U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES

National Institutes of Health

AN ANNUAL PLAN AND BUDGET

PROPOSAL FOR FISCAL YEAR 2012

National Cancer Institute

The Nation’s Investment in 

Cancer Research

CANCER

CHANGING THE CONVERSATION
 

 

 

 

 

 

 

 

CONTENTS

1 Foreword: Changing the Conversation
�

3 Cancer Biology 

10 Prevention and Screening 

18 Care and Treatment 

24 The NCI Portfolio 

28 Partnering for Progress 

32 Preparing a New Generation for Cancer Research 

33 Provocative Questions 

34 Profiles of Six Cancers: Introduction 

34 • Melanoma 

38 • Glioblastoma 

41 • Acute Myeloid Leukemia 

44 • Neuroblastoma 

46 • Lung Cancer 

48 • Ovarian Cancer 

52 Revitalizing the Nation’s Cancer Clinical Trials System 

54 Director’s Afterword 

56 Budget 
 

FOREWORD: Changing the Conversation

Advances accrued over the past decade of cancer research have fundamentally changed the conversations that Americans can have about 

cancer. Although many still think of a single disease affecting different 

parts of the body, research tells us—through new tools and technologies, 

massive computing power, and new insights from other fields—that cancer is, 

in fact, a collection of many diseases whose ultimate number, causes, and 

treatment represent a challenging biomedical puzzle. Yet cancer’s complexity 

also provides a range of opportunities to confront its many incarnations. 

We now know that cancer is a disease caused by changes in a cell’s genetic 

makeup and its programmed behavior. Sometimes these changes are spontaneous, and sometimes they arise from environmental or behavioral triggers, such 

as ultraviolet radiation from sunlight or chemicals in tobacco smoke. We have 

at hand the methods to identify essentially all of the genomic changes in a cell 

and to use that knowledge to rework the landscape of cancer research, from 

basic science to prevention, diagnosis, and treatment. 

This knowledge brings us—and our national conversation—to a crucial opportunity for acceleration in the study of cancer and its treatment. The emerging 

scientific landscape offers the promise of significant advances for current and 

future cancer patients, just as it offers scientists at the National Cancer Institute—and in the thousands of laboratories across the United States that receive 

NCI support—the opportunity to dramatically increase the pace of lifesaving 

discoveries where progress has long been steady but mostly incremental. Some 

of the important scientific discoveries and their potential implications are recounted in the pages that follow. 

The scientific puzzles we work to solve are illustrated in this document through 

profiles of six cancers in which the arc from basic research to clinical utility to 

patient outcomes is especially evident. We could have picked other cancers, 

and in future reports we undoubtedly will, but each of these profiles highlights 

the unique contribution that federal investment through NCI has made and 

can make. 

N A T I O N A L C A N C E R I N S T I T U T E | 1 
 

In this report we also hope to spark a broader conversation about the value of 

the nation’s portfolio of investments in efforts to control cancer—from basic 

research, to prevention and diagnosis, to education about cancer causes and 

cancer care and treatment, to the support of cancer survivors. Indeed, we have 

a lot to talk about. 

While those perspectives are only beginning to inform the American public’s 

perception about cancer and its treatment, the trajectory of cancer deaths 

reflects real and sustained reductions over the past decade or so for 

numerous cancers, including the four most common: breast, colorectal, lung, 

and prostate. We have identified proteins and pathways that different cancers 

may have in common and represent targets for new drugs for these and many 

other cancers—since so often research in one cancer creates potential benefits 

across others. And we have made great strides in strategies to prevent cancer 

(such as quitting smoking and limiting hormone replacement therapy), 

and to detect cancer earlier, when treatment is more effective and outcomes 

more favorable. 

We reap the rewards of investments in cancer made over the past 40 years or 

more, even as we stake out a bold investment strategy to realize the potential 

we see so clearly. No matter what the fiscal climate, NCI will strive to commit 

the resources necessary to bring about a new era of cancer research, diagnosis, 

prevention, and treatment. 

A fair share of those resources will be committed to the technical work 

required to understand the full dimensions of the molecular basis of cancer, 

coupled with the intricate analyses that translate that understanding into 

actionable strategies to reduce the burden of cancer. And we are continually 

reminded that cancer research, perhaps more than the study of any malady, 

involves the deepest knowledge of human biology. 

| 2 N A T I O N A L C A N C E R I N S T I T U T E 
 N A T I O N A L C A N C E R I N S T I T U T E 3 | 

 Cancer Biology 

Scanning electron micrograph 

of breast cancer cells clumped 

together to form a tumor. Cancer is a disease of cells gone awry, of uncontrolled proliferation, of 

the loss of normal patterns of cell behavior. Cancer arises from a series 

of genetic and epigenetic changes (usually DNA-associated proteins 

that influence gene expression) that endow the cancer cell with its malignant 

behavior. During their transformation from normal to cancer, tumor cells 

undergo a large number of key changes. At the simplest level, cancer cells divide 

at inappropriate times. They don’t respond to the stop and go signals that normal 

cells do. In their development into tumors, they acquire a range of characteristics 

that help them survive, proliferate, invade, and grow. These changes include 

the production of new blood vessels (angiogenesis) to bring needed nutrients for 

continued tumor growth, and also include physiological actions that block the 

body’s attempts to get rid of cancerous cells through immunological responses. 

The tumor develops into what researchers now realize is essentially a new tissue— 

perhaps even analogous to a new organ—becoming a complex mixture of tumor 

and normal cells in the tumor microenvironment that help support the existence 

and continued proliferation of the embedded cancer cells. And, most devastatingly, cancer cells learn to move from their initial home to new, sometimes 

distant, sites in the body. 

Despite these complexities and challenges, scientists now have a rapidly growing 

knowledge of the biology of a vast array of cancers, across a wide range of sites, 

both in solid tissue and blood. Some cancers exhibit characteristic changes, while 

changes in other cancers may be more heterogeneous. What are the changes? 

What causes each change? Where in its unnatural life cycle is a cancer cell most 

vulnerable? It is a hugely complicated set of questions. But it is also a list against 

which we have made huge strides. 
 

The study of cancer biology must be as diverse as the stages of tumor development and the panoply of diseases being studied. Understanding the biology of 

cancer requires intensive work at the laboratory bench, in the cold room, at the 

computer, and at the blackboard. It utilizes such diverse tools as cells grown in 

culture, frozen human tissues, and organisms as simple as fruit flies or yeast. 

It involves dialogues and conversations, in person and in the scientific literature. 

NCI’s cancer biology research—initiated largely by investigators in hundreds of 

NCI-funded laboratories across the U.S.—helps build the basic knowledge of 

normal and cancerous cells, developing an ever-deeper understanding of 

biological mechanisms that may provide the basis for clinical applications to 

follow. We support and coordinate research projects at NCI and at universities, 

hospitals, research foundations, and businesses across the U.S. and abroad. This 

lofty mission starts with the simplest of questions: What is—and isn’t—normal? 

From such deceptively simple questions, the study of cancer biology builds the 

foundation for progress in cancer prevention, screening, diagnosis and treatment. 

Conceptual illustration of DNA. 

Cancer research today, especially on the frontiers America’s cancer researchers 

are renowned for spearheading, requires investment at a scale unimaginable 

40 years ago.

The discoveries of basic biology in cancer are usually more than a simple step 

away from clinical application. These are the scientific advances, however, that 

drive further research into new drugs and treatments—the backbone, if you will, 

of progress for patients in the future. 

To help illustrate the power of this dynamic research engine, we present two 

stories to show the dynamic nature of this field and the way that cancer research 

gets done. 

| 4 N A T I O N A L C A N C E R I N S T I T U T E 

The study of cancer biology touches on a number of important threads. Researchers 

study cancer-related mechanisms of DNA damage and repair, and investigate 

tumor immunology, as well as other responses of the body to cancer, and the 

biology of malignancies of the immune system. They identify interactions of 

cancer cells with the host microenvironment, and seek to better understand the 

molecular mechanisms of tumor growth and progression to more aggressive 

behaviors, such as angiogenesis, invasion, and metastasis. They develop 

genetically engineered mouse models of cancer to understand the progression 

of cancers and test interventions in intact organisms, and they analyze cancers 

as complex systems via computational models.
 N A T I O N A L C A N C E R I N S T I T U T E 5 | 

 

How do tumor cells acquire their new characteristics? 

One way is through the acquisition of mutations in their 

genes that, in turn, lead to production of abnormal 

proteins. In this way, cancer cells can co-opt, or highjack, a normal physiological process and generate new 

characteristics that help them survive or proliferate. 

Cancer biologists continue to identify and characterize 

these types of mutations. 

Even more importantly, if the mutant IDH proteins are 

eliminated from cells, the cells revert to their normal 

behavior. To gain more insight into how IDH gene mutations affect the growth and survival of cancer cells, and 

building on other NCI-funded basic research, the Broad 

Institute of MIT and Harvard is participating in NCI’s 

Cancer Target Discovery and Development Network 

(http://ocg.cancer.gov/programs/ctdd.asp), to identify 

small molecules that block the production of hydroxyIDH, an enzyme (a protein that speeds up, or catalyzes, glutarate by mutant IDH proteins. 

chemical reactions in the body) plays an essential role in 

converting simple carbohydrates into the molecule that 

the cell uses as a key energy source. About two years 

ago, mutations in the IDH gene were identified in glioma, 

a type of brain cancer. Prior to that time, scientists were 

not aware that IDH and the pathway in which it works 

played an essential role in the development of any 

cancer. Since then, however, more than 70 percent of 

low-grade gliomas and secondary glioblastomas (more 

aggressive tumors that arise from low-grade gliomas) 

have been found to have mutations in the IDH gene. 

Research has also confirmed that some cases of 

two other very different tumor types, acute myeloid 

leukemia, a cancer of the blood and bone 

marrow, and lung cancer, carry mutations 

in these genes. 

The enzyme activities of the proteins 

produced by mutant forms of the IDH 

gene are different from those of normal proteins. IDH normally changes 

the simple carbohydrate isocitrate into 

a new compound, ketoglutarate. The 

mutations make this enzyme dysfunctional. Instead of making ketoglutarate, 

IDH now consumes ketoglutarate and 

makes a third compound, hydroxyglutarate. One consequence of this difference 

is that the tumor cells with IDH gene 

mutations produce much more hydroxyglutarate and much less ketoglutarate, 

metabolic changes common to cancer 

cells. These two compounds regulate a 

wide range of biological processes, such 

as how the cells use sugars or iron and how 

they respond to oxygen levels. In essence, 

these changes force cells to take on the energy 

metabolism of cancer cells. 

Computed tomography (CT) 

scan in axial section through 

the head of a 30-year old 

man with a malignant, 

rapidly growing glioma 

(yellow, lower right). 

A CONTROL GOES WRONG: IDH GENE MUTATIONS 
 

 

 

 

 

HARNESSING THE IMMUNE SYSTEM FOR THERAPEUTIC 

INTERVENTION IN CANCER 

Another area of intense research in cancer cell biology 

is aimed at understanding how tumors evade the body’s 

immune system, its natural defense against infections 

and other diseases, including cancer. 

