIV had been identified as the virus that 

causes AIDS, but what stymied medical investigators was how to grow 

the virus quickly and in sufficiently large quantities for pharmaceutical 

companies to develop a diagnostic test to determine whether a patient—

or a potential blood donor—carried HIV. 

As it happened, NCI scientists were well versed in tumor virus culture 

from work they’d already done on similar retroviruses that cause cancer. 

So the nation turned to NCI to solve this problem, and NCI turned to its 

Frederick National Laboratory for Cancer Research for solutions. FNLCR 

shifted gears in its virus production facility from churning out virus on 

their current project to churning out HIV. NCI partnered with five private 

companies, with which it shared the HIV viruses, and in less than a 

year this public-private effort had produced a validated FDA-approved 

blood test for HIV. Access to the blood test changed the trajectory of 

the epidemic because the blood supply could finally be protected from 

products containing HIV, and people were once again willing to receive 

donated blood. The blood test has also been used to identify people in the 

general population who are infected with HIV.

This is the kind of fast-response, one-of-a-kind research for which 

the FNLCR was created. “Our work benefits the greater scientific 

community,” said David Heimbrook, Ph.D., who became chief 

executive officer of SAIC-Frederick, Inc., the contractor that 

manages FNLCR, in 2011 (see Q&A on p. 59). “We provide 

solutions to move their science forward.” 

FNLCR remains ready to respond to such emerging priorities, 

acting as a test bed for new technologies and novel research 

concepts in genomics, proteomics, imaging, high-performance 

biomedical computing, nanotechnology, and others. Leaders 

at NCI and SAIC-Frederick are exploring new opportunities or 

challenges that could be addressed through FNLCR’s ability to 

marshal people and expertise.

A Place and a Way of Doing Business

Located on the Fort Detrick campus in Frederick, Maryland, (about 18 

miles northwest of the main NIH campus), FNLCR is a government-owned 

facility that is currently operated largely through a contract with SAICFrederick, Inc. Approximately 1,900 SAIC scientists and technicians 

at the facility perform a range of highly specialized research functions, 

several of which are described below, that give NCI the capacity and 

flexibility to respond quickly as new priorities emerge. 

The FNLCR campus also houses approximately 800 NCI staff members, 

including 80 principal investigators from NCI’s Center for Cancer 

Research whose work focuses on genomics and proteomics, structural 

biology, signaling, gene regulation, and other areas. 

Craig Reynolds, Ph.D. (left), 

associate director of the 

Frederick National Laboratory 

for Cancer Research, and 

David Heimbrook, Ph.D., 

chief executive officer of 

SAIC-Frederick.

Above: Budding HIV particles. 

Colored scanning electron 

micrograph (SEM) of HIV 

particles (yellow) budding from 

the membrane of the host cell 

(blue). 
52 | NATIONAL CANCER INSTITUTE

After NCI, the largest user of FNLCR’s services is the National Institute 

of Allergy and Infectious Diseases, which relies on FNLCR to support 

its efforts to develop and test vaccines for HIV, influenza, and other 

infectious diseases. 

FNLCR is more than a collection of research facilities up the road from 

Bethesda. The “glue” that makes FNLCR a national laboratory instead 

of just another research campus lies in the contracting mechanism 

enabled by the laboratory’s status as a Federally Funded Research and 

Development Center (FFRDC). 

FFRDCs are independent nonprofit entities sponsored and funded by the 

U.S. government to meet specific long-term research and development 

needs that cannot be met by any other single organization. FFRDCs 

typically assist government agencies with scientific research and analysis, 

systems development, and systems acquisition. They bring together 

the expertise and outlook of government, industry, and academia to 

solve complex technical problems. FFRDCs are typically operated by 

a university, nonprofit parent organization, or an industrial firm in 

accordance with statutory and regulatory rules, and these organizations 

act as the government agency’s strategic partner. 

First established during World War II, FFRDCs operate in the industries 

of defense, energy, aviation, space, health and human services, and 

tax administration. There are currently 39 FFRDCs funded by the 

government. Examples are the Argonne National Laboratory, Brookhaven 

National Laboratory, Lawrence Berkeley National Laboratory, Los Alamos 

National Laboratory, and Sandia National Laboratories. FNLCR is the only 

FFRDC operated by the Department of Health and Human Services, and 

the only one dedicated exclusively to biomedical research.

Unlike a typical contract that has a defined statement of work, an FFRDC 

has a broad charter that provides flexibility without the need to issue 

change orders as projects are added, terminated, or revised. Where speed 

and timeliness are required, or a special skill set needs to be pulled 

together quickly to address a scientific challenge, the FFRDC can turn 

on a dime to provide the tools and environment scientists need to move 

forward. Among the areas where the FFRDC mechanism has proved 

helpful are developing prototype drugs for testing; supporting regulatory 

approval for new drugs, vaccines, and other therapies; setting standards 

for nanotechnology applications; generating large amounts of clinicalgrade vaccines; and developing genetically engineered mouse models for 

research use. 

Here, we focus on a handful of programs currently operated under FFRDC 

authority for NCI and the research community: the Nanotechnology 

Characterization Laboratory, the Biopharmaceutical Development 

Program, core facilities on the campus, the Natural Products Branch, 

the Vaccine Pilot Plant, the Core Genotyping Facility, and the Advanced 

Technology Research Facility.
NATIONAL CANCER INSTITUTE | 53

Nanotechnology Characterization Laboratory 

The relatively new science of nanotechnology enables scientists to study 

and manipulate molecules to detect cancer-related molecules in the body 

and devise new anticancer therapies. With excitement over the potential 

opportunities of nanotechnology came many questions. The nanoparticles 

can carry drugs or imaging agents through the body directly to tumor 

cells while hiding them from the immune system and keeping them away 

from healthy tissue. But how would these particles—so small that 8,000 

of them side by side would equal the thickness of a human hair—act in 

the body? What were the safety issues? No one had the answers, or even 

knew how to get them. As scientists at universities, small businesses, 

and biotech companies began sending proposals to FDA for the testing of 

nanotech drug delivery systems in humans, the field hit a wall. FDA told 

the developers they would have to figure out how to do safety testing. 

To break the logjam and move the field forward, FNLCR was tasked with 

determining how to get these unique compounds—which combine a 

physical particle and a drug—into clinical trials. The FNLCR launched 

the Nanotechnology Characterization Lab (NCL) as part of NCI’s Alliance 

for Nanotechnology in Cancer in a formal collaboration with the FDA and 

the National Institute of Standards and Technology (NIST) to perform 

preclinical efficacy and toxicity testing of nanoparticles. The NCL 

characterizes the particle’s physical attributes and biological properties, as 

well as certain biological effects that can be measured in animal models. 

More than 250 nanomaterials have been characterized from more than 75 

collaborators (90 percent non-governmental). Five nanomaterials are now 

in clinical trials, according to Piotr Grodzinski, Ph.D., director of NCI’s 

Office of Cancer Nanotechnology Research. 

Nanotechnology also offers opportunities to resurrect cancer drugs that 

have failed during development because of toxicity. Nanoparticles can be 

used to encapsulate or carry very toxic drugs and deliver them directly to 

the tumor, breaking down and releasing the drugs only once they are out 

of the general bloodstream, so the drugs affect only the cancer cells. For 

example, NCL tested CytImmune Sciences’ Aurimune, gold nanoparticles 

with tumor necrosis factor (TNF) bound to their surface. TNF is a potent 

chemotherapeutic agent that was tested in clinical trials in the 1990s, but 

its development was stopped because of adverse side effects. In a recent 

phase 1 clinical trial of Aurimune, however, researchers were able to 

safely direct up to three times what had previously been a lethal dose of 

TNF directly to tumors, avoiding most of the negative side effects that 

plagued direct administration of the drug. 
54 | NATIONAL CANCER INSTITUTE

Biopharmaceutical Development Program

The Biopharmaceutical Development Program makes novel antibodies 

and other proteins that require early development or aren’t ready for 

industry to take on. The program’s biopharmaceutical production and 

testing facilities are compliant with current FDA guidelines for good 

manufacturing practices. For example, FNLCR is manufacturing a 

monoclonal antibody to treat advanced forms of neuroblastoma, a cancer 

of nerve tissues that primarily affects children. The monoclonal antibody, 

called ch14.18, was first tested in NCI-supported early-phase trials. 

A later phase 3 multicenter study led by the Children’s Oncology Group 

showed that immunotherapy with ch14.18, in combination with three 

other agents, significantly improved patient survival. (Two-year eventfree survival was 66.5 percent in the experimental treatment group versus 

46.5 percent in the standard therapy group without ch14.18.) FNLCR is 

manufacturing ch14.18 to meet an immediate need for the antibody while 

the production process is transferred to a commercial pharmaceutical 

manufacturer (United Therapeutics Corp.). 