The immune system is comprised of white blood cells, 

including B-cells and T-cells, natural killer cells, macrophages, and dendritic cells, as well as other components; it can usually control or destroy invading bacteria 

and viruses. But cancer cells often evade that fate, 

because they resemble normal, healthy cells in enough 

ways to impede immune responses from being directed 

against them. In addition, even as tumors grow and their 

cells develop more and more genetic mutations, in effect 

becoming more “foreign” to the body, they can suppress 

the function of normal cells in their microenvironment to 

further thwart the immune system’s ability to attack and 

destroy cancer cells. Over the past decade, NCI funding has supported a number of researchers studying 

ways to strengthen the body’s immune response against 

tumors or harness the power of the immune system. 

This therapeutic strategy, called immunotherapy, often 

involves the use of laboratory-made antibodies, socalled monoclonal antibodies, that hone in on specific 

proteins or antigens located on the surface of cancer 

cells. When the antibodies bind to their corresponding 

antigens on cancer cells, they can alert the immune 

system that the cancer cells are foreign invaders that 

must be eradicated. Binding 

of these antibodies to cancer 

cells may also disrupt communications systems inside 

the cells, causing the cells 

to self-destruct. Although 

some antigens targeted in this 

manner are also found on the 

surface of normal cells, they 

are often much more abundant 

on cancer cells, making 

them excellent targets for 

immunotherapy. 

The monoclonal antibody 

trastuzumab was developed 

in part through NCI-supported 

research. 

One particularly well known monoclonal antibody, 

trastuzumab (Herceptin), developed in the 1990s, can 

exert its anti-cancer effects by several mechanisms, 

including targeting a cell-surface protein called HER2. 

This protein was first identified over a decade earlier 

when researchers studying cancer in rodents discovered that the rodent version of HER2 contributed to the 

development of tumors, which led to the subsequent 

recognition in humans that approximately one-quarter 

of women who develop breast cancer have tumors that 

produce much more HER2 than normal (referred to as 

HER2-positive). These cancers are particularly aggressive, but trastuzumab treatment greatly improves the 

overall survival of many women with HER2-positive 

disease and is usually administered in combination with, 

or after treatment with, conventional chemotherapy and 

possibly radiation. 

As with much of the research NCI funds, findings about 

one kind of cancer can translate into advances against 

others. In 2010, the Food and Drug Administration 

approved the use of trastuzumab to treat HER2-positive 

stomach cancer after a clinical trial showed patients 

treated with this antibody had improved survival. Stomach cancer is a notoriously difficult to treat cancer, and 

trastuzumab is the first promising new therapy approved 

for this disease in two decades. 

| 6 N A T I O N A L C A N C E R I N S T I T U T E 
 

 COMPUTATIONAL MODELS 

Cancer systems biology applies computational and 

mathematical modeling to better understand the complexities of cancer. Its growth has been spurred over the 

past few years by significant technological advances in 

high-throughput techniques, such as microarrays, next 

generation genome sequencing, and techniques used to 

analyze protein interactions with DNA. 

Traditional engineering sciences use computational modeling to predict what effects a broken wire will have on an 

electronic circuit. In the same fashion, cancer systems 

biology modeling can predict what effects various anticancer drugs will have on a cell or a patient. Traditional 

approaches to drug design rely primarily on linear logic 

or one-gene models, but blocking one target molecule is 

not always sufficient, because cells often find alternative 

routes to escape the blockage. This is one reason why 

many current drug design strategies fail. The systems 

biology approach is well suited for analyzing diseases 

such as cancer, which involve a large number of genes 

and pathways interacting via complex networks. Many 

researchers believe that a systems biology approach has 

the potential to overcome the limitations of linear models 

and identify new options for cancer treatment. 

Computational modeling works by investigating the 

relationships between the pathways that control the cell’s 

response to inflammation, growth factors, DNA damage, 

and other events. The goal is to create a dynamic model 

of the biological processes related to cancer initiation, 

progression, and metastasis. The resulting data are then 

applied to sophisticated mathematical, statistical, and 

computational methods, and the results are used to predict patients’ responses to new drugs. “With computational models, you might be able to intelligently guess what 

will and won’t work for a patient before you try it,” said 

Paul Spellman, Ph.D., a researcher at Lawrence Berkeley 

National Laboratory, supported in part by the NCI Integrative Cancer Biology Program, or ICBP. “It offers the 

chance to learn about biological phenomena that might 

take thousands of hours in the laboratory to discover.” 

These types of advances are critically dependent on NCIfunded research, such as the ICBP, which currently funds 

nine Centers for Cancer Systems Biology. 

A transcriptional network of proteins related to brain tumors. Arrows 

indicate possible protein relationships 

derived from computational modeling, overlayed on immunofluorescent 

stains of tumor cells. 

N A T I O N A L C A N C E R I N S T I T U T E | 7 
 | 8 N A T I O N A L C A N C E R I N S T I T U T E 

THE CANCER GENOME ATLAS 

Near the end of 2005, NCI and the National Human 

Genome Research Institute announced plans for an 

intriguing new initiative. Each committed $50 million 

over several years to what would be a pilot project, 

designed to determine whether large-scale sequencing, 

followed by intricate analysis and characterization, could 

accelerate understanding of the molecular basis of cancer. It was an ambitious undertaking, conducted through 

a network of more than 150 researchers at dozens of 

institutions across the nation, including a biospecimen 

resource to collect, process, and distribute tissue samples; genome sequencing centers; and genome characterization centers, which are identifying larger-scale 

genomic changes, such as gene copy number changes 

(increases and decreases), gene expression, DNA modification, and chromosomal translocations that can lead 

to cancer’s development and progression. The first types 

selected for study were brain, ovarian, and lung cancers.
�

Fewer than three years after its announcement, 

The Cancer Genome Atlas (TCGA, as it was nicknamed) 

delivered its first results. In glioblastoma multiforme, 

the most common—and deadly—form of brain cancer, 

TCGA researchers identified three previously unrecognized mutations that occur in the disease with significant 

frequency, along with core pathways that are disrupted 

Sequencing of 

DNA involves many 

complex procedures, 

including those 

depicted here: Loading beads, comprised 

of long pieces of DNA, 

into wells on plates 

(middle), which are 

then placed into a 

DNA sequencer 

(at left) and read 

as scatter plots 

(at right) or “satay 

plots,” whereby 

each colored dot 

on the plot is one 

base pair in a DNA 

sequence. 

in glioblastoma. The results, based on the genomes 

of 206 patients, also pointed to a potential mechanism 

of resistance to a chemotherapy drug commonly used 

in glioblastoma. A follow-up finding from this study, 

announced in 2010, showed that glioblastoma is not a 

single disease, but appears to be four distinct molecular 

subtypes, each susceptible to different treatments. This 

knowledge has potential, over time, to lead to therapies 

better tailored to each subtype. 

TCGA’s science is providing the catalyst for further 

research that holds promise to affect the treatment of 

many forms of cancer—beginning with the knowledge 

of its genes and how they go wrong. 

TCGA’s plan for the next few years is as ambitious 

in today’s environment as it was at the beginning: 

sequence, characterize, and understand the genomic 

changes of 20 or more additional tumor types. 

In addition to looking at genetic changes, TCGA will also 

be exploring epigenetic changes, which involve the addition or removal of chemical tags and DNA-associated 

proteins to the DNA itself. These epigenetic changes 

can lead to the development and spread of cancer and 

are vital to the understanding of the cancer process. 
 

 

JAVED KHAN, NCI MOLECULAR BIOLOGIST
�

“During my 

training as 

a pediatric 

oncologist at 

Cambridge 

University in 

the early 1990s, 

I was struck by 

how limited our 

knowledge was 

about the biology of childhood cancers.” 

That stark 

assessment, 

particularly 

the inability 

to know why 

some patients 

with a given 

type of cancer respond 

to treatment, 

while others do 

not, led Javed 

Khan, M.D., 

to the study of 

molecular biology—and ultimately to join the Pediatric 

Oncology Branch in NCI’s Center for Cancer Research. 

Importantly, sequencing genomes of patients 

and tumors is a starting point. Once an alteration in a gene has been discovered, said Khan, 

further research needs to be done in order to 

determine whether that changed gene affects 

behavior in a cell. “The easiest mutations to 

understand are those that affect the proteincoding regions of DNA, which comprise 2 percent of the genome. That’s important because 

proteins can be good drug targets.” 

“You have to sequence many hundreds of genomes to look for what’s commonly changed in 

that 2 percent,” added Khan. “And if it’s commonly changed, then you would hypothesize 

that’s actually an important area; this may be 

a gene that’s important for driving that tumor.” 

This type of change is known as a driver mutation. “It is most likely,” said Khan, “that most 

of the changes that we see are not going to be 

driver mutations; the majority of the changes 

are not going to be functionally significant. Perhaps five or 10 genetic alterations will be the 

drivers that become targets for future therapies in pediatric cancer.” 

“I came to NCI to do a combination of clinical practice 

and cutting-edge science—what is now called translational medicine,” said Khan. That led him to genomics 

and recently to a sweeping effort in children’s cancers. 

Launched in 2010, the NCI-sponsored Pediatric Cancer 

Genome Project is sequencing the genomes of tumors 

from hundreds of children with cancer to discover 

genetic changes causing or driving the disease. 

The goal, Khan said, is to “identify the Achilles’ heel 

of these cancers.” 

Researchers involved in this project are at St. Jude 

Children’s Research Hospital and the Washington 

University School of Medicine in St. Louis. St. Jude 

has a repository of biological samples and clinical 

information from children who have been treated there 

since the 1970s. The collection represents a treasure 

trove of information about cancer, and it can now be 

scrutinized using the latest genomic technologies. 

Initially, genomic characterization will assist 

clinicians in prescribing appropriate treatments. By 

genomic profiling of patients, Khan said, “we find that 

we can separate the tumors out into the good and poor 

players. The good players we know respond to therapy.” 

Because they are childhood cancers, added Khan, “at 

the genetic level, they’re not as complicated as, say, 

breast cancers, which have accumulated multiple mutations over many years.” Yet, these single mutations or 

changes identified in rarer childhood cancers may be 

important drivers in many other cancers. 

Winnowing down a list of potential therapeutic targets 

will be one of NCI’s key contributions in the years ahead, 

posited Khan. The pharmaceutical industry, he said, will 

not follow every discovery of a single mutated gene. NCI 

and academia will primarily be the players responsible 

for validating the importance of gene mutations and 

alterations in cancer biology and resolving which are the 

ones best suited for drug development. It is, said Khan, 

all about a “translatable type of research.” 

N A T I O N A L C A N C E R I N S T I T U T E | 9 
 

Prevention and Screening 

Prevention and screening represent the twin pillars of our pre-emptive 

defenses against cancer. Cancer prevention includes efforts to forestall 

the process that leads to cancer, along with the detection and treatment 

of precancerous conditions at their earliest, most treatable stages, and the 

prevention of new, or second primary, cancers in survivors. Cancer screening 

identifies either precancers or early cancers that are still highly amenable to 

treatment while the number of malignant cells is very small. 

Research on cancer prevention and screening focuses on three main areas: 

developing early detection and screening strategies that result in the identification and removal of precancerous lesions and early-stage cancers; developing 

medical interventions, such as drugs or vaccines, to prevent or disrupt the 

carcinogenic process; and risk assessment, including understanding and 

modifying lifestyle factors which increase cancer risk. To illustrate our progress 

in this area, we present three examples—colorectal cancer screening, cervical 

cancer vaccines, and ending tobacco use—of different approaches to cancer 

prevention and screening that can dramatically reduce cancer burden. 

Virtual colonoscopy uses CT scans 

to create an image of the colon 

and detect precancerous polyps. 

10 N A T I O N A L C A N C E R I N S T I T U T E | 
 N A T I O N A L C A N C E R I N S T I T U T E 11 | 

Screening for Colorectal Cancer 

A prime example of the power of prevention research is the substantial progress we have made in reducing colorectal cancer incidence and death, with new 

insights illuminating the way toward even greater reductions in the near future. 

Colorectal cancer, currently the second leading cause of cancer death in this 

country, is frequently preventable and highly treatable if detected early. From 

1975 through 2007, mortality from this disease declined by 40 percent in the U.S., 

due to changes in risk factors, increased screening, and advances in treatment. 

The Cancer Intervention and Surveillance Modeling Network (CISNET), sponsored 

by NCI’s Division of Cancer Control and Population Sciences, estimates that more 

than 50 percent of this decline can be attributed to screening tests, including 

fecal occult blood tests (FOBT), flexible sigmoidoscopy, and colonoscopy. These 

screening tests help reduce colorectal cancer mortality by identifying early-stage 

cancers and adenomatous polyps, which can be precursors to colorectal cancer, 

for removal. 

Besides improvements in risk factor modification and treatment, there are substantial opportunities for improvements in colorectal cancer screening, through 

better adherence to screening recommendations and increased accuracy of 

screening tests. According to a 2008 survey conducted by the Centers for Disease 

Control and Prevention, only 64 percent of respondents age 50 or older reported 

having an FOBT within the preceding year or a sigmoidoscopy or colonoscopy 

within the previous 10 years. Factors that likely contribute to this lack of full 

compliance include limited access to affordable health care, resistance to dietary 

limitations imposed prior to screening, and aversion to bowel cleansing techniques and invasive procedures associated with colonoscopy and sigmoidoscopy. 

Colorectal Incidence and Mortality 1975-2007 

INCIDENCE 

MORTALITY 

70 

60 

50 

40 

30 

20 

Rates per 100,000 people

10 

0 

1975 1977197919811983198519871989199119931995199719992001200320052007
 

Because no cancer screening test is 100 percent accurate, scientists continue 

to develop new screening tests and improve existing tests. In one cutting-edge 

area of research, scientists supported by the NCI Alliance for Nanotechnology 

in Cancer are trying to improve the accuracy of colonoscopy using gold-coated 

nanoparticles to target cancerous or precancerous cells in the colon wall 

before a visible growth has formed. Light emitted from the colonoscope would 

be reflected by the nanoparticles, allowing the abnormal cells to stand out 

better from the surrounding normal cells. The use of nanoparticles to deliver 

toxic agents to cancerous cells in the colon is also being investigated. 

Another line of research focuses on the use of drugs or other agents to prevent 

colorectal cancer, especially among individuals at increased risk of this disease. 

Clinical trials sponsored by NCI’s Division of Cancer Prevention, Division of 

Cancer Epidemiology and Genetics, and Division of Cancer Treatment and 

Diagnosis, have already shown that nonsteroidal anti-inflammatory drugs 

(NSAIDs)—aspirin, celecoxib, and sulindac (plus difluoromethylornithine)—can 

reduce the incidence of new adenomatous polyps in people who have had one 

or more polyps removed previously. Moreover, a recent analysis of data from 

four clinical trials showed that aspirin taken for several years at a dose of at 

least 75 milligrams per day reduced colorectal cancer incidence and mortality. 

Because NSAIDs have been associated with a number of adverse effects, 

finding even safer, more-effective preventive agents than those already identified 

is an important emphasis of further research. 

A Vaccine to Prevent Cervical Cancer 

As recently as the 1940s, cervical cancer was a major cause of death among 

women of childbearing age in the U.S. Widespread introduction of the Papanicolaou test (better known today as the Pap test) in the 1950s, which allows 

early detection of abnormal and cancerous cells in the uterine cervix, helped 

reduce cervical cancer incidence and mortality in this country by more than 

70 percent. Cervical cancer now ranks 14th as a cause of cancer death among 

American women. 

Nevertheless, in certain populations and geographic regions of the U.S., cervical 

cancer incidence and death rates are still high, due in large part to limited access 

to cervical cancer screening and follow-up care. Cervical cancer incidence and 

death rates also remain high in developing countries, where more than 80 percent of cervical cancer cases occur. Worldwide, cervical cancer is the third most 

common cancer among women and the second most frequent cause of cancerrelated death, accounting for nearly 300,000 deaths annually. As in this country, 

limited access to cervical cancer screening and follow-up care are significant 

factors contributing to the burden of cervical cancer. 

| 12 N A T I O N A L C A N C E R I N S T I T U T E 
 N A T I O N A L C A N C E R I N S T I T U T E 13 | 

In recent decades, increased understanding of how cervical cancer develops 

has led to major advances in the early detection and prevention of this disease. 

We now know that persistent infections with certain types of the human 

papillomavirus (HPV) are the cause of the vast majority of cases of cervical 

cancer. Scientists in NCI’s Division of Cancer Epidemiology and Genetics made 

crucial discoveries that led to this awareness, and scientists in NCI’s Center 

for Cancer Research pioneered techniques that enabled the development of 

two FDA-approved vaccines to prevent cervical cancer. These vaccines target 

two types of HPV that cause approximately 70 percent of cervical cancer cases 

worldwide, and one of the vaccines additionally targets two types of HPV that 

cause about 90 percent of cases of genital warts. 

Scientists at NCI have made crucial discoveries that led to the awareness of how 

cervical cancer develops and pioneered techniques that enabled the development 

of vaccines to prevent the disease.

HPV infection causes several types of cancer—anal, vulvar, vaginal, and 

oropharyngeal—in addition to cervical cancer. There is potential for vaccines 

to prevent these other HPV-associated cancers. 

Human papillomavirus particle 

visualized using a transmission 

electron micrograph. 

Despite this success, much more needs to be done. At least 13 other types of 

HPV are classified as oncogenic, or high-risk for cancer. The approved HPV 

vaccines offer modest cross-protection against some, but not all of these 

additional high-risk virus types. 

Developing new vaccines that provide broader 

and more effective cross-protection— 

ideally, against all oncogenic types of 

HPV—is a priority. The availability of 

vaccine formulations that are less 

costly to produce and might not 

require refrigeration would also 

encourage the implementation 

of vaccination programs more 

widely, especially in less 

developed countries. 
 

 THE NATIONAL LUNG SCREENING TRIAL 

Recent initial 

results from the 

National Lung 

Screening Trial 

(NLST), a randomized national study involving more than 

53,000 current 

and former 

heavy smokers 

ages 55 to 74, 

demonstrated 

that screening 

with low-dose 

helical computed tomography (CT), compared to standard chest X-ray, 

resulted in 20 percent fewer lung cancer deaths among 

trial participants screened with low-dose helical CT. 

These results of the NLST, sponsored by NCI at a cost of 

over $250 million over a period of eight years, provide a 

method to prevent death from lung cancer by screening 

people at especially high risk. In particular, those who 

have been heavy smokers may benefit the most from 

a helical CT, which can find small, potentially lethal 

lesions at early, treatable stages of the disease. 

“This is the first time that we have seen clear evidence 

of a significant reduction in lung cancer mortality with a 

screening test in a randomized controlled trial. The fact 

that low-dose helical CT provides a decided benefit is a 

result that will have implications for the screening and 

management of lung cancer for many years to come,” 

said Christine Berg, M.D., NLST project officer at NCI. 

The NLST was an extremely complicated study to 

coordinate. To ensure and enhance the representativeness of the results, NLST was conducted at 33 centers 

throughout the country. The expertise of designing and 

managing very large-scale clinical trials with very clear, 

closely monitored communication was something that 

demonstrated, yet again, the importance of a federal 

role in coordinating and managing a trial with tens of 

thousands of subjects. 

A large number of detailed analyses of NLST data due 

out in 2011 should provide scientists with a deeper 

understanding of this disease, its causes, and other 

potential ways to reduce its burden. The NLST clearly 

Scans of a normal lung 

using computed tomography, or CT. 

offers a tool for the 

screening of highrisk people, along 

with a prescient 

reminder that the 

best way to avoid 

being at high risk 

is to avoid smoking. 

As with all cancer 

clinical trials, the 

NLST provided answers to a set of specific questions related to a specific 

population. Whether those answers can be used to provide general recommendations for the entire population 

will be the subject of future analysis and study. The vast 

amount of data generated by NLST, which are still being 

collated and studied, will greatly inform the development of clinical guidelines and policy recommendations. 

Those, however, are decisions that ultimately will be 

made by other organizations. 

According to Richard Fagerstrom, Ph.D., co-chief 

statistician for the NLST, “There are many other things 

that we will learn from this study, other than just 

whether screening with helical CT decreases lung 

cancer mortality. We will also get considerable information about the cost-effectiveness of the technique. This 

will be important input for third-party payers for the 

procedure, such as Medicare, to see whether this will 

actually be economical. This could have a major positive 

impact on the health care system as far as costs go.” 

Fagerstrom also noted that there is a sizable amount 

of information to be parsed with respect to different 

kinds of specimens, including sputum, blood, and even 

urine. And the database is open to investigators at other 

institutions, not just those affiliated with the trial. 

Important as these findings are, they will not curtail 

NCI’s efforts to reduce or eliminate the use of tobacco. 

Smoking cessation is still the best way to prevent death 

from lung cancer. 

| 14 N A T I O N A L C A N C E R I N S T I T U T E 
N A T I O N A L C A N C E R I N S T I T U T E 15 | 

 

 

 

 

 

 

 

 

Curbing the Use of Tobacco 

The prevalence of cigarette smoking in the U.S. remains unacceptably high, and 

the decline in tobacco use observed since the early 1970s has stalled in recent 

years. Current estimates of smoking prevalence for U.S. adults indicate that one 

in five smokes cigarettes. 

Overall smoking prevalence figures mask vast disparities in tobacco use and 

lung cancer mortality when education level, race, ethnicity, and other factors 

are taken into account. For example, among all population groups in the 

U.S., black men have the highest death rate from lung cancer. Smoking rates 

in the U.S. are inversely associated with education: the higher one’s level of 

education, the less likely he or she is to smoke. For example, 41 percent of 

adults with the end-product of a high school education smoke, whereas only 

6 percent of adults with a graduate degree smoke. Among military personnel, 

42 percent of men between the ages 18 and 25 are smokers, while 22 percent of 

white servicemen between the ages of 18 and 24 use smokeless tobacco. These 

figures emphasize the need for new strategies and interventions to reduce 

tobacco use among population groups that have been only marginally influenced 

by existing strategies and interventions. 