Core Facilities

The core facilities at FNLCR can do many things that an individual 

investigator’s lab generally cannot. For example, NCI bought every 

commercially available drug, as well as about 30 drugs that were not 

commercially available, and ran them through a panel of 60 different 

human tumor cell lines, representing leukemia, melanoma, and cancers 

A technician at the Frederick 

National Laboratory for Cancer 

Research prepares test plates 

containing samples of the 

NCI-60, one of the most

commonly used sets of cell 

cultures in cancer research, 

for reading.
NATIONAL CANCER INSTITUTE | 55

of the lung, colon, brain, ovary, breast, prostate, and kidney (the NCI-60). 

They made the data available to help researchers choose the most 

promising drugs to test against different types of cancer. Anyone who 

wants to do an experiment with drug X can see what concentration to use 

and where to begin. FNLCR went a step further and reformulated many of 

the drugs so their quality is controlled, and is giving away test samples of 

the drugs so researchers can study them in cell lines.

Natural Products

Of approximately 170 antitumor drugs approved worldwide 

since the 1930s, more than 65 percent are derived from 

natural products, ranging from deep-sea sponges to the 

flowers and insects of our planet’s jungles and rainforests. 

More than 50,000 plant samples and 10,000 marine 

invertebrates and marine algae have been collected with 

partners worldwide and are stored at FNLCR. Because 

many of these compounds are difficult to work with, 

NCI sent large numbers of extracts to the NCI-designated 

cancer center at the Sanford-Burnham Medical Research 

Institute in La Jolla, California, where researchers made 

them soluble and dispersed them into plates to be used for 

screening drugs. Now extracts from the repository—considered a 

national resource—are being made in 1,584-well plates, and will be 

available in the future for distribution to qualified organizations. 

Vaccine Pilot Plant

FNLCR helps develop vaccines for some of the world’s most devastating 

infectious diseases, including AIDS, influenza, and possible bioterrorism 

agents. After September 11, 2001, the White House and the Department 

of Health and Human Services asked NIH to enhance its capacity to 

make vaccines for emerging infectious diseases, including Ebola, HIV, 

and SARS, as well as for biodefense. FNLCR quickly set up the capacity 

to make pilot-scale vaccines for testing before moving into large-scale 

commercial production. Working with the Vaccine Research Center of 

the National Institute of Allergy and Infectious Diseases, the facility has 

developed several next-generation vaccines, including vaccines for SARS, 

Ebola, and West Nile Virus. “Many vaccines coming out of NIAID come 

through the Vaccine Pilot Plant at FNLCR,” said Craig Reynolds, Ph.D., 

associate director of FNLCR.

The Core Genotyping Facility

The Core Genotyping Facility at FNLCR provides researchers with tools 

to explore the role of genetic variation in cancer risk and outcome. It is 

one of several ways that FNLCR supports NCI’s molecular and genetic 

epidemiology studies. Through genome-wide association studies (GWAS), 

researchers scan the entire genome looking for small variations (known as 

single nucleotide polymorphisms, or SNPs) that occur more frequently in 
56 | NATIONAL CANCER INSTITUTE

people with a particular disease than in people without the disease. From 

these associations emerge hypotheses about how the underlying disease is 

caused, and therefore how it might be treated.

Under FNLCR, the Core Genotyping Facility has genotyped nearly 70,000 

subjects, including participants in large, NCI-supported epidemiologic 

studies such as the Prostate, Lung, Colorectal and Ovarian cancer screening 

trial, according to Stephen Chanock, M.D., director of the Core Genotyping 

Facility and chief of the NCI Laboratory of Translational Genomics, both 

within the NCI Division of Cancer Epidemiology and Genetics (DCEG). 

DCEG investigates the etiology of cancer by examining known risk 

factors, such as smoking habits or body mass index, together with genetic 

variations to assess cancer risk. The division’s GWAS studies investigate the 

contribution of germline DNA, the constitutional DNA that people inherit 

from their parents, to the risk of developing various types of cancer.

“We needed to ramp up to genotyping and other assay capacity for largescale population-based studies,” said Peggy Tucker, M.D., director of 

the Human Genetics Program in DCEG. “To do so, we needed a capable 

and flexible group of scientists who could essentially industrialize 

the boutique assays that were done in academic labs and do them 

reproducibly, efficiently, and with cost savings. FNLCR has given us 

this important capability.” 

Riverside Research Park, Frederick, MD., 

showing the existing buildings and proposed 

development.
NATIONAL CANCER INSTITUTE | 57

Advanced Technology Research

Facility in Riverside Research Park, 

Frederick, MD.

DCEG researchers have engaged in large-scale collaborations with 

extramural investigators to conduct GWAS research on a range of cancers 

that include lung, prostate, renal cell, and urinary bladder cancers, as well 

as other common and uncommon cancers. “To date, we have completed 

about 12 GWAS studies, with a number still in the pipeline,” Tucker said. 

“All of the genotype data are made available to investigators. We receive 

about 500 requests each year for this information.”

Advanced Technology Research Facility

The Advanced Technology Research Facility (ATRF) is a new 

330,000-square-foot facility that opened in the summer of 2012. Located 

5 miles from the FNLCR campus, the leased facility will consolidate 

many of FNLCR’s high-tech resources, including biologics manufacturing, 

nanotechnology, sequencing, genomics, and informatics. About 60 

percent of the space will be occupied by SAIC-Frederick programs 

and about 11 percent by NCI’s intramural research programs and other 

federal programs. The remaining space will be made available to outside 

entities—such as industry, academic, and nonprofit groups—to pursue 

partnerships that leverage the ATRF’s resources and expertise to rapidly 

translate the latest genetic and molecular discoveries about cancer into 

new treatments. 

“By consolidating our work in a state-of-the-art facility, and by setting 

aside space for outside partners to work with us side-by-side, we hope 

to see stronger interactions and cross-fertilization of ideas,” said David 

Heimbrook, Ph.D., chief executive officer of SAIC-Frederick. (See sidebar 

on page 59.) 

The ATRF, which sits on 33 acres, is part of the 177-acre Riverside Research 

Park. The ATRF is the anchor tenant for the park, and NCI has temporary 

right of refusal for other companies that want to build within the 33 acres. 

The park’s developer hopes to add a state-supported technology incubator 

and higher education center. A Charles River Laboratories animal facility is 

located adjacent to the site.
58 | NATIONAL CANCER INSTITUTE

The Future of FNLCR

The current suite of research and other activities at FNLCR is broad and 

hits many of the critical areas of science that NCI invests in. Programs like 

ATRF, however, signal that the new focus of FNLCR is on what lies in the 

future: What will be the emerging issues or challenges for the national lab 

in the next decade and beyond? The newly established advisory committee 

for the FNLCR will have both a short-term role in helping to develop 

a strategic plan to guide FNLCR and a continuing role to identify new 

projects and new collaborations that could use the FFRDC approach to gain 

efficiencies and expand capacities for biomedical research, said Reynolds. 

In particular, the committee is interested in finding the best role for FNLCR 

in a rapidly changing research environment. Unlike many of the other 

FFRDCs across the federal government, FNLCR doesn’t have a 

unique core facility like a reactor or light beam source 

to pin its mission to. But the tremendous challenges 

inherent in cancer genomics, for example—storing 

the tsunami of data coming in from sequencing 

thousands of tumors, annotating the information, 

and making it available to researchers at many 

institutions in accessible common formats—

offer one potential area of exploration for an 

expanded opportunity at FNLCR. 
NATIONAL CANCER INSTITUTE | 59

David Heimbrook 

The new chief executive officer of SAIC-Frederick 

brings a depth of knowledge of drug development 

and project oversight in the pharmaceutical industry. 

David Heimbrook, Ph.D., was the global head of 

discovery for the Oncology Discovery and Translation 

Area of Hoffman-LaRoche, Inc. He was responsible 

for developing and implementing Roche’s oncology 

research strategy, including personalized health 

care and partnering relationships, and supporting 

development of compounds through clinical proofof-concept to pivotal registration studies. Heimbrook 

previously held positions with Merck Research 

Laboratories and Smith Kline & French Laboratories.

What surprised you when you arrived at FNLCR in 

May 2011? 

I was inspired by the dedication of the scientists at 

the bench level and the sense of collaboration and 

shared mission among the NCI scientists and the SAICFrederick scientists. I found that to be invigorating. 

What are your goals for FNLCR?

Like all of my colleagues here, I’d like to expand our 

impact on translating research, development, and 

diagnostic discoveries into meaningful benefits for 

patients afflicted with cancer and AIDS. One way we 

can help achieve this is to streamline some of the 

processes and remove barriers to communication 

and collaboration, both internally and externally. For 

example, it is apparent that many potential external 

partners don’t understand the opportunity for 

collaboration with FNLCR. The FFRDC structure provides 

some distinctive approaches, and we have to exploit 

those.

How is genomics research helping drug development?

We now understand that diagnosing and treating cancer 

based on its location in the body and its physical 

appearance are inadequate. Molecular examination of 

the patient’s tumor can provide insights on what caused 

it and what maintains it, and therefore how to treat it. 

We’re linking treatment with particular drugs to genetic 

mutations that exist within a patient’s tumor. This 

can provide better safety and efficacy for the patient, 

because if the patient doesn’t have the matching profile, 

we don’t treat with the drug—the patient is not exposed 

to the risk or the cost of a drug that won’t help them, 

and other treatment options can be considered. We’re 

seeing more examples of “precision medicine” coming 

to fruition. It’s not a concept anymore; it’s happening. 

I’m not saying that all cancers will submit to this type 

of approach. We’re a long way from having that detailed 

level of understanding of most cancers, and we don’t 

have drug candidates for many different potential 

targets. Genomics is only part of the story. There is 

regulation of cell growth and survival at many levels. 

Even when we can genetically match a patient and a 

drug, responses often aren’t durable. The cancer picks 

up other mutations as it goes. This was evident in a new 

melanoma drug that I was fortunate enough to work 

on at Roche. But the pace of discovery is accelerating. 

Programs like The Cancer Genome Atlas will provide 

much more insight into the genetic variability in many 

different types of cancer, and we have to distill this 

information into actionable targets. The global cancer 

research and development community is generating 

an armamentarium of small molecules and biologics 

targeting specific proteins. And in some instances, FDA 

is allowing physicians to combine unapproved drugs in 

trials to try to achieve more durable responses. All of 

these efforts should accelerate the pace of translating 

biological knowledge into meaningful therapies for 

patients.

You were a cancer researcher in industry for 25 years. 

What changes have you seen?

It’s an exciting time in cancer research and drug 

discovery. Really transformational, and it’s been a 

long time coming. Twenty-five years ago, there wasn’t 

much evidence that all of the investment in cancer 

cell biology would translate into new drugs, but now 

that’s happening. Industry has also changed. There is 

recognition that internal research and development 

alone are insufficient to drive the bottom line, even 

in the companies that do it best. So, there is now 

much more focus on partnering and collaboration, 

and investment overseas. This increases the diversity 

of ideas while keeping costs down. The enthusiasm 

for partnerships is a big opportunity for academics, 

biotechs, and NCI. This is one reason why the new 

Advanced Technology Research Facility at FNLCR is so 

important: Its shared partnering space is specifically 

designed for collaboration. We hope that it will help 

catalyze the next wave of research—therapeutic and 

diagnostic discoveries that will benefit cancer patients. 

That’s why we’re here.
60 | NATIONAL CANCER INSTITUTE

Small Business Innovation Research, Small 

Business Technology Transfer (SBIR, STTR)

Catalyzing the translation of cancer research into technologies and products for the benefit 

of patients involves the collaboration and engagement of both public and private sectors. 

Small businesses are an important part of the cancer research enterprise. Small businesses 

are not only vital to the U.S. economy, providing jobs for over half of the nation’s private 

workforce, but they are also key drivers in cancer research. Congress created, and recently 

expanded, the Small Business Innovation Research (SBIR) and Small Business Technology 

Transfer (STTR) Programs to strengthen the role of small businesses in fostering research and 

development (R&D) and to facilitate the commercialization of technologies across a range of 

industry sectors.
NATIONAL CANCER INSTITUTE | 61

A

t the NCI, small businesses and research institutions foster R&D 

in a variety of cancer-related areas, including anticancer agents, 

diagnostics, health information technologies, medical devices, 

and imaging technologies. This work is conducted by small 

biotech companies with strong scientific and business expertise, 

but without the access to capital needed to fund the translation and 

ultimate commercialization of the technology. To address this problem 

and accelerate technological innovation in cancer, NCI takes an active 

role in supporting small companies and research institutions through 

grants, contracts, partnership development, and small business support. 

The ultimate goals of the NCI SBIR & STTR Programs are to support NCI’s 

mission to reduce cancer incidence, morbidity, and mortality; extend 

survival; and increase the quality of life of cancer patients. 

For fiscal year 2013, federal agencies with extramural R&D budgets of 

more than $100 million are required to set aside 3.05 percent of their 

R&D budgets for SBIR/STTR contracts or grants to small businesses. The 

SBIR & STTR Reauthorization Act of 2011 will gradually increase the setaside amounts to 3.65 percent by 2017, and expand eligibility to include 

small businesses majority-owned by venture capital operating companies, 

hedge funds, or private equity funds in 2013.

The NCI Portfolio

In FY2012, NCI provided more than $115 million in seed funding to 

support nearly 400 early-stage projects focused on cancer technology 

development. Over 40 percent of these projects are developing targeted 

therapeutic agents or devices for cancer therapy; and 38 percent are 

developing diagnostic and imaging technologies to support early detection, 

treatment planning and stratification, monitoring, and secondary 

prevention. About 19 percent of the portfolio is devoted to cancer biology 

to advance cancer research tools and to cancer control and epidemiology to 

advance primary prevention. (See Figure 1.)

Therapeutics 32%

Devices for Cancer Therapy 11%

Imaging 14%

In Vitro Diagnostics 24% 

Cancer Biology 8%

Cancer Control and Epidemiology 11% 

Figure 1. The NCI SBIR Portfolio
62 | NATIONAL CANCER INSTITUTE

NCI’s SBIR portfolio aims to stimulate small business 

involvement in several areas: development of small 

molecule drugs and biologics, cancer diagnostics, 

cancer imaging, and electronic health and education 

tools.

One of NCI’s SBIR grant recipients, Acoustic 

MedSystems, Inc. (AMS) in Champaign, Ill., is 

developing a minimally invasive technology to destroy a 

tumor, while minimizing harm to healthy tissue nearby. 

These devices deliver high-intensity ultrasound energy 

to targeted areas. The technology is being tested 

for treating tumors in a wide range of soft tissues, 

including the kidneys, liver, cervix, prostate, brain, and 

breast, as well as metastatic spine tumors, multiple 

myeloma, and uterine fibroids. Devices are planned for 

lung and bladder cancers as well.

For cancers in the kidneys and liver, the approach 

involves a needle that is guided by real-time imaging. 

High-intensity ultrasound is delivered through the 

needle into the tumor. In animal studies, the device 

kills the tumor without harming nearby tissue. A similar 

approach is used for targeting metastatic spine tumors 

using a different device configuration. For cervical or 

colorectal cancers, the ultrasound is delivered through 

a transvaginal or transrectal applicator probe.

According to founder and CEO Clif Burdette, Ph.D., 

“The SBIR & STTR programs have been pivotal to the 

development of nearly every product by our company. 

Without the initial support of the SBIR program, 

most of the medical products that our group has 

commercialized would not have been developed.” 

AMS has leveraged its $6.8 million in NIH SBIR 

($6.1 million contributed by NCI) funding to attract 

$11 million in private financing and more than 

$19 million in non-federal revenue from products 

and services since 2000.

Targeting cancer cells and sparing 

healthy tissue 

In addition to providing funding through SBIR & STTR, NCI created an 

SBIR Development Center to provide strategic and partnership development 

support to SBIR & STTR award recipients, mentor awardees throughout 

the SBIR grant/contract on their technology goals and commercialization 

strategy, and assist them in finding follow-on investments. As part of 

efforts to help small businesses translate cancer research concepts to the 

commercialization stage, the NCI SBIR Development Center created the 

NCI SBIR Investor Forum to bring together 200 investors, strategic partners, 

and SBIR awardees. Participating SBIR companies in a recent forum 

secured additional funding and strategic partnerships worth up to $230 

million, an amount that is twice the value of the entire NCI SBIR & STTR 

Programs budget. The SBIR Development Center is focused on attracting 

top small business applicants; driving innovation in emerging, high-impact 

technology areas; and providing the support needed to help stimulate novel 

approaches to cancer control and care to help patients in need.
NATIONAL CANCER INSTITUTE | 63

The California-based company Advanced Cell 

Diagnostics (ACD) is using SBIR funding to translate 

its RNAscopeTM technology to detect and profile at 

the molecular level circulating tumor cells (CTCs) 

(see related story p. 42). In contrast to current 

CTC detection technology that is protein-based, 

RNAscopeTM, an automated system launched in 2008, 

is a technology capable of detecting messenger 

RNA molecules in individual cells with very high 

sensitivity and specificity. Multiple RNA targets can 

be detected and measured simultaneously. ACD is 

now working to adapt the tool as a way of scanning 

the gene expression phenotype of CTCs from cancer 

patients. Already, tests of RNAscopeTM have shown 

that it can detect differences in messenger RNA 

profiles between normal tissues and tumor tissue 

specimens from patients with breast, cervical, and 

head and neck cancers. The next generation version 

of this technology, CTCscopeTM, is an automated 

assay designed to specifically look simultaneously 

at as many as 11 distinct messenger RNAs in order to 

better understand and predict CTC biology, and make 

correlations. Unlike current CTC detection technology, 

CTCscopeTM does not require a step to concentrate 

CTCs, avoiding the potential loss of important CTCs in 

the sample. In addition, CTCscopeTM detects live CTCs, 

the rare tumor cells that have the potential to form 

new tumors and are targets for therapy.

In San Diego, Epic Sciences, one of the first awardees 

of an SBIR contract focused on CTC analysis, is 

also developing technologies to improve CTC 

detection. Unlike the CTC scope, the Epic HD-CTC 

(High Definition-Circulating Tumor Cell) test does 

not require a step to concentrate or isolate CTCs, 

avoiding the potential loss of CTCs in the sample. 