To address significant gaps in research on understudied and underserved 

populations relating to tobacco-related health disparities, NCI, in partnership 

with the American Legacy Foundation, created a network of researchers, the 

Tobacco Research Network on Disparities or TReND (http://www.tobaccodisparities.org). One of TReND’s first research projects sought to develop an index 

to measure how various racial, ethnic, and socioeconomic groups are exposed 

to, and perceive, tobacco-related messages. 

NCI supports a large portfolio of smoking cessation research and the 

National Network of Tobacco Cessation Quitlines (1-800-QUIT-NOW) and 

Smokefree.gov (http://www.smokefree.gov). In 2009, NCI launched Smokefree 

Women (http://women.smokefree.gov) to provide evidence-based cessation 

guidance tailored to the needs of female smokers and to develop an online 

support community, utilizing websites for women who want to quit. NCI 

researchers are also working to help NCI-designated Cancer Centers improve 

delivery of cessation services to patients who smoke. Continued smoking in 

patients with cancer can reduce the effectiveness of cancer treatments, slow 

healing times, and increase the risk of second primary cancers. 

The area of cancer prevention that has the potential to yield the largest public 

health benefit in the U.S. and worldwide is accelerating efforts aimed at prevention and hastening cessation of tobacco use. Tobacco use, in particular cigarette 

smoking, is the nation’s leading cause of preventable death, not only from cancer 

but also from heart disease and several other conditions. Besides causing most 

cases of lung cancer, tobacco has been linked to cancers of the throat, mouth, 

nasal cavity, esophagus, stomach, pancreas, kidney, bladder, and cervix, among 

others. Tobacco use accounts for approximately 30 percent of all U.S. cancer deaths.
 

 | 16 N A T I O N A L C A N C E R I N S T I T U T E 

NCI CENTER TO REDUCE CANCER HEALTH DISPARITIES 

Cancer’s burden is not equally distributed. There are 

differences in the incidence, prevalence, and mortality 

of cancer among specific population groups in the 

United States. The Center to Reduce Cancer Health 

Disparities (CRCHD) is the component of NCI 

dedicated to confronting those inequities, particularly 

in understanding how biological, environmental, 

social, and cultural factors contribute to differences 

in cancer prevention, care, and treatment. 

Another CRCHD program of note is the Patient Navigation Research Program. A patient navigator, who could 

be a registered nurse, a social worker, or even a patient 

who has been treated for cancer at that center, acts 

as a guide through the often daunting treatment of cancer. Navigators work with patients, survivors, families, 

and caregivers to help them access and chart a course 

through the healthcare system, overcoming barriers to 

quality care. 

One of CRCHD’s flagship programs, the Community 

Networks Program (CNP), features innovative 

partnerships among academic institutions, 

community organizations, and community-serving 

healthcare providers. For example, a program called 

CNP-Redes en Acción [Networks in Action] increased 

enrollment of children in clinical trials by 48 percent, 

and CNP-Hawaii demonstrated an increase in 

mammography screening rates from 35 percent 

to 62 percent among Filipino women through the 

use of educational billboards on buses.
N A T I O N A L C A N C E R I N S T I T U T E 17 | 

 

 

 

 

 

 

GLOBAL HEALTH AND A GLOBAL PERSPECTIVE
�

No nation exists 

in a vacuum, and 

cancer is clearly 

a disease that 

defies borders. 

American researchers benefit 

from a broader 

perspective by 

engaging in 

research outside 

U.S. territories, 

just as international researchers 

make significant contributions to NCI’s overall mission 

while acquiring knowledge, skills, and abilities to enhance 

the research environment in their home countries. 

The global burden of cancer is large and growing larger. 

Each year, more than 11 million people are diagnosed 

with cancer worldwide. By the year 2020, this number is 

expected to increase to 16 million. Cancer causes more 

than eight million deaths each year, or approximately 13 

percent of all deaths worldwide. Within developing countries, cancer is projected to increase rapidly over the next 

few decades. Unless current trends change, cancer in 

developing countries is expected to represent 70 percent 

of the global cancer burden by the year 2030, a statistic 

driven by demographic shifts toward more elderly populations and the movement toward more Western lifestyles, 

most notably increased per capita tobacco consumption 

and higher-fat, lower-fiber diets. 

A global cancer research perspective offers myriad opportunities that a U.S.-only research focus would not 

afford. For example, international studies enable us to 

investigate rare cancers—such as certain inherited, 

familial types of kidney cancer, melanoma, and other 

cancers—by providing access to much larger populations 

of patients than can be found within the confines of our 

national borders. A global perspective also expands the 

diversity of environments occupied by humans, providing 

unique opportunities to explore relationships between 

genes and specific environmental exposures, including 

infectious agents that may be associated with cancer. 

We are often reminded today that the world is interconnected, politically and economically. Nations have 

obligations to each other, and biomedical research 

is no exception. NCI can help other nations confront 

and study their unique cancer burdens. In that vein, 

NCI will soon be strengthening its commitment, with 

the establishment of a center for global health. 

The new center will have much to do, from addressing 

cancer burdens of nations with populations numbering 

many hundreds of millions, to overcoming the seemingly 

simple barrier of delivering vaccines to places that 

lack even the infrastructure for refrigeration of such 

medications. 

Consider, for example, that sub-Saharan African countries are least prepared to address a growing cancer 

burden, yet 20 percent of cancers in Africa may be 

preventable, because they are linked to infectious agents 

such as viruses, bacteria, and parasites. Two overwhelmingly preventable cancers, liver and cervical, account for 

approximately 60 percent of the cancer-related deaths in 

eastern and western regions of Africa. In many areas of 

Africa, liver cancer is the top cancer for males and cervical cancer is the leading cancer for females. This kind of 

prevention will not be a simple matter, however. The lead 

time for the development of vaccines against cancercausing agents is measured in decades. In the case of 

hepatocellular cancer caused by hepatitis B virus, to take 

just one example, there is a vaccine available; for hepatocellular cancer caused by hepatitis C, none yet exists. 

There are other parts of the world where cancer risks 

are high, some even higher than in Africa; as an 

example, nasopharyngeal carcinoma is common in parts 

of Asia. By evaluating high-risk areas around the world, 

we have gained a better understanding of previously unknown risk factors and the underlying causes of cancer. 

Several such international studies are examining possible environmental and genetic risk factors in different 

populations, including exposures from polycyclic aromatic 

hydrocarbons, environmental pollutants that may contribute to increased incidence rates of a variety of cancers. 

Looking at variations in cancer risk in children globally 

can also have striking implications. NCI-supported 

scientists, including Cheryl Willman, M.D., pathology 

professor at the University of New Mexico, have studied 

leukemia in Hispanic children. Some of these children 

have a significantly increased risk of relapse for acute 

lymphoblastic leukemia (ALL), which is independent of 

other prognostic factors. Findings from studies in this 

high-risk population characterized unique clusters of 

genes associated with the children who also have a high 

percentage of Native American ancestry. These studies 

also reveal the striking clinical and genetic heterogeneity in high-risk ALL and point to novel genes which may 

serve as new targets for diagnosis, risk classification, 

and therapy. 
 

 Care and Treatment

T

he development of more efficient and effective cancer treatments—treatments that destroy cancer cells while leaving surrounding healthy tissue 

unharmed—is a critical element of NCI’s research agenda, particularly the 

development of therapies tailored to the cancers of individual patients. While the 

immediate goal is cancer treatment, targeted interventions may ultimately have 

an important role in cancer prevention, as well. 

Our understanding of the molecular changes in cancer is leading to the dawn of 

an age of genetically informed cancer medicine. We are now designing precise 

therapies to hone in on specific targets that drive tumor cell proliferation and 

survival, including not only targets in cancer cells, but also targets in surrounding 

cells, the so-called tumor microenvironment. 

We are also learning that the complexity of molecular interactions within and 

among cancer cells, and between cancer cells and normal cells, will require 

refinement of multi-agent treatment approaches against cancer. As a result, 

development of future treatments will require innovative strategies and partnerships—among academics, the public sector, and industry. Fashioning this new 

approach will require NCI’s involvement and leadership at every step, particularly 

when it comes to combinations of experimental drugs produced by more than 

one company. 

Woman being positioned in front 

of radiation gantry device (tilted 

at 45 degree angle) for breast 

cancer treatment. 

| 18 N A T I O N A L C A N C E R I N S T I T U T E 
 N A T I O N A L C A N C E R I N S T I T U T E 19 | 

 MATCHING DIAGNOSIS WITH TREATMENT 
�

We are still in the 

early days of genetically informed 

cancer medicine. 

Much of the focus 

has been on the 

development 

of molecularly 

targeted therapies, such as 

imatinib (Gleevec) 

and trastuzumab 

(Herceptin). But 

cancer researchers and pharmaceutical and 

biotechnology 

companies are 

beginning to 

devote greater attention to another 

part of the therapeutic equation: the tests—or molecular diagnostics, as 

they are often called—that are needed to determine not 

only whether a patient’s tumor expresses the molecule 

being targeted, or whether it is mutated, but also whether the cancer cell’s overall mutational gene expression 

profiles predict a good response to the treatment. 

It’s all part of the move away from nonselective therapeutics, explained Paul Mischel, M.D., a researcher at 

UCLA’s Jonsson Comprehensive Cancer Center. “If we’re 

dealing with therapies that target specific enzymes, the 

alterations in those enzymes and the pathways that they 

regulate are often different in patients with the same 

types of cancers, so having molecular diagnostics is 

essential to selecting optimal therapies,” he said. 

In 2002, for example, an international research team 

that included scientists from NCI and the Sanger Institute in Britain, as well as other international partners, 

identified a specific mutation in a gene called BRAF that 

is present in about 60 percent of tumor samples from 

patients with metastatic melanoma, a disease with a 

poor prognosis and for which treatment advances have 

been rare. Additional laboratory studies showed that 

the mutated BRAF gene alone could transform normal 

cells into cancerous cells. These findings led researchers to develop several drugs that target the mutated 

BRAF gene. One of these 

drugs, PLX4032, has already moved into a phase 

III clinical trial, enrolling 

only patients whose tumor 

cells have mutations in the 

BRAF gene, based on the 

results of a diagnostic test. 

Earlier trials of PLX4032 

had demonstrated promising results, with the majority of patients experiencing 

tumor shrinkage, including 

some patients in whom 

tumors were eradicated. 

A drug called crizotinib has 

followed a similar path to 

PLX4032. Initially developed 

to treat tumors with mutations in a gene called MET, 

crizotinib also inhibits a 

protein called ALK that has been associated with the 

development of some cancers, including lung cancer. 

In 2007, in lab and mouse model studies, researchers showed that a genetic alteration in ALK—a fusion 

with another gene, EML4—could lead to inappropriate 

expression of ALK and to tumor development. They also 

found the EML4-ALK gene fusion in a small percentage 

of tumor samples from patients with one type of lung 

cancer. Based on the discovery, an early clinical trial 

testing crizotinib that was already enrolling patients was 

altered to enroll more patients with advanced lung cancer whose tumors had the ALK gene alteration. Based 

on the excellent response of these patients to crizotinib 

in this early trial, the drug is now being tested in a phase 

III clinical trial of patients with ALK-positive lung cancer. 