The test has been able to find significant numbers 

of CTCs in patients with advanced prostate, breast, 

lung, and pancreatic cancer. Initial studies indicate 

that the Epic CTC test has been especially effective in 

detecting CTCs in metastatic lung cancer patients, a 

group in which it has been historically difficult to find 

significant numbers of CTCs. On top of its detection 

platform, Epic is developing assays to study the 

expression of key cancer genes in CTCs and detect any 

new mutations that appear during cancer progression. 

This information could be used to tailor the therapy 

to every patient. In a recent study, senior investigator 

Peter Kuhn, Ph.D. at Scripps Research Institute and cofounder of Epic Sciences, demonstrated that HD-CTC is 

capable of detecting CTCs even in patients with earlystage cancer, suggesting that the test may one day be 

used to diagnose cancer. 

Epic is collaborating with a number of academic 

partners, including researchers at Yale, the 

University of Texas M.D. Anderson Cancer Center, the 

Translational Genomics Research Institute (TGen), 

and Moffitt Cancer Center, as well as major companies, 

including Genentech, Pfizer, and Celgene to develop 

HD-CTC commercially for diagnostic products in 

personalized cancer care. In partnership with a major 

pharmaceutical company, Epic recently launched its 

first international clinical trial of the technology. 

Through these academic and pharma collaborations, 

Epic has tested their technology in more than 1,000 

patient samples from clinical trials.

Speeding development of technologies to detect and 

analyze circulating tumor cells 

Circulating Tumor Cells 

When a patient has cancer, a small number of cells may shed from 

the primary tumor and enter the bloodstream, leading to metastasis. 

Technologies that detect tumor cells circulating in the blood may offer 

a new avenue for diagnosing cancer and guiding treatment. 
64 | NATIONAL CANCER INSTITUTE

Company Location 

(Founding Year) 

Technology Description Why?

Omniox, Inc.

www.omnioxinc.com

San Francisco, CA (2006) Oxygen delivery technology 

(called H-NOX) that sensitizes 

tumors to radiation and 

chemotherapy.

Strong preclinical data showing that 

the lead candidate, in combination 

with radiation, leads to significant 

tumor growth delay and enhanced 

survival in mouse models. Major 

improvement over prior clinical efforts 

to re-oxygenate tumors. Approved for 

Phase IB clinical trials in glioblastoma. 

Etubics Corporation

www.etubics.com

Seattle, WA (2006) Immunization platform 

technology to generate 

therapeutic and preventive 

vaccines.

Completed Phase I and II clinical 

trials for an immunotherapeutic to 

treat colorectal cancer patients, and 

preparing to move to Phase III clinical 

trial. Additional immunotherapies 

are moving toward clinical trials 

for treatment of breast cancer. 

The Etubics platform solves issues 

involved with current adenovirusbased immunotherapy, including 

improved safety. 

Eutropics 

Pharmaceuticals

www.eutropics.com 

Boston, MA (2005) Development of a drug to 

trigger cell death specifically 

in cancer cells, along with a 

companion diagnostic tool to 

identify which patients will 

respond to this drug. Targeting 

multiple myeloma, small 

cell lung cancer, and ovarian 

cancer. 

Development of companion diagnostic 

tools along with therapeutics informs 

treatment decisions, guiding the use 

of the therapeutic to treat the right 

patients. The diagnostic assay in 

development may also be useful for 

other therapeutic drugs currently on 

the market that depend on cell death 

pathways. 

Presage 

Biosciences

www.presagebio.com 

Seattle, WA (2008) Device that can inject multiple 

drugs into a tumor at once. 

This technology allows the direct 

comparison of drug effects with each 

other, as well as the testing of drug 

combinations, to determine the most 

effective treatment for an individual. 

Presage is working with major 

oncology pharmaceutical company 

Millennium Pharmaceuticals to enable 

the identification of effective novel 

drug combinations to treat solid 

tumors.
NATIONAL CANCER INSTITUTE | 65

Company Location 

(Founding Year) 

Technology Description Why?

Firefly BioWorks, Inc.

www.fireflybio.com

Cambridge, MA (2009) Biomarker detection platform 

useful for diagnostic tests and 

discovery research, starting 

with detecting microRNA to 

diagnose cancer and other 

diseases.

First product, kit for detecting 

microRNA in life sciences research, 

has been launched commercially. The 

Firefly platform enables detection of 

clinically relevant biomolecules with 

an unprecedented combination of 

performance, flexibility, throughput, 

and cost. This technology lends itself to 

simple bedside or handheld devices for 

early disease detection or point-of-care 

diagnostics.

Metabolomx

www.metabolomx.com

Mountain View, CA 

(2008) 

Breath test for lung cancer 

that is non-invasive, rapid, and 

inexpensive. 

Currently in clinical trials, this 

technology can detect lung cancer and 

other cancers in about 5 minutes, for 

less than $100, and non-invasively by 

“smelling” the chemical profile present 

in the bloodstream and picked up in 

exhaled breath.

Thermedical

www.thermedical.com

Somerville, MA (2008) SERFTM Ablation therapy uses 

heat to rapidly and completely 

remove large solid tumors. 

SERFTM Ablation therapy for liver 

cancer is under review by the FDA. 

This technology can treat tissue 

100 times the volume of tissue that 

conventional radiofrequency energy 

can heat, expanding treatment options 

to patients with larger tumors.

Gamma Medica

www.GammaMedica.com

Northridge, CA (2001) Gamma Medica’s FDA-approved 

LumaGEM® Molecular Breast 

Imaging (MBI) device can 

image cancer regardless of 

breast density, making it 

possible to detect cancer where 

mammography often misses it.

Gamma Medica has developed a 

commercially successful system for 

breast cancer secondary diagnosis, 

and is expanding the system’s use 

for breast cancer screening, biopsy 

and surgery guidance, and treatment 

monitoring. The cost of the system 

is less than 1/3 of MRI, and this 

technology can be applied to prostate, 

brain, and other small organ cancer 

imaging.

eMedonline

www.eMedonline.com 

Crystal Lake, IL (1990) Medication management 

system that uses smartphones 

and behavioral informatics 

to facilitate medication 

compliance. 

eMedonline integrates the patient, 

caregiver, and provider to monitor the 

status of a patient and provide timely 

feedback. Through randomized control 

clinical trials, it has demonstrated 

sustainable compliance levels of 

98 percent along with clinically 

significant improvements. More than 

38,000 doses have been successfully 

administered among a variety of 

patient populations.
66 | NATIONAL CANCER INSTITUTE

NCI Center for Global Health

Cancer doesn’t stop at national borders. Yet, there are differences in how any given cancer 

may manifest itself in different countries and different peoples, and science increasingly 

must confront cancer rates that vary from nation to nation, causes that are affected by living 

conditions, and screening and treatment options that are culturally appropriate in one region 

but not another. One fact, however, has become clear: We will not gain the upper hand on 

cancer unless we address it as a global public health problem.
NATIONAL CANCER INSTITUTE | 67

I

n 2008, nearly 7.6 million people died from cancer worldwide. By 

2030, the number of cancer deaths may be as high as 13.2 million, 

with more than two out of three deaths occurring in low-income and 

middle-income countries. More than 35 percent of these deaths may 

be preventable by controlling tobacco use, diet, and alcohol use, and 

by immunizing against infections that can lead to cancer—especially 

HPV, which is responsible for nearly all cases of cervical cancer and 

large percentages of anal, vulvar, and oropharyngeal cancers. Screening 

for breast, cervical, and colorectal cancer—when combined with 

effective treatments—can also prevent deaths from those diseases. 

In 2011, NCI established the Center for Global Health to coordinate and 

prioritize NCI’s research efforts that can have a direct impact on global 

cancer, primarily in low-income and middle-income countries. Ted 

Trimble, M.D., M.P.H., is director of the new center. 

The Center for Global Health will strengthen collaborations with other 

NIH entities, including the National Institute of Allergy and Infectious 

Diseases, which has large research programs overseas on infectionrelated cancers. NCI will work with the National Heart, Lung, and Blood 

Institute and the National Institute of Diabetes and Digestive and Kidney 

Diseases on issues related to overcoming obesity, an important cancer 

risk factor. In March 2012, the center convened a 2-day planning meeting 

with stakeholders from NCI and other federal agencies, as well as from 

academia and industry, to set priorities for global cancer research. 

“We have an opportunity to help people ward off diseases,” Trimble 

said, with benefits that will be felt abroad and within the United States. 

“We have the highest obesity rates in the world and our tobacco use rates 

remain stubbornly high. We can learn from other countries.” 

Combating cancer on a global level is also a priority for NCI’s director, 

Harold Varmus, M.D. The topic is getting extra attention, thanks to the United 

Nations’ new focus on non-communicable diseases in the developing world,

which began with a high-level forum held in September 2011. 

“I think everyone recognizes that it’s time to put cancer on the marquee 

for global health,” Varmus said.

Global Issues, Local Solutions

University of Chicago researcher Olufunmilayo “Funmi” Olopade, M.D., is 

one of a growing cadre of cancer researchers whose work takes place in the 

global cancer arena but whose ties are to NCI-funded programs in the United

States (see sidebar on p. 71). Her genetics and genomic studies of women in 

Africa have helped explain why African American women are more often 

diagnosed with breast cancer at younger ages than white women in the 

United States.

Ted Trimble, M.D., directs 

NCI’s Center for Global Health.
68 | NATIONAL CANCER INSTITUTE

Similarly, some NCI-designated cancer centers have been working to 

establish cancer control programs in developing countries in Africa 

and Latin America. Each of those cancer centers has made a long-term 

commitment to build sustainable programs that meet the needs of the local 

populations, several of which are described here. 

Fred Hutchinson Cancer Research Center in Uganda 

The Uganda Cancer Institute (UCI) in Kampala is the sole cancer treatment 

facility in a country of 32 million people. It was founded in 1967 through 

collaboration between the Ugandan Ministry of Health and NCI. 

The most common cancer 

in Ugandan children, 

Burkitt lymphoma, was 

first described in Kampala 

in 1957 by Irish surgeon 

Dr. Denis Burkitt, and 

studies by the UCI and 

NCI characterized the 

remarkable response of 

this tumor to combination 

chemotherapy. The UCI, 

in its early years, also 

conducted seminal research 

on Kaposi sarcoma and 

hepatocellular carcinoma, 

but the collaboration with 

NCI was halted in 1972 

amid political turmoil in Uganda. International collaborators returned to 

the UCI in the 1990s, and in 2004 the Fred Hutchinson Cancer Research 

Center began its close partnership with the UCI. In October 2011, the UCI/

Hutchinson Center Cancer Alliance broke ground for the first collaborative, 

comprehensive cancer training and outpatient treatment facility in subSaharan Africa.

Fred Hutchinson researcher Corey Casper, M.D., M.P.H., and colleagues 

are asking: What strategies can we find to deal with the enormous problem 

of cancer in low-income and middle-income countries? Three important 

cancers in Uganda are Burkitt lymphoma, which is caused by the EpsteinBarr virus, and two HIV-related cancers: Kaposi sarcoma and non-Hodgkin 

lymphoma. In Uganda, the problem is especially complex because more 

than 1.2 million Ugandans are living with HIV/AIDS. 

This problem led researchers to ask whether chemotherapy regimens for 

patients with non-Hodgkin lymphoma should be modified when the patient 

also has HIV. Their study revealed that among patients with NHL and 

HIV, four less toxic oral drugs offered the same outcomes as intravenous 

chemotherapy. 

Fred Hutchinson researcher 

Corey Casper, M.D., M.P.H.

(right).
NATIONAL CANCER INSTITUTE | 69

“We believe we can adapt regimens we use in the United States to be used 

in Uganda and make them equally effective,” Casper said.

Now the UCI/Hutchinson Center Cancer Alliance has set an ambitious goal: 

to improve survival rates for patients with Kaposi sarcoma from the current 

10 percent to 90 percent in 3 years. To succeed, they will have to overcome 

four obstacles: low knowledge of cancer among providers and the public, 

weak infrastructure and training, drug shortages, and a lack of supportive 

care. Right now, 90 percent of all cancer patients at the UCI are diagnosed 

with stage 3 or stage 4 cancer. To diagnose patients earlier requires 

improving the public’s knowledge of signs and symptoms of cancer. With 

Kaposi sarcoma, this is made easier because it usually presents as cancer of 

the skin. Providers and patients who are at highest risk for Kaposi sarcoma, 

those with HIV, can be trained to do skin exams and detect cancers at stage 

1 or stage 2. A better infrastructure requires more space and supplies and 

more well-trained health care providers. In 2004, there was a single cancer 

specialist in Uganda. Today, there are seven cancer specialists who have 

been trained through the NIH Fogarty International Center and NCI. By the 

end of 2012 there will be 11. The Ugandan Minister of Health has made 

a commitment to obtain chemotherapy drugs and make them available to 

patients. The final key is supportive care, Casper said. To survive cancer, 

patients have to survive treatment, which means preventing infection and 

making people comfortable during care. “If we do all four, we’ll have a 

meaningful impact,” Casper said. “In 3 years,” Casper continued, “we 

want to be able to show we’ve built capacity and that in the international 

setting, we can make meaningful progress in treating cancer and flip 

mortality rates—and that there are scientific advances to help people in 

the United States that justify the work we do overseas.”

University of North Carolina Lineberger Comprehensive 

Cancer Center in Malawi

The University of North Carolina (UNC) began its work in Malawi in the 

early 1990s. UNC has 17,000 square feet of laboratory space at Kamuzu 

Central Hospital in Lilongwe, with 250 Malawian employees. The original 

focus was HIV-related clinical trials in this impoverished country of 14 

million people in southeastern Africa. The core of the activity is still 

research on HIV, but they are using the existing research capacity to expand 

into cancer research. 

In 2006, UNC surgeon Carol Shores, M.D., Ph.D., traveled to Malawi to 

help obtain biopsies from children with Burkitt lymphoma. Through an 

NCI-supported grant, Shores and colleagues completed a proof-of-principle 

study, published in Clinical Cancer Research in April 2010, suggesting 

that a common chemotherapy, cyclophosphamide, can shift Epstein-Barr 

virus to a stage of its life cycle that is more susceptible to antiviral therapy. 

The group has completed a phase 1 study of the antiviral valacyclovir with 

cyclophosphamide in Burkitt patients. Their findings provide the rationale 
70 | NATIONAL CANCER INSTITUTE

for a trial testing synergistic tumor cell killing using cyclophosphamide 

with an antiviral drug. They also illustrate the importance of having cancer 

researchers on the ground in third-world countries, developing and testing 

new approaches to treatment. 

Training is another key component of the UNC/Malawi partnership. Today 

there are 25 surgeons in Malawi. UNC Surgery and Otolaryngology, in 

collaboration with Kamuzu Central Hospital, has established a surgery 

residency program, setting the stage to double the number of surgeons in 

the country in 15 years. The Malawian surgery residents are involved in 

research alongside U.S. trainees at Kamuzu. In August 2011, the program 

obtained full certification from the College of Surgeons of East, Central, 

and Southern Africa, so that training at Kamuzu is recognized throughout 

Africa and the European Union.

“Train Malawian surgeons to provide much-needed clinical 

care and these surgeons will become principal investigators in 

Malawi-based research projects, nurturing a sustainable, vibrant 

health care system,” said Shores. 

The Indiana University Melvin and Bren Simon Cancer 

Center in Western Kenya

Kenya spends $8.30 per person on health care each year. 

A system of such limited resources needs an approach that is 

heavy on “MacGyver moments,” said IU Simon Cancer Center 

director Patrick Loehrer, M.D., referring to the hero of a 1980s 

TV series about an always-inventive secret agent. They need to use 

their resources—including older, off-patent drugs and limited diagnostic 

capabilities—as efficiently as possible for the biggest benefit. Cervical 

cancer screening is a prime example. 

In 2001 a consortium of North American academic medical centers and 

the Moi University School of Medicine in Eldoret, Kenya, established the 

AMPATH program to combat HIV/AIDS in western Kenya. AMPATH—

Academic Model Providing Access to Healthcare—is supported by the 

United States Agency for International Development and delivers care to 

70,000 patients. Through the existing infrastructure, AMPATH-Oncology 

provides clinics in pediatric, adult, and gynecologic oncology plus cervical 

screening and palliative care. The program is run by Kenyans providing 

clinical care that is reinforced by research and education.

With help from Lineberger’s Division of Bioinformatics, UNC established 

the Kosciusko Community Hospital Cancer Database in September 2010. This 

Web-based system contains details on more than 1,800 cancer cases, including 

demographic data and information on site and histology of the cancer. The system 

will include treatment and outcome data in the future. 
 | NATIONAL CANCER INSTITUTE 71

Olufunmilayo “Funmi” Olopade

As director of the Center for Clinical Cancer Genetics at 

the University of Chicago Medical Center, Olufunmilayo 

“Funmi” Olopade, M.D., has been studying breast cancer 

in U.S. and in Nigerian women, learning how to better 

treat both.

When she began seeing patients in Chicago, the 

Nigerian-born Olopade saw differences among women 

with breast cancer. Her African American patients were 

more likely than white patients to be diagnosed at 

younger ages, and their cancers were more aggressive. 

She set out to learn why and eventually expanded 

her research to study breast cancer across the African 

diaspora. 

Her group found that breast cancers in African women 

exhibit a different pattern of gene expression than 

is seen in white women. Tumors in African women 

are more likely to be estrogen-receptor negative and 

originate from different cells within the breast. The 

tumors are also less likely to respond to many standard 

therapies. 

“We treat patients with cancer in this country who come 

from diverse backgrounds,” said Olopade. 

“Until we have a deeper knowledge and understanding 

of how cancer incidence and etiology vary 

geographically and how they affect the immigrant 

populations in this country, we’re never going to be 

able to reduce cancer health disparities.” 