The technological and logistical aspects of molecular 

diagnostics are not the only difficulty. There are 

numerous interconnected pathways in a cancer cell,” 

said Sheila Taube, Ph.D., of NCI’s Program for the 

Assessment of Clinical Cancer Tests. “If you cut off one 

pathway, there may be another pathway the cell uses 

to accomplish the same end,” said Taube. “So if you 

measure only one piece of a pathway that may be 

involved, that may not be sufficient to know whether 

the patient will respond to the drug.” 
 

NCI and its partners are taking steps to enhance the process of drug development—from target identification and validation, to high-throughput screening 

and chemical design optimization, to testing in animal models, to the design of 

mechanisms for monitoring in vivo activity. At the end of the process is translation of discoveries into human clinical trials and treatments. The challenge now 

is to prioritize which targets to pursue and then to move them into an efficient 

platform for development. NCI’s mission is not to compete with the private sector. 

Rather, we work to develop therapies for both common and rare cancers that 

are not being vigorously pursued by industry. NCI’s resources, from chemistry to 

toxicology, are also of great utility for many academic researchers. 

For the majority of cancer patients, surgery—often followed by radiation or 

chemotherapy—remains a key component of treatment and one that NCI is 

continually working to improve. One outcome of a major surgical study supported 

by NCI and its sponsored cooperative groups gained attention recently when it 

was shown that, for 20 percent of breast cancer diagnoses, extensive removal of 

cancerous lymph nodes from the axilla had no advantage. The surgery did not 

change treatment outcome, improve survival, or make the cancer less likely to 

recur, while it did increase recovery time and result in complications such as 

lymphedema and infection. Extensive lymph node removal proved unnecessary 

because the women in the study had chemotherapy and radiation, which probably 

eliminated any disease in the nodes. 

Many chemotherapy drugs used in breast and other cancers over the decades 

have their foundations in NCI research. Today, NCI’s Chemical Biology 

Consortium, a network of institutions that have formally agreed to collaborate, 

is working in the early phases of the drug discovery process in high-throughput 

screening studies to identify small molecules that have anticancer activity. 

This integrated research consortium stands at the interface of chemical biology 

and molecular oncology. 

As potential treatments—drug-like small molecules, large biologic molecules, 

and those that target immunologic function—emerge, researchers will need to 

develop new ways to assess their efficacy and establish the proper treatment 

regimens. Likewise, NCI is aggressively seeking to enhance the clinical trials 

system to better accommodate targeted therapies and accurately assess 

genomic changes in patients. 

We can expect that over time, tailored treatment that depends on the molecular 

profile of the tumor will become the norm for most malignancies. The challenge 

is finding the best match between the tumor and therapeutic regimen for each 

patient. The field is taking steps now to ensure that in the years ahead, targeted 

therapies are available for many types of cancer. 

20 N A T I O N A L C A N C E R I N S T I T U T E | 
 

N A T I O N A L C A N C E R I N S T I T U T E 21 | 

POPULATION SCIENCE AND CO-MORBIDITY
�

The diagnosis and treatment 

of cancer, already complex 

in nature, are made all the 

more difficult by the fact that 

many patients also have other 

diseases. According to recent 

research, much of which was 

funded by NCI grants, these 

co-morbidities—particularly 

diabetes, hypertension, and 

obesity—are common in breast, 

prostate, colorectal, and lung 

cancer patients, especially in 

those who are older and of lower socioeconomic levels. Studies also show an increased risk 

of death in patients with comorbidities, as these patients 

often have poorer prognoses 

and fewer treatment options. 

Patients with multiple diseases are typically disqualified 

from clinical trials, thereby restricting researchers who 

study co-morbidities to the use of observational data. 

Early on, NCI recognized an opportunity to work within 

this limitation. NCI researchers have refined alreadyexisting indices of co-morbidity and enhanced older 

analyses, resulting in an easy-to-implement measurement algorithm for co-morbidity. This new tool permits 

investigators using databases such as NCI’s SEERMedicare data registry to study the four most common 

cancers tied to co-morbidity in a more in-depth and 

efficient manner. 

Consider another example of a co-morbid cancer 

condition about which we’re gaining greater knowledge. 

Chronic obstructive pulmonary disease (COPD) is a 

well-established risk factor for lung cancer, and both 

diseases are strongly linked to smoking. Recent genome-wide association studies (which search across 

the genome for common, small variations in inherited 

genes) have identified a genetic region on chromosome 

number 15 that is associated with smoking behavior, 

lung cancer, and probably COPD. NCI-supported 

research is underway to better understand whether 

this region helps to regulate smoking behavior, which 

can modify the risk for both lung cancer and COPD. 

Genome-wide association studies are also uncovering 

genetic loci that are linked to diseases not previously 

thought to be related to one another. Variants of genes 

CDKN2A and CDKN2B are now associated with contributing to the risk of melanoma and type 2 diabetes. 

A variant of another gene, CDKAL1, is linked to type 2 

diabetes and prostate cancer, and the gene JAZF1 to 

type 2 diabetes and prostate cancer. While these studies are still mostly in their early stages, linking different 

diseases to the same common genes or gene variants 

could point toward common treatments in the future. 

Much research remains to be conducted before scientists can develop treatments to help patients struggling 

with co-morbidities and individuals with multiple chronic 

conditions. 

“There is a compelling need to better understand the 

prevalence and consequences of cancer co-morbidities, 

especially given the rising rates of other chronic conditions such as obesity and diabetes,” said Robert Croyle, 

Ph.D., director of NCI’s Division of Cancer Control and 

Population Sciences. “Clinicians need evidence-based 

guidance concerning complex patients who don’t match 

the characteristics of patients enrolled on clinical trials. 

Multidisciplinary coordinated care shows promise for 

patient management, but we’ll have to expand trials 

and observational data collection to answer the many 

questions we have about co-morbidities.” 
22 N A T I O N A L C A N C E R I N S T I T U T E | 

AN IMAGING AGENT REBORN 

Since 2009, the halt in operations of several nuclear reactors caused a global shortage of isotopes commonly 

used in medical imaging and diagnostic procedures, 

particularly in cancer. In the rush for a solution to the 

shortage, NCI played a new and vital role. 

Many diagnostic imaging tests, including bone scans 

that utilize Single Photon Emission Computed Tomography (SPECT), require the use of tracers. Bone scans are 

essential tools in the diagnosis of bone metastases in 

cancer patients, especially those with cancers (such as 

breast and prostate) that tend to metastasize to bone. 

In January 2011, FDA approved a New Drug Application 

(NDA) from NCI for a previously approved drug, Sodium 

Fluoride F18, to be used in bone scans. The NDA is the 

vehicle through which drug sponsors formally propose 

that the FDA approve a pharmaceutical for sale and 

marketing in the U.S. and was required at this time, 

because this would be a new use for this substance. 

In contrast to the only previously approved radioactive 

tracer for bone scans, Sodium Fluoride F18 is not 

subject to the supply problems that led to the 

recent nationwide shortages of the more commonly 

used tracer, Tc-99m. 

Sodium Fluoride F18 is more expensive than the other 

tracer, but it can be produced in medical cyclotrons, 

which are available at many research universities and 

commercial suppliers in the United States. This drug 

also provides better images because it uses Position 

Emission Tomography (PET) instead of SPECT imaging, 

allowing for improved, earlier detection of abnormalities. 

In bringing this imaging agent to FDA for approval, 

NCI made an agent available that, because of its high 

development costs coupled with its limited market, no 

commercial entity had an interest in developing. NCI 

moved forward with this drug approval for public health 

reasons and to facilitate treatment of rare diseases. 

New Drug Applications are expensive for a variety of 

reasons, including the cost of clinical trials to demonstrate safety and efficacy of the new substance, filing 

fees, and manufacturing and distribution costs, all of 

which could easily amount to many millions of dollars. 

Medical cyclotron for production 

of radioactive tracers 
 N A T I O N A L C A N C E R I N S T I T U T E 23 | 

Fast Facts for Advances in Cancer Treatment 

New drugs and clinical trials 

• 12 new drugs or drug uses were approved for oncology by the FDA in 2010. 

• 348 phase III oncology trials are ongoing in the U.S. 

• 861 cancer medicines from industry are in some step of the trial process 

(2009 data). 

• 2,000-plus clinical trials accepting children and young adults are in progress. 

• 200-plus prevention trials are open. 

• 100-plus screening trials are open. 

Selected 2010 highlights and trends in drug development. 

• The first-ever therapeutic cancer vaccine was approved. 

• Drug inhibitors for specific targets, such as BRAF and ALK genes, are 

being developed. 

• There are a vast number of new targeted therapies entering trials. 

• Advances in understanding drug resistance are being turned into 

new therapies. 

Approved 

drugs 

Phase 0 

Does agent hit 

intended target? 

Phase I 

Safe? 

Phase II 

Effective? 

Phase III 

Better than 

current? 

0 

1 

2 

3 

Major Stages of Clinical Trials: 

How New Agents are Tested 
24 N A T I O N A L C A N C E R I N S T I T U T E | 

 The NCI Portfolio

Extramural Research: Funding and conducting innovative research are 

the highest priorities at NCI. The NCI Extramural Research Program 

reaches nearly 650 universities, hospitals, Cancer Centers, and other sites 

throughout the U.S. and more than 20 other countries. Over 80 percent of NCI’s 

current budget funds extramural research activities. NCI has six divisions and 

several key centers. 

Five of the divisions oversee and coordinate extramural activities: 

•	� The Division of Cancer Biology provides funding for research that investigates 

the basic biology behind all aspects, including the causes, of cancer. 

•	� The Division of Cancer Control and Population Sciences supports a 

comprehensive program of genetic, epidemiologic, behavioral, social, and 

surveillance cancer research. 

•	� The Division of Cancer Prevention supports research to determine and reduce 

a person’s risk of developing cancer, as well as research to develop and 

evaluate cancer screening procedures. 

•	� The Division of Cancer Treatment and Diagnosis works to identify and 

translate promising research areas into improved diagnostic and therapeutic 

interventions for cancer patients. 

•	� The Division of Extramural Activities coordinates the scientific review 

of extramural research funding applications and provides systematic 

surveillance of that research after awards are made. 

Intramural Research: A portion of NCI’s research dollars supports the work of 

scientists in the two intramural sections: 

•	� The Center for Cancer Research is home to more than 250 scientists and 

clinicians, organized into more than 50 branches and laboratories, conducting 

basic, clinical, and translational science to advance knowledge of cancer and 

AIDS. The Center’s researchers translate their discoveries into clinical applications by utilizing the infrastructure provided by the NIH Clinical Center, 

the largest clinical research hospital in the world. 

•	� The Division of Cancer Epidemiology and Genetics conducts population 

and multidisciplinary research to discover the genetic and environmental 

determinants of cancer and new approaches to cancer prevention. 

In addition to the six divisions and the Center for Cancer Research, NCI’s Office of 

the Director contains a number of offices that perform important functions and 

provide services across the institute, including bioinformatics, training, health 

disparities, and HIV/AIDS, among others, and supports research in several 

high-technology areas through the Center for Strategic Scientific Initiatives. 
 N A T I O N A L C A N C E R I N S T I T U T E 25 | 

 

Research Project 

Grants 42.5% 

0.2% 

Career 

Programs 

1.5% 

NRSA 

Fellowships 

1.3% 

Intramural 

Research 15.8% 

Other 

Research 

7.2% 

Centers 

12.0% 

Research & 

Development 

Contracts 

12.0% 

Research Management 

and Support 7.5% 

Buildings and Facilities 

Funding Categories for Fiscal Year 2010 

Funding Category Funding % of Total 

[in thousands] 

Research Project Grants $2,168,058 42.5% 

Intramural Research $805,332 15.8 % 

Other Research $367,699 7.2% 

National Research Service Award Fellowships $67,564 1.3 % 

Career Programs $74,914 1.5 % 

Centers $611,133 12.0 % 

Research & Development Contracts $613,762 12.0 % 

Research Management and Support $381,765 7.5 % 

Buildings and Facilities $7,920 0.2 % 

Total FY2010 Budget $5,098,147 

Figures for FY2010 exclude American Recovery & Reinvestment Act (ARRA) funding. 
 

26 N A T I O N A L C A N C E R I N S T I T U T E | 

THE AMERICAN RECOVERY AND REINVESTMENT ACT (ARRA)
�

In February 2009, after President Obama 

signed into law the American Recovery and 

Reinvestment Act, NCI began to face the kind 

of problem most of us would love to have: 

spending an unexpectedly large amount of 

money. The recovery act—or ARRA, as it 

became known—provided NCI with approximately $1.3 billion in additional funding over 

its annual appropriation, to be allocated over 

a two-year period. This special allocation was 

a welcome infusion, but one that also altered 

funding expectations for the years to follow. 

ARRA spending carried with it some particular 

concerns, not the least of which was separately managing two-year economic stimulus 

funds alongside NCI’s annually appropriated 

budget. ARRA was, first and foremost, about 

jobs and hiring, about sustaining and building the American workforce. NCI committed 

approximately $747 million, or 60 percent of 

ARRA funds, to the support of 573 research 

grants, through supplements to existing, 

longer-term grants and to new, competing 

research proposals, many funded for two 

years. Mindful of our responsibility to increase 

the scientific workforce, NCI also invested in 

new faculty awards to NCI-designated Cancer 

Centers and to minority institution/NCI Cancer 

Center partnerships. 

In scientific terms, however, two years is a 

very short time. This is, after all, a field that 

generally makes incremental progress, building experiment on experiment, publication on 

publication, with most projects carried out 

over a multiyear period. In planning for ARRA 

spending, NCI’s leaders were well aware that 

many two-year grantees would apply for extensions or follow-on research in years ahead. 

Likewise, there was a clear expectation that 

many unsuccessful, but meritorious, ARRA 

applications would be revised and resubmitted 

for conventional research support. In short, we 

continually asked ourselves: How much appropriated money will we have in the years ahead 

to support work begun under ARRA? 

That’s still a somewhat open question, as we 

wait to see what appropriations and application pools look like in the near future. In a 

continued time of economic difficulty, however, 

careful scrutiny will be key, even in the most 

optimistic of scenarios. 

NCI’s planning for ARRA was not built solely 

around grants; the institute funded a number 

of new initiatives and, importantly, added to 

some ongoing grants so that a certain amount 

of risk in the years beyond those for which 

funding was designated was lessened. 

In particular, The Cancer Genome Atlas, 

already a prominent program, received ARRA 

funding from NCI and its sister institute, the 

National Human Genome Research Institute, 

to begin to identify all of the relevant genomic 

alterations in 20 or more tumor types. Reflecting its significance, the National Institutes of 

Health named TCGA as one of its seven signature ARRA projects and Vice President Biden 

named it as the No. 2 ARRA project for the 

nation. Other NCI ARRA investments included 

the funding of nearly 40 early-phase clinical 

trials of new, molecularly targeted treatments; 

enhancement of the NCI Community Cancer 

Centers Program; development of methods 

of banking biological samples and for creating bioinformatics platforms; efforts to bring 

scientists from other disciplines to the study 

of cancer; and supplemental funding for 

NCI-designated Cancer Centers. 
 

 

 N A T I O N A L C A N C E R I N S T I T U T E 27 | 

Clinical Community Oncology Program 

Minority-based Community 

Oncology Program 

NCI Community Cancer Centers Program 

NCI-designated Cancer Centers 

NCI’S NATIONWIDE REACH 

Promising laboratory discoveries, the foundation of biomedical science, begin a lengthy 

process to translate scientific knowledge into new treatments for cancer patients. 

Along that path, from the laboratory to the clinic, NCI supports a number of important 

initiatives across the United States. 

NCI’s Cancer Centers, which currently number 66 facilities nationwide, are largely 

based in research universities that are home to many of the hundreds of NCI-supported 

scientists who conduct a wide range of intense, laboratory research into cancer’s origins and development. Their work is echoed throughout this document. 

The Cancer Centers Program focuses on trans-disciplinary research, including population science and clinical research. Those centers with a comprehensive designation, of 

which there are currently 40, must have a robust portfolio of research in basic, population, and clinical research, and must additionally demonstrate professional public 

education activities in the communities they serve. 

Many of the Centers are also treatment facilities that deliver the latest medical advances 

to patients, including the support of cancer survivors and outreach out to underserved 

populations. Cancer Centers, like all NCI programs, are subject to peer review each 

time they apply for renewal of their support grants. 

The NCI Community Cancer Centers Program came into existence to test the concept 

of a national network of community cancer centers to expand and deliver advanced 

care in local communities. 

NCI’s Clinical Community Oncology Program (CCOP) connects more than 3,000 

community-based physicians at nearly 400 hospitals in 34 states and Puerto Rico with 

academic investigators, to accelerate implementation of NCI-sponsored cancer treatment, prevention, and control clinical trials. By providing community level access to 

clinical trials CCOPs boost the participation of underserved populations. 

NCI’s Minority-based Community Oncology Program, a companion program to the 

CCOP, is focused in areas where physicians serve sizable minority populations. 
28 N A T I O N A L C A N C E R I N S T I T U T E | 

 

 

 

 

 

 

 

Partnering for Progress 

Progress in cancer research depends upon partnerships—in the use of new technologies; in collaborations to advance experimental techniques; in innovative 

methods of helping fund the earliest stages of development of small companies 

working in the cancer field; and in the testing of new molecular agents in cancer patients. 

Supporting partnerships touches NCI programs too numerous to mention encyclopedically, but certainly includes programs such as those detailed on the next few pages. 

NCI’s Experimental Therapeutics Program (NExT) makes available to outside researchers— 

from academia and industry—research resources not readily available at most medical 

centers. These resources can shave years from the 10-year to 12-year development cycle 

of a new drug, as well as help bring down the nearly billion-dollar development cost 

of many cancer drugs. NExT is also facilitating the earliest phase of clinical testing in 

humans, known as phase 0, which tests new, molecular agents in sub-therapeutic doses, 

in small numbers of patients, to see whether potential new anticancer agents hit their 

intended targets. 

As a model of working with industry to promote and develop new drugs, the first substance tested as part of a phase 0 trial was the drug ABT-888, a drug candidate that 

inhibits a cancer protein called PARP, which was provided by Abbott Laboratories. 

“The successful and expeditious conduct of this trial, and the impact it has had on the 

development timeline of ABT-888 at Abbott, provide an initial example of improved 

therapeutics development in oncology,” said James H. Doroshow, M.D., director of 

NCI’s Division of Cancer Treatment and Diagnosis, who spearheads the NExT program. 

NCI is also utilizing the phase 0 trial to test new imaging agents. 
 N A T I O N A L C A N C E R I N S T I T U T E 29 | 

Scientist examining wells 

containing cell cultures. 

Molecular Technologies 

As an example of another partnership, in 1998, NCI established the groundwork 

for a program focused on technology development to meet the needs of cancer 

researchers and clinicians. 

Taking risks on early-stage, potentially transformative technologies, the 

Innovative Molecular Analysis Technologies (IMAT) program has contributed to 

many technologies that are now on the market and in frequent application across 

cancer research and clinical communities. As with other NCI programs, IMAT 

subjects all applications to competitive peer review. 

Commercial products now in widespread use, such as RNALater, Affymetrix gene 

chips, Illumina bead platforms, and Quantum dot labeling to monitor complex interactions within living cells, were considered high-risk ideas when initially funded 

through the IMAT program. Yet, their current availability and applicability to multiple 

clinical and basic sciences research settings are a testament to the pay-off that 

such transformative technologies have provided to the field of cancer research. 

To take just one example of the program’s success, James Landers, Ph.D., 

professor of chemistry at the University of Virginia, used IMAT funding to help 

develop a technology for T-cell lymphoma diagnosis he calls a “lab on a chip.” 

This highly integrated system is capable of detecting infectious agents present 

in complex biofluids in less than 30 minutes, and the diagnosis of certain blood 

cancers in under an hour. 
 

Small Business Innovation 

Funding is a vital component of any partnership, and NCI has become one of the 

largest sources of early-stage cancer research technology financing in the U.S. 

Its Small Business Innovation Research (SBIR) program, along with the closely 

allied Small Business Technology Transfer Program, are NCI’s engines for 

developing and commercializing novel technologies to prevent, diagnose, and 

treat cancer. 

The two programs seek to increase small business participation and private 

sector commercialization of technology developed through federal research and 

development. The SBIR program has made great strides in confronting one key 

funding gap between the end of an award and the subsequent round of private 

financing needed to advance a product or service toward commercialization. 

To cover this gap, NCI’s unique Bridge Award is specifically designed to incentivize partnerships between second phase SBIR awardees and third-party investors and strategic partners. The Bridge Award more than triples the amount of 

funding available to SBIR applicants, and has often proved an entrée into private 

funding. 

One of the first companies to receive NCI Bridge funding was Florida-based Altor 

BioScience Corp., which is advancing the discovery and development of targeted 

immunotherapeutic agents for the treatment of cancers, viral infections, and 

inflammatory diseases. Altor used funding from a $3 million SBIR Bridge grant to 

support clinical development of ALT-801, an immunotherapeutic agent. 

In January 2011, Altor announced it had raised more than $10 million in private 

financing to complete multiple phase II clinical trials of the new agent. In looking 

for such investments, companies “have their own due diligence,” said Altor chief 

executive Hing C. Wong, Ph.D., “but they always love to see what NIH thinks about 

the product and the technology. They really like that kind of validation.” 

30 N A T I O N A L C A N C E R I N S T I T U T E | 

NCI has become one of the largest sources of early-stage cancer research 

technology financing in the U.S.
 

 N A T I O N A L C A N C E R I N S T I T U T E 31 | 

ImaginAb

To the casual observer, biomedical imaging still means 

devices such as a CT scan or X-ray: technology that 

looks inside the body to visualize everything from broken 

bones to masses inside organs. For Anna Wu, Ph.D., 

of the Crump Institute for Molecular Imaging at UCLA, 

today’s most advanced molecular imaging technologies 

are “tools to look at very specific biological questions in 

living people.” 