In 2011, President Obama appointed Olopade to the 

National Cancer Advisory Board. “It’s really very 

exciting that NCI is taking global leadership in cancer 

research and investing in the new Center for Global 

Health. We should do research where the interesting 

problems are,” she said. Olopade is also an executive 

council member of the African Organization for 

Research and Training in Cancer, which aims to further 

research related to cancers prevalent in Africa, support 

the management of training programs in oncology for 

health care workers, address the obstacles to creating 

cancer control and prevention programs, and raise 

public awareness of cancer in Africa.

“It’s important to continue to advocate for more 

resources in cancer,” said Olopade. “If we continue with 

the trajectory we’re on, cancer will be the leading cause 

of death by 2030, even in Africa.” And many of those 

cancer deaths are preventable. 
72 | NATIONAL CANCER INSTITUTE

NCI-Designated Cancer Centers

Outside the Washington Beltway, when the public thinks about NCI or about cancer research more 

generally, chances are they’re thinking about research and care at one of the nation’s 67 NCIdesignated cancer centers. Represented in every region of the United States, these cancer centers—

established as a full-fledged program in the 1971 National Cancer Act—are NCI’s “boots on the 

ground” in conducting leading-edge basic research, driving informatics and genomic applications 

in cancer diagnosis and treatment, recruiting patients for clinical trials, and developing and testing 

new standards of practice in cancer screening, diagnosis, treatment, and care.

Alexis Nees, M.D., (foreground) and Lisa Newman, M.D., M.P.H., 

University of Michigan Comprehensive Cancer Center.
NATIONAL CANCER INSTITUTE | 73

NCI’s 67 designated cancer centers, located in 34 states 

plus the District of Columbia, form the national 

backbone of the institute’s programs for studying 

and controlling cancer. The centers are the primary source of new 

discoveries into cancer’s causes, prevention, diagnosis, and treatment. 

They deliver up-to-date care to patients and their families, inform health 

care professionals and the general public, and offer the potential to 

reach many diverse, and often underserved and understudied, patient 

populations. Every state with a density of more than 150 people per 

square mile contains at least one NCI-designated cancer center.

Receiving that designation is no small achievement. The qualification 

process is stringent, involving an intense and thorough review. Cancer 

centers receive a core support grant from NCI, in addition to the substantial

funding for cancer research the centers obtain from other competitive 

grants and contracts with NCI and other sources, both public and private.

NCI offers two designations: Cancer Center and Comprehensive Cancer 

Center. A Cancer Center has a scientific agenda focused on one of 

three major areas—laboratory, clinical, or population science—or some 

combination of the three. The Comprehensive Cancer Centers have 

depth and breadth of research activity in all three areas and also must 

demonstrate a commitment to public education and dissemination of 

advances into the communities they serve, as well as continual education 

of professions responsible for cancer care. Forty-one of the NCI-designated 

cancer centers are Comprehensive Cancer Centers and 26 are Cancer 

Centers. Of the 26, seven centers conduct only basic research and offer no 

clinical programs.

The centers are continually updating and reshaping themselves to take 

advantage of new scientific opportunities, with particular emphasis today 

on the genetic and genomic underpinnings of cancer, clinical trials of new 

therapies, and the bioinformatic tools and technologies that make fruitful 

the huge volumes of data emanating from laboratories. They work along a 

continuum, from basic research to translational studies that bridge the lab 

and the clinic, as well as with long-term observation studies and outreach. 

NCI-designated cancer centers are unique because of their 

interdisciplinary nature, says Linda Weiss, Ph.D., director of NCI’s Office 

of Cancer Centers. “The collaborative environment created at each cancer 

center—and across cancer centers—fosters creativity that helps move 

science forward.” 

Collaboration between centers is proving particularly valuable in the area 

of cancer genomics. Researchers at the University of New Mexico Cancer 

Every state with a density of more than 150 people per square mile contains at 

least one NCI-designated cancer center.
74 | NATIONAL CANCER INSTITUTE

NCI’s 67 designated cancer centers, 

located in 34 states plus the District of 

Columbia, form the national backbone 

of NCI’s programs for studying and 

controlling cancer. 

Center, for example, observed a significant increase in acute lymphoblastic 

leukemia (ALL) among their pediatric Hispanic population. Knowing that 

ALL patients of Hispanic or of American Indian genetic ancestry have 

historically experienced some of the disease’s worst outcomes, the New 

Mexico scientists turned to comprehensive genomic and gene sequencing 

methods in the hope they could identify new mutations that might be 

causing the high-risk disease and therapeutic resistance they were seeing in 

their patients. Working with the Children’s Oncology Group, a cooperative 

research organization sponsored by NCI and St. Jude Children’s Research 

Hospital in Memphis, Tenn., the team employed several NCI-supported 

tools and initiatives, including TARGET, TCGA, and Strategic Partnering to 

Evaluate Cancer Signatures (SPECS). The team of investigators discovered 

a unique mutation in a gene called CRLF2 (cytokine receptor-like factor 2), 

which is strongly associated with Hispanic ethnicity and American Indian 

ancestry, as well as mutations in a gene called JAK. They are now studying 

novel therapeutics to target these mutations and, with the Children’s 

Oncology Group, have opened new clinical trials testing targeted therapies 

for these mutations.

This spirit of collaboration is especially strong in the many NCI-designated 

cancer centers that are embedded with America’s largest research 

universities. For them, collaboration begins with inter-departmental 

linkages.

The Massachusetts Institute of Technology (MIT) has had a cancer center 

focused on basic research that has been designated by NCI since 1974. 

In 2007, it became the Koch Institute for Integrative Cancer Research at 

MIT, with a novel plan to combine the faculty of the center with an equal 

number of MIT engineers. Today, the work of that faculty includes efforts to 

develop systems to deliver drugs to cancer cells more effectively, designing 

new agents to perturb the cancer cell, and modifying cells to improve 
NATIONAL CANCER INSTITUTE | 75

the body’s response to therapy. MIT’s Robert Langer, Sc.D., has created 

nanoparticles that are “smart bombs” embedded with high concentrations 

of cancer drugs—on the order of 10,000 to 100,000 drug molecules per 

nanoparticle. The outside of the particle is decorated with materials that 

allow it to travel unnoticed through the body. Then, tags on the surface of 

the nanoparticle bind to the surface of the cancer cells. A phase 1 safety 

trial conducted by Bind Biosciences, a company launched by MIT and 

Harvard scientists, began in January 2011. 

MIT researchers are also trying to figure out how to use small RNAs, 

which are key regulators of gene expression and genome function, to 

inhibit gene function and stop a tumor. “I’m extremely optimistic that 

we will get small RNA therapies to work for cancer,” said Koch Institute 

director and National Cancer Advisory Board member Tyler Jacks, Ph.D. 

“It’s not a brand new idea, but the challenges have been in their 

delivery. It’s an engineering problem and we’re working on that.” 

By combining nanomaterials with small interfering RNAs 

(siRNAs), short strands of RNA that can selectively intercept 

and destroy messenger RNA before it delivers its instructions, 

MIT’s Sangeeta Bhatia, M.D., Ph.D., tackled this problem 

with William Hahn, M.D., Ph.D., at Boston’s Dana-Farber 

Cancer Institute. Hahn determined which genes are relevant 

to an ovarian cancer cell’s survival and Bhatia devised 

a nanoparticle that, in mice with human ovarian cancer, 

successfully delivered siRNAs to silence one of those genes. It 

shrank the tumors and prolonged the lives of the mice. 

Tyler Jacks, Ph.D., Director, 

David H. Koch Institute for 

Integrative Cancer Research 

at MIT and chair of the NCI’s 

National Cancer Advisory Board.

The Koch Institute also has invested heavily in making the 

immune system a stronger ally to defend the body against cancer. 

Researchers such as Darrell Irvine, Ph.D., who has a materials science 

background, are using nanomaterials as a kind of “feedbag” attached to 

the immune system’s T cells. The nanomaterials help the T cells stay alive 

longer and resist the agents that tumors secrete to fight the immune system. 

In the laboratory, the researchers have demonstrated that these modified 

T cells are much more effective than regular T cells, and they are moving 

quickly toward clinical application. 

Clinical Trials

NCI-designated cancer centers have a proud history of leadership in clinical 

trials that have led to important advances in treatment and prevention. 

In 2011 alone:

•	A	study	led	by	scientists	from	Memorial	Sloan-Kettering	Cancer	Center	

in New York found that the combination of bevacizumab, a widely 

used anticancer drug, with standard chemoradiation is safe and could 

prolong survival in patients with advanced nasopharyngeal carcinoma.

•	A	study	led	by	researchers	at	the	Chao	Family	Comprehensive	Cancer	

Center at the University of California, Irvine, showed that combining 
76 | NATIONAL CANCER INSTITUTE

two anti-estrogen drugs, anastrozole and fulvestrant, extended the 

median survival time of women with hormone receptor-positive 

metastatic breast cancer by more than 6 months, compared with 

those who underwent standard treatment with anastrozole alone.

•	Researchers	at	the	University	of	California,	San	Francisco,	Helen	Diller	

Family Comprehensive Cancer Center and colleagues reported that the 

HPV vaccine can safely and effectively prevent anal cancer. 

Many cancer centers develop partnerships with other organizations in 

their regions that are involved in clinical care, research, and community 

outreach.