Image of a prostate 

cancer grafted onto a 

mouse (lit up in yellow at 

hip) and detected using 

a tracer developed by 

ImaginAb 

Wu is the founder of, and chief scientific advisor to, a 

small California-based biotechnology and nanotechnology company called ImaginAb, Inc., which is focused 

on developing a new class of highly targeted proteins 

for imaging and therapy, based on engineered antibody 

fragments. 

Antibodies, which detect and help destroy invaders, are 

substances that can also be engineered to bind to the 

molecules on the surface of cells that display specific 

proteins. The antibodies may be used therapeutically to 

prevent tumor growth by blocking specific cell receptors or by delivering chemical doses to a specific target. 

What ImaginAb has done is to reformat antibodies into 

smaller fragments suitable for diagnostic imaging in 

order to target a given cancer. These small antibody 

fragments are tied to a positron emitting isotope that 

allows for molecular imaging of cancer cells using 

PET (Positron Emission Tomography). 

NCI’s SBIR program, through its competitive peer 

review process, made ImaginAb one of its SBIR funding 

awardees. That infusion, says Wu, “has been invaluable 

to the company’s survival and growth. The NCI funding helped us move forward at a very tough time when 

investment capital was simply not available.” Today, 

ImaginAb has major global companies as clients 

and has re-engineered over a dozen therapeutic 

antibodies into fragments for imaging and possibly for 

novel therapies. 
 

 Preparing a New Generation for Cancer Research 

T

ogether, NCI’s training programs span basic research, investigational 

therapeutics, and population-based studies. The NIH is, in many ways, 

analogous to a large research university. Its investigators are often referred 

to as faculty, and many of its scientists are able to qualify for tenure in the intramural programs of their institutes. 

The largest program is run by the Center for Cancer Research, which, as part of 

the NCI intramural research program, offers fellowships for training in the basic 

and translational sciences, as well as in the clinic on the NIH campus. About 

1,300 fellows are enrolled in the program each year. For clinical fellows, the NIH 

Clinical Center brings together, under one roof, the treatment of patients with 

laboratory science—a unique arrangement for researchers who typically don’t 

get to do both clinical and basic research on the same research project. 

In addition to providing intramural training, the NCI Center for Cancer Training 

(CCT) is dedicated to building cancer research capacity at institutions across the 

nation and fostering the next generation of the cancer research workforce—a 

diverse, multidisciplinary workforce. NCI supports a range of fellowships, Career 

Development Awards, Institutional Training Awards, and Institutional Education 

Awards to help early-stage scientists and clinicians become independent investigators and to encourage senior scientists to become mentors for their younger 

colleagues. 

NCI also has a long history of bringing students into the labs on the NIH campus 

in Bethesda, Md. Each summer, the campus is infused with new faces of 

undergraduates and graduate students who spread out in labs and clinics. 

Several years ago, these opportunities were expanded to include gifted high 

school students. 

Training also takes place beyond the NIH campus in Bethesda. NCI’s campus in 

Frederick, Md., runs student internship programs that enroll local high school 

students over the summer and during the school year. 

32 N A T I O N A L C A N C E R I N S T I T U T E | 
N A T I O N A L C A N C E R I N S T I T U T E 33 | 

Provocative Questions

T

his has been a challenging and hopeful time for NCI to lead the nation’s 

cancer research program. Over the past two decades researchers have 

unraveled some of the mysteries that happen to the genome of a cancer 

cell and how a cancer cell behaves in its local environment. With better understanding and recent technological advances in many fields, such as genomics, 

molecular biology, biochemistry, and computational sciences, progress has 

been made on many fronts, and a portrait has been made of many cancers. 

With sustained and accelerated funding, NCI can build upon today’s cancer 

advances with provocative thinking by asking research questions that build 

on recent discoveries. 

NCI is reaching out to researchers in various disciplines to pose and articulate 

“provocative questions” that can help guide the nation’s investment in cancer. 

Provocative questions may be built on older, neglected observations that have 

never been adequately explored, or on recent findings that are perplexing, or 

on problems that were traditionally thought to be intractable but now might be 

vulnerable to attack with new methods. 

Through face-to-face meetings and a public website, the Provocative Questions 

initiative is intended to engage NCI’s scientific community in serious debate and 

energize NCI’s many constituencies. Here are some of the questions that have 

been discussed at workshops and online: 

•	� What molecular mechanism(s) are responsible for the well-documented 

association of obesity with certain types of cancer? 

•	� Why are some disseminated cancers cured by chemotherapy alone? 

•	� Why do many cancer cells die when suddenly deprived of a protein encoded 

by an oncogene? 

You can read, submit, and comment on questions at: http://provocativequestions. 

nci.nih.gov. 
34 N A T I O N A L C A N C E R I N S T I T U T E | 

Cancer Profiles: 

Introduction 

The progress achieved against the six 

cancers that are profiled in this section 

exemplify NCI’s investment in scientific 

research, from basic and population 

science to applications in prevention 

and cancer care. The stories of these 

cancers illustrate how molecular and 

genomic data have enhanced identification of cancer subtypes and provided insight into potential therapeutic 

targets, yielding tangible benefits for 

patients, sometimes in less than 10 

years from the time of genetic discovery to initial clinical trials. Every cancer 

has a different part of the story to tell— 

whether it is simply the ability to distinguish which patients would benefit from 

more aggressive therapy, as with acute 

myeloid leukemia, or a new drug with 

potential therapeutic benefits for two 

different cancers, as with neuroblastoma and lung cancer. The element tying 

these stories together is the role of NCI. 

While we made great progress in some 

of the cancers highlighted in this section, there are others that continue to be 

more formidable. It is for these cancers 

that NCI’s continued support cannot be 

underestimated. We are just beginning 

to untangle the mysteries underlying 

these diseases, and we must maintain 

that momentum to make progress that 

could lead to new screening, diagnosis, 

or treatment techniques. Such progress is achievable, but not inevitable. 

Each passing year brings real progress, 

but also deeper understanding of how 

difficult these diseases are to conquer. 

Continued progress will require heightened dedication to using science to 

better understand and counteract the 

collection of diseases we call cancer. 

M E L A N O M A 

ignated as non-melanoma skin cancers. 

T

he majority of skin cancers are 

basal or squamous cell carcinomas, which together are also desMost forms of non-melanoma skin 

cancer are highly curable and can be 

prevented by reducing sun exposure. 

Sun exposure can also increase the risk 

of melanoma, a form of skin cancer 

that begins in melanocytes, the cells 

that produce melanin. Although 

melanoma accounted for fewer than 

70,000 of more than two million cases 

of skin cancer in 2010, it caused more 

deaths than any other type, with an 

estimated 8,700 deaths in 2010. Over 

the past 30 years, the incidence of melanoma in the U.S. has nearly tripled. 

The majority of melanoma patients 

are diagnosed with localized disease, 

and surgery is curative in most localized 

cases. The significance of early detection of melanoma, when it is still at a 

localized stage and treatable, cannot 

be minimized. However, melanoma patients with advanced metastatic disease 

rarely survive more than a year after 

diagnosis, with a five-year survival rate 

of 15 percent. 

Outcomes for advanced-stage 

melanoma have not improved substantially for decades, but results of recent 

clinical trials suggest that new therapeutic strategies may change this trend. 

In August 2010, Plexxikon, a small 

drug development company, announced 

that one of its drugs—PLX4032—had 

elicited a response in more than 80 

percent of melanoma patients in an 

early-phase clinical trial. PLX4032 

caused the tumors in 24 of the 30 trial 

participants to shrink by at least 

30 percent, while the tumors of two 

patients disappeared. 
 N A T I O N A L C A N C E R I N S T I T U T E 35 | C A N C E R P R O F I L E S : M E L A N O M A 

Micrographic image of a 

melanoma cell. 

Just a few months later, evidence of 

the drug’s effectiveness grew even stronger: a clinical trial involving hundreds 

of participants across many institutions 

showed that metastatic melanoma 

patients treated with PLX4032 lived 

longer than those who had been given 

the chemotherapy drug dacarbazine, 

which is the current standard of care. 

Taking a closer look at the research 

that made this promising drug possible 

provides a powerful example of how 

basic cancer research is translated into 

therapeutic potential. PLX4032 is a 

molecularly targeted therapy, a drug 

that is intended to be used to change 

the activity of a specific molecule or 

group of molecules. This drug was 

designed to inhibit the activity of a 

mutant form of a protein called BRAF. 

BRAF is the most commonly mutated 

gene in melanoma (mutated in over half 

of all melanomas) and is also mutated 

to a lesser degree in at least a few other 

cancer types, including lung cancer. 

Knowledge of the BRAF protein 

as a pro-growth signaling molecule 

emerged initially from years of basic 

laboratory research. Subsequently, 

BRAF gene mutations in melanoma 

were discovered by scientists in the 

United Kingdom in 2002, and these 

mutations were shown to render 

the BRAF gene oncogenic. The high 

prevalence of BRAF gene mutations in 

melanoma made it a candidate therapeutic target and, according to Harvard 

Medical School professor and NCIfunded investigator Lynda Chin, M.D., 

was a transformative event that helped 

spur enthusiasm for cancer genome 

sequencing. This newfound enthusiasm 

eventually grew into large-scale efforts 

such as The Cancer Genome Atlas. 

Early attempts to target BRAF in 

melanoma were unsuccessful in the 

clinic, in part because the drugs used 

interfered with BRAF function in both 

cancer and normal cells. To address 

this issue, a team that included NCIsupported investigators used highthroughput screening, in combination 

with structural biology, to identify 

compounds that inhibit the activity 

of the mutant form of the BRAF gene 

found in most melanomas, but have 

little effect on the BRAF gene found in 

normal cells. This research demonstrated that it is possible to selectively target 

the mutant form of the BRAF gene 

with PLX4032. The results from the 

phase I clinical trials testing the efficacy 

of PLX4032 were published just eight 

years after the discovery of the BRAF 

gene mutation. 

Clinical researchers will continue to 

evaluate PLX4032 in patients, and 

additional laboratory research will be 

conducted in parallel to gain insight 
36 N A T I O N A L C A N C E R I N S T I T U T E | 

 

into how melanoma cells respond to 

BRAF inhibition. There already is 

evidence that many tumors initially 

responsive to PLX4032 eventually 

become resistant to the drug, a phenomenon that occurs with many molecularly 

targeted drugs, as cancer cells evolve to 

bypass the blocked signaling pathway. 

In many cases, the bypass mechanisms 

that allow tumors to become resistant 

to the drug are understood. Next-generation strategies based on the knowledge of these bypass mechanisms will 

allow researchers to use combinations 

of drugs to target multiple pathways 

simultaneously and hopefully prevent 

or reduce resistance. Researchers also 

are seeking clues about why some 

melanoma patients with the mutant 

BRAF gene do not respond as well to 

PLX4032 as others do. This information will ensure that PLX4032 can be 

used in patients most likely to benefit 

from the drug and may drive development of new or combination strategies 

to treat other patients. Furthermore, 40 

percent of melanomas lack a mutation 

in the BRAF gene; for these patients, 

identification of new pathways is even 

more critical. 