For example, like other cancer centers, the Huntsman Cancer Institute 

(HCI) at the University of Utah relies on partnerships to offer clinical trial 

opportunities throughout a geographically large yet sparsely populated 

state. HCI teams with Intermountain Healthcare, the state’s largest 

insurance carrier/hospital system, to expand its reach. “Together, Huntsman 

Cancer Institute and Intermountain see 85 percent of the state’s cancer 

patients,” said Wallace Akerley, M.D., HCI’s senior director of community 

oncology research, who has high hopes for the relatively young partnership. 

“Working with a large multi-hospital network allows HCI to bring our 

investigator-initiated clinical trials to a much larger group of patients and 

gives us room to expand clinical research participation across our entire 

state. This will allow us to answer key questions much faster.”

The Holden Comprehensive Cancer Center at the University of Iowa 

is evaluating whether a ketogenic diet—a relatively high-fat, lowcarbohydrate diet that limits blood glucose levels—can increase sensitivity 

to cancer therapy. The cancer center was awarded an NCI grant in 2011 for 

a clinical study of whether a ketogenic diet can increase the effectiveness 

Case Western researchers are 

studying effects of exercise on 

outcomes in older cancer patients.
NATIONAL CANCER INSTITUTE | 77

of radiation and chemotherapy for patients with lung and pancreatic 

cancers. “We have real expertise in a number of research areas, including 

free radical cancer biology, cancer immunology, and novel clinical trials in 

pancreatic cancer,” said George Weiner, M.D., the center’s director.

Case Western Reserve Cancer Center in Cleveland has a program focused 

on older people with cancer called the Aging and Energy Balance Program, 

which has a clinical trials component. Its four priority areas are: treatment 

efficacy and tolerance, effects of comorbidities, psychosocial aspects of 

cancer in the elderly, and biology of aging and cancer. The program is 

well positioned to study how treatments are tolerated among people age 

70 and older, identify approaches to quality of life issues, and understand 

the impact of comorbidities (see related story p. 39). The program’s codirector, Julia Rose, Ph.D., and colleagues are using randomized clinical 

trials to explore coping and communications in advanced cancer patients, 

with an effort to look at age group differences. Historically, older adults 

with cancer are reluctant to get involved with psychosocial programs. Her 

group designed an intervention to see if older adults would engage in an 

intervention if they could control the level of contact. When given the 

opportunity to do so on their own terms, older adults were engaged in the 

intervention as much as middle aged adults. Both age groups saw benefits 

in reduced depression, increased satisfaction with their oncologists’ 

explanations, and decision-making about care. Families also had more 

contact with the team and saw positive outcomes. 

Case Western scientists are 

studying how well older patients 

tolerate cancer treatment.
78 | NATIONAL CANCER INSTITUTE

Translational Research

A major part of every NCI-designated cancer center’s portfolio is work 

to move laboratory findings to the clinic as quickly as possible. At Case 

Western, researchers used a special mouse model to explore the impact of 

exercise on outcomes in older cancer patients. They engineered a transgenic 

mouse model that overexpresses an enzyme called phosphoenolpyruvate 

carboxykinase (PEPCK) in muscle. The mice with the extra enzyme 

exercises more than normal mice. They also eat more, weighs less, and 

have a longer lifespan and more reproductive months than normal mice. 

The researchers also noticed that the mice were not getting spontaneous 

cancers, as mice often do. So they crossed a PEPCK mouse with a mutated 

mouse, the Apc-min mouse, which develops hereditary intestinal tumors. 

Bioinformatics. One of the important roles the cancer centers play is in creating 

and implementing a national cancer bioinformatics enterprise. Bioinformatics provides 

researchers with the tools, information technologies, and analytical methodologies 

needed to manage the large volumes of data generated by today’s genomic studies, 

large observational studies, and networked clinical trials—and to harvest insights from 

the information that is collected. Even in a time when high-volume storage of digital 

data is plentiful and less costly than just a few years ago, the amount of information 

from genomic studies is astronomical, pushing beyond gigabytes and terabytes to 

petabytes. The collection and storage of that data remain a stiff challenge that pales 

in comparison to the computing capacity necessary for its analysis. Finding common 

protocols for data collection and analysis is also key to information sharing among all 

of NCI’s components and grantees, and many others. Consequently, from genomics to 

clinical trials, bioinformatics capacity becomes a critical asset. Moffitt Cancer Center 

recognized that managing the large multi-site Total Cancer Care effort requires a 

dedicated workforce. So, it launched M2Gen, a company wholly owned by Moffitt that 

employs 152 people to implement Total Cancer Care. The Huntsman Intermountain 

Health Care Program pulls together data from multiple sources, including Utah’s 

unique population database linked to data from the Department of Motor Vehicles, the 

Division of Vital Statistics in the Health Department, and IHC’s own databases. Its end 

goal is to link all outcomes on a statewide basis. With the Utah population database, 

IHC can develop risk profiles going back three generations. Geocoding is also possible, 

so the team knows where patients live and can crosslink with Utah environmental 

records, including radon exposure, radiation exposure, and selenium levels in the soil. 

To make data gathered from patients in clinical trials available for use in standard 

care, NCI recently created a computer tool to support interoperability between 

clinical research and electronic health record systems. Using templates developed by 

the health care industry’s standards-making body, the freely available software will 

facilitate data exchange between systems with diverse applications and information 

models, a task that is normally time- and resource-intensive. The first application of 

the new software will be within a breast cancer trial known as I SPY2, led by Laura 

Esserman, M.D., at the University of California, San Francisco, Helen Diller Family 

Comprehensive Cancer Center.
NATIONAL CANCER INSTITUTE | 79

The progeny of the crossed mice also exercised more than normal mice and 

their colon tumors occurred later and grew more slowly than in the usual 

Apc-min mice. 

With additional study, the researchers saw a relationship between lowered 

insulin and certain cytokines known to stimulate cancer. To move these 

findings into geriatric patients, the Case Western group has launched a 

feasibility study in African American women who just finished treatment for 

breast cancer. The women are put on an exercise program, including aerobic 

and resistance exercise, for 20 weeks, with progressive increases in aerobic 

activity. “We want to determine the amount of exercise required to get cytokine 

levels down,” said Nathan Berger, M.D., co-director of Case Western’s Aging 

and Energy Balance Program. “We will also look at how exercise affects 

quality of life, time to recurrence, and progression-free survival.”

Todd Soplinski, M2Gen Laboratory 

at the Moffitt Cancer Center, 

prepares a slide of a patient’s 

tumor for analysis.
80 | NATIONAL CANCER INSTITUTE

Research Over the Long Term

Long-term NCI support of cancer centers allows many of them to undertake 

the kinds of research that spans years, if not decades. In 2003, the 

Moffitt Cancer Center in Tampa, Florida, began developing Total Cancer 

Care (TCC), a massive observational study including cancer patients 

from 18 health care sites in 10 states (see box, p. 78). Patients volunteer 

to contribute their tumor tissue and clinical and quality-of-life data 

throughout their lives. To date, more than 80,000 patients are enrolled 

and 300 to 400 new patients are being added weekly. The aim of TCC is to 

improve the standard of cancer care by combining information technology, 

science, and clinical treatment to meet the needs of individual patients. 

A large part of TCC is identification of genetic biomarkers that will help 

doctors predict who is at high risk for cancer and to offer better detection 

and predictors of response to therapy, on an individualized basis.

Patients at each site are enrolled in a single protocol and are asked three 

questions: May we follow you throughout your lifetime? If you have 

a tumor that is biopsied or removed, may we study the tissue using 

molecular technology, including genetic and genomic profiling? If we find 

something of benefit, may we re-contact you? Participants in TCC complete 

a comprehensive history and quality-of-life questionnaire online, including 

information on risk factors—alcohol and tobacco use, physical activity, 

and family history—as well as other medical problems and comorbidities. 

Already, TCC is yielding research results. Moffitt researchers have 

published data on biomarkers and gene expression patterns in lung cancer 

and colorectal cancer that may help doctors nationwide predict which 

patients will respond best to certain treatments. 

Richard Gilbertson, M.D., Ph.D., 

Director, Comprehensive Cancer 

Center (left), and Paul Gibson, 

Ph.D., of the Molecular Clinical 

Trials Core, St. Jude Children’s 

Research Hospital.
NATIONAL CANCER INSTITUTE | 81

Clinicians who enroll patients have a portal to TCC, so they can ask 

their own questions of the research team: How many patients look like 

the one I just enrolled? What therapies did they receive? What were 

the outcomes? Researchers can compare cases to learn what treatment 

worked best for what kind of patient, and to tailor cohort identification 

for research projects based on the molecular data and other information 

collected. Patients have access to the portal, as well.

“We’re not just taking data from them,” said William S. Dalton, Ph.D., 

M.D., president/CEO and director of the center. “It’s extremely important 

that this is a grassroots effort with community involvement. The 

program’s users have a say in how this is developed.” For part-time 

residents, which represent a large segment of Florida’s population, the 

patient portal allows them to access their records from anywhere. TCC is 

working to develop algorithms so that ultimately patients will be able to 

ask questions and find information relevant to their specific experience. 

St. Jude Children’s Research Hospital, an NCI-designated cancer center, 

launched its long-term population study, called St. Jude Life, to learn 

about long-term effects of treatments given to children with cancer 

and learn how to improve cure rates while leaving survivors with 

fewer side effects. Every St. Jude survivor who agrees to participate 

travels to Memphis periodically for a comprehensive battery of blood, 

neurocognitive, and performance assessments. Close to 75 percent of 

those patients contacted have agreed to participate. 

Beth Eastwood, left, and Sabrina Haralson, 

University of Michigan Comprehensive 

Cancer Center.
82 | NATIONAL CANCER INSTITUTE

Outreach to Rural, Minority, and Underserved Populations

“In the last decade, cancer centers have been playing a much larger role 

within their communities,” explained Max Wicha, M.D., a cancer researcher 

and founding director of the University of Michigan Comprehensive 

Cancer Center. “We develop clinical trials prevention studies with partners. 

Many states have launched consortia to reduce the burden of cancer, 

and in most cases, the cancer centers are leading the effort. We have the 

Michigan Cancer Consortium, a statewide effort involving all cancer-related 

institutions, and the Department of Public Health.” 

Iowa’s Holden Comprehensive Cancer Center is a leader in statewide cancer 

control efforts, in collaboration with the Iowa Department of Health and the 

Centers for Disease Control and Prevention. Cancer Center Director George 

Weiner, M.D., is president of the Iowa Cancer Consortium, a partnership 

between the cancer center, local hospitals, the American Cancer Society, 

and the Department of Public Health to raise awareness about cancer. A 

current focus of the group is radon, a naturally occurring, invisible, and 

odorless radioactive gas. Radon exposure is the leading cause of nonsmoking related lung cancer, according to Environmental Protection 

Agency estimates. Every county in Iowa has high radon levels. Cancer 

center staff members are doing health communication research and public 

policy evaluations to find the best way to increase the number of homes 

and schools that are tested for radon. 

The University of New Mexico Cancer Center builds partnerships with 

its multiethnic communities and the state’s scientific and engineering 

communities. As a result, it offers a unique blend of outreach to all citizens 

of New Mexico. New Mexico has the highest rate of uninsured citizens 

in the country, 26 percent. The state also has the largest percentage of 

Hispanics in the United States and is home to 19 pueblos, two Apache 

nations, and three bands of the Navajo nation; these populations experience 

very different patterns of cancer incidence and mortality. Before the 

university decided to start a cancer center, “our population did not have 

access to state-of-the-art care,” said Cheryl Willman, M.D., the center’s 

director and CEO. “We argued that all New Mexicans deserve state-of-theart care and deserve to benefit from the fruits of great cancer research.” 

The cancer center received its NCI designation in 2005. For its outreach 

activities, the UNM Cancer Center is building extensive community 

networks with the state’s Hispanic and American Indian populations 

on cancer screening, clinical trials education, and patient navigation 

(see related story on p. 44). 

Many cancer centers reach the research community and patients through 

their websites. St. Jude functions as a national resource, for example, by 

sharing the results of laboratory studies, clinical trials, and long-term 

survivorship studies through scientific publications and its website, 

Cure4kids.org.
NATIONAL CANCER INSTITUTE | 83

Glossary of Terms

Angiogenesis: Blood vessel formation. Tumor 

angiogenesis is the growth of new blood vessels that 

provide tumors with oxygen and nutrients they need to 

survive and grow. This process is caused by chemicals 

that are released by the tumor and by host cells in the 

tumor’s microenvironment.

Apoptosis: A type of cell death in which a series of 

molecular steps in a cell lead to its death. This is one 

method the body uses to get rid of unneeded or abnormal 

cells. The process of apoptosis may be blocked in cancer 

cells. Also called programmed cell death.

B cell: A B cell is a type of white blood cell (also called a 

B lymphocyte) that produces antibodies. B cells are part 

of the immune system and develop from stem cells in the 

bone marrow.

DNA methylase: An enzyme (a protein that speeds up 

chemical reactions in the body) that attaches methyl 

groups to DNA. (A methyl group is a chemical group 

containing one carbon and three hydrogen atoms.)

Also called DNA methyltransferase.

Driver mutation: Mutations in cancer genomes that push 

cells toward cancer.

Epigenetics: The study of how age and exposure to 

environmental factors, such as diet, exercise, drugs, 

and chemicals, may cause changes in the way genes are 

switched on and off without changing the actual DNA 

sequence. These changes can affect a person’s risk of 

disease and may be passed from parents to their children.

Exome: The part of the genome formed by exons (the 

protein coding portion of genes).

Gene expression profile: Information about all messenger 

RNAs that are made in various cell types. A gene 

expression profile may be used to find and diagnose 

a disease or condition and to see how well the body 

responds to treatment. Gene expression profiles may be 

used in precision medicine.

Genome: The complete genetic material of an organism.

Kinase: A type of enzyme that causes other molecules 

in the cell to become either active or inactive. Kinases 

work by adding chemicals called phosphates to other 

molecules, such as sugars or proteins. Kinases are a part 

of many cell processes. Some cancer treatments target 

certain kinases that are linked to cancer.

Mutation: Any change in the DNA sequence of a cell. 

Mutations may be caused by mistakes during cell 

division, or they may be caused by exposure to DNAdamaging agents in the environment. Mutations can be 

harmful, beneficial, or have no effect. If they occur in 

cells that make eggs or sperm, they can be inherited; 

if mutations occur in other types of cells, they are not 

inherited. Certain mutations may lead to cancer or other 

diseases.

Passenger mutation: Mutations in cancer genomes that 

do not contribute to the growth of the cancer but have 

occurred during the growth of the cancer.

Proteasome: A large protein complex that helps destroy 

other cellular proteins when they are no longer needed. 

Proteasome inhibitors are being studied in the treatment 

of cancer.

Protein: A molecule made up of amino acids. Proteins 

are needed for the body to function properly. They are 

the basis of body structures, such as skin and hair, and of 

other substances such as enzymes and antibodies.

Protein expression: Refers to the production of proteins 

by cells. The study of protein expression in cancer cells 

may give information about a specific type of cancer, the 

best treatment to use, and how well a treatment works.

Receptor: A molecule inside or on the surface of a cell 

that binds to a specific substance and causes a specific 

effect in the cell.

Signaling pathway: Describes a group of molecules in 

a cell that work together to control one or more cell 

functions, such as cell division or cell death. After the 

first molecule in a pathway receives a signal, it activates 

another molecule. This process is repeated until the last 

molecule is activated and the cell function is carried 

out. Abnormal activation of signaling pathways can 

lead to cancer, and drugs are being developed to block 

these pathways. This strategy may help block cancer cell 

growth and kill cancer cells.

T cell: A T cell is a type of blood cell. T cells belong to a 

group of white blood cells called lymphocytes. They are 

part of the immune system and develop from stem cells 

in the bone marrow. T cells help protect the body from 

infection and may help fight cancer. 
84 | NATIONAL CANCER INSTITUTE

The 2013 Budget Request

National Cancer Institute

At a Glance (dollars in thousands)

 Fiscal Year 2012 Estimate 5,072,183

Current Services Increase 177,227 

Subtotal 5,249,410 

Fiscal Year 2013 Additional Resources

Support Individual Investigators 173,000 

Genomics 145,600 

Clinical Trials 125,000 

Translational Sciences 115,000 

Provocative Questions 25,000

Subtotal 583,600 

Total NCI $5,833,010 

This budget request consists of two 

components: the increase required 

to maintain our present level of 

operations (current services) and 

the increase required to initiate new 

initiatives and expand existing ones.

It should be noted that we have 

carefully reviewed our current 

expenditures and have found 

important efficiencies and savings. 

The current services increase is 

the amount that will be required to 

sustain NCI programs, restore some 

of the funding cuts that have been 

implemented over the past several 

fiscal years, and provide for minimal 

growth. Noncompeting Research 

Project Grants (RPGs) would be 

funded at committed levels, the 

number of competing RPGs would 

slightly increase, and most other 

mechanisms would receive sufficient 

increases to cover cost of living 

adjustments based on the Biomedical 

Research and Development Price 

Index (BRDPI). This budget level 

also includes increased funds to 

support critically needed capital 

repairs and improvements at the 

Frederick National Laboratory for 

Cancer Research.

The second component’s request 

for additional funds reflects the 

Institute’s assessment of where 

more funding will make the greatest 

difference in reducing cancer 

incidence and mortality. Together 

with growing the research grants 

portfolio, these new or expanded 

initiatives – cancer genomics, 

transformation of the clinical 

trials system, and more effective 

translation of research results to 

clinical utility – offer the greatest 

current hope of advances against 

cancer.
Contributing writers: Cori Vanchieri, Sarah C.P. Williams

Photo credits: Sam Ogden (pages 35 and 37), Justyn Strother (page 70), 

and St. Jude Children’s Research Hospital (page 80).
NIH Publication No. 13-7957

Printed November 2012

NIH...Turning Discovery Into Health®