Research continues to contribute to the body of knowledge on the 

mechanisms that drive malignant cell 

behavior. Understanding these mechanisms may lead to targets other than 

the BRAF gene. For example, germline 

mutations in the p16 gene have been 

identified in about half the patients with 

familial melanoma. A recent genomewide association study identified three 

additional genes associated with risk of 

melanoma. As illustrated with the example of PLX4032, NCI plays a pivotal 

role in rapidly moving drugs through 

the full arc of research from the laboratory to the clinic. NCI support is critical 

to continued efforts to build on the 

successes of drugs such as PLX4032 so 

that clinical results can fuel the cycle for 

the next generation of promising new 

drugs for melanoma. 

MELANOMA RISK ASSESSMENT TOOL 

An online Melanoma Risk Assessment Tool is now available to help physicians assess a person’s risk of developing the 

disease. Developed by a group of researchers from NCI, the University of Pennsylvania School of Medicine, Memorial 

Sloan-Kettering Cancer Center, and the University of California, San Francisco, the tool uses easily obtainable information to estimate a person’s risk of developing skin cancer within the next five years. The research team identified 

several factors that can predict skin cancer risk, including geographic area, hair color, complexion, sunburn type, tan 

type, age, and moles and freckling. 

The program (available on the NCI website at http://www.cancer.gov/melanomarisktool), uses a complex mathematical formula to calculate risk, and allows doctors to quickly and easily identify patients at increased risk for developing 

melanoma (and indirectly for other skin cancers), who could then undergo interventions, such as a complete skin 

exam, special counseling to avoid sun exposure, regular self and professional surveillance of moles, or participation 

in clinical trials for skin cancer prevention. 
 N A T I O N A L C A N C E R I N S T I T U T E 37 | 

IMMUNOTHERAPIES FOR MELANOMA

C A N C E R P R O F I L E S : M E L A N O M A

In a simple sentence, the New York Times on March 25 

reported a significant step against a feared cancer: 

“The first drug shown to prolong the lives of people with 

the skin cancer melanoma won approval from the Food 

and Drug Administration on Friday.”

The new drug, Yervoy (ipilimumab), was developed by 

James Allison, Ph.D., who is today head of the immunology 

program at the Memorial Sloan-Kettering Cancer Center in 

New York. The new medication stands out in its mechanism 

of action, as well. “The treatment,” Allison told the New 

York Times, “is of the immune system, it’s not of the tumor.”

For more than two decades, Allison has studied the 

mechanisms that regulate the immunologic responses of 

T lymphocytes, which are commonly referred to as T-cells; 

he works to manipulate T-cell response, in order to develop 

novel tumor immunotherapy approaches.

“The success of ipilimumab underscores the importance 

of basic research to clinical achievement,” Allison said in 

a statement. “The concept came directly out of our studies on fundamental mechanisms of regulation of T-cell 

responses.”

According to the FDA, “Yervoy’s safety and effectiveness 

were established in an international study of 676 patients 

with melanoma.” Patients were randomly assigned to 

receive one of three treatment regimens: Yervoy plus an 

experimental tumor vaccine called gp100, Yervoy alone, or 

the vaccine alone. Those who received the combination of 

Yervoy plus the vaccine or Yervoy alone lived an average 

of about 10 months, while those who received only the 

experimental vaccine lived an average of 6.5 months.

Prior to the recent approval, treatments for melanoma 

were more limited, given that many melanomas are 

relatively resistant to standard chemotherapeutic agents. 

Two FDA-approved drugs, interleukin-2 (IL-2) and 

dacarbazine, produced a response in only 10 percent 

to 20 percent of patients.

Other approaches to stimulate immunity against tumors 

use a technology called adoptive T-cell therapy. During this 

therapy, specific T-cells from the immune system of the 

patient, or a matching donor, are harvested from the blood. 

The T-cells are then activated outside the body in the 

laboratory to recognize tumor cells and destroy them. 

The modified T-cells are then infused back into the patient 

and are “adopted” by the body to enhance its natural 

immune system. This treatment approach is being tested 

in various early-stage and late-stage clinical trials. NCI 

trials, led by Steven Rosenberg, M.D., Ph.D., chief of surgery 

at NCI, tested adoptive transfer therapy in melanoma by 

transfusing patients with tumor-specific T-cells called 

tumor infiltrating lymphocytes. 

Rosenberg believes adoptive T-cell therapy may prove a 

useful tool in cancers beyond melanoma. “We have 

demonstrated that gene-modified T-cells can recognize 

and kill melanoma cells over-expressing a specific antigen, 

leading to a clinical response in 

some patients,” 

said Rosenberg. 

“With these 

trials, we hope to 

extend this type 

of immunotherapy to patients 

with more common cancers, 

such as breast 

and colon.”
38 N A T I O N A L C A N C E R I N S T I T U T E | 

G L I O B L A S T O M A

Cancers of the brain are 

relatively rare but often 

devastating diseases; just 

1.5 percent of malignant primary 

cancers originate in the brain. Glioblastoma multiforme (GBM) is the 

most common form of primary 

brain cancer and is one of several 

types of glioma, a tumor type that 

arises in cells of the brain and spine 

called glial cells. In the U.S., roughly 

11,000 people are diagnosed with 

primary GBM every year. Though 

GBM rarely metastasizes to other 

organs, it spreads aggressively within 

the brain and is more deadly than 

most other brain malignancies. 

Patients with newly diagnosed 

GBM generally respond poorly to 

conventional treatments and have a 

median survival of approximately 

one year following diagnosis. 

Recently, research has proceeded 

from small, incremental improvements to greater progress in our understanding and treatment of GBM. 

Through the coordinated efforts 

of NCI-funded initiatives—including The Cancer Genome Atlas, the 

Glioma Molecular Diagnostic Initiative (GMDI) and the Repository 

of Molecular Brain Neoplasia Data 

(REMBRANDT)—scientists have 

collected and molecularly characterized an unprecedented number of 

these rare tumors. Analysis of TCGA 

sequencing data revealed that GBM 

is not a single disease but has at least 

four molecular subtypes: proneural, 

neural, classical, and mesenchymal. 

Because different cellular pathways 

are affected in these subtypes, differences in treatment responses are 

observed. This finding is paving the 

way for more informed selection of 

therapies for GBM patients, who 

have traditionally all been treated the 

same way because their tumors look 

alike under a microscope. 

TCGA has also identified connections between features such as 

the age of the patient and molecular 

subtype. The proneural subtype is 

associated with younger patients, 

mutations in the IDH1 and TP53 

genes, and resistance to chemotherapy 

and radiation. 

Alternatively, the classical subtype with abnormalities in the EGFR 

gene has shown the best response 

to therapy. The next step is to 

Glioblastoma cells seen 

using fluorescent dyes 

to highlight cellular 

structures and proteins. 
 N A T I O N A L C A N C E R I N S T I T U T E 39 | C A N C E R P R O F I L E S : G L I O B L A S T O M A 

determine how to leverage advanced 

diagnostic procedures, such as 

molecular profiling, and to identify 

various GBM subtypes and match 

them with more appropriate patient 

therapies. Drugs that affect some of 

these pathways are available and, 

though promising in theory, have 

had mixed results in clinical trials. 

The difficulty of translating 

information about genetic abnormalities into successful treatments 

underscores the need for a viable 

laboratory model of GBM. It has 

been difficult to culture these cells in 

a manner that retains their unique 

characteristics and molecular profiles. Recently, researchers from the 

NCI intramural program and other 

institutions isolated rare cells from 

glioma tissues that resemble normal 

neural stem cells but have all the 

genetic abnormalities of the tumor. 

These “cancer stem cells” likely will 

be a better model for studying GBM 

and screening hundreds of drugs 

or combinations of drugs than the 

traditional cancer cell lines used until 

now. The hope is that improved cancer models will speed the availability 

of treatments to patients. 

specifically developed as an angiogenesis inhibitor. NCI played a key 

role in promoting the use of bevacizumab for the treatment of GBM— 

the first new FDA-approved treatment for recurrent GBM in nearly 

30 years. 

Angiogenesis, the formation of 

new blood vessels, is a critical process during the development of nearly 

all tumors, including GBM. As a 

tumor continues to grow, it needs a 

sufficient supply of nutrients that can 

only be provided by the development 

of new blood vessels to the tumor. 

By understanding the mechanisms of 

angiogenesis, potential therapeutic 

targets can be identified. Bevacizumab (Avastin) became the first 

FDA-approved agent that was 

In the future, tumors like GBM 

will no longer be defined solely under 

the microscope, but also on the basis 

of their molecular characteristics. 

As we expand molecular diagnostics 

to the full GBM genome, NCI will 

continue to play a pivotal role in 

providing resources and expanding 

the scientific infrastructure to apply 

findings to inform the next steps of 

discovery. 

MRI of an adult brain with 

invasive glioblastoma in left 

frontal lobe, colored red. 
40 N A T I O N A L C A N C E R I N S T I T U T E | 

Over the past 20 years, scientists have developed and 

refined a great wealth of laboratory techniques, such as 

PCR (a process that amplifies DNA or RNA) and protein 

and DNA microarrays comprised of small chips dotted with 

thousands of microscopic pieces of DNA, thus spurring the 

next generation of technological tools—molecular profiling. Molecular profiling uses an amalgamation of these 

techniques and others, to provide a more comprehensive 

picture of an individual tumor’s characteristics. Some of 

these characteristics include mutations or other changes 

in the DNA sequence, epigenetic changes, and unique 

patterns in the expression of thousands of genes and 

proteins. By providing a molecular map of an individual 

cancer, molecular profiling may allow clinicians to determine the origin of a cancer, its potential for metastasis, its 

drug responsiveness, and the probability of its recurrence, 

resulting in treatment strategies tailored specifically to 

individual patients. 

MO L ECU L AR PROFILIN G

Microarray of diffuse large B-cell lymphoma. 

NCI-supported researchers were among the first to demonstrate that molecular profiling could help classify similar 

types of cancers. They used two different types of leukemia 

—acute myeloid leukemia (AML) and acute lymphoblastic 

leukemia (ALL)—as test cases to demonstrate the utility 

of this approach. Distinguishing AML from ALL is critical 

for successful treatment, and although the distinction 

between AML and ALL has been well established, there is 

no single test that is sufficient to establish the diagnosis 

and identify the tumor type. Current clinical practice involves interpretation of the tumor’s morphology and other 

physical characteristics, which are determined by several 

specialized tests. Although usually accurate, errors occur, 

and leukemia classification remains imperfect. By using a 

more systematic approach to classify cancer—molecular 

profiling—researchers were able to not only distinguish 

between the two types of leukemia, but also to predict 

their responsiveness to chemotherapy. Molecular profiling 

has the potential to offer significant improvements in the 

molecular diagnosis and targeted treatment of the disease, 

providing a useful supplement to existing diagnostics. 

Numerous other NCI studies have used molecular profiling techniques to further classify two types of diffuse large 

B-cell lymphoma (DLBCL)—the most common type of nonHodgkin lymphoma. These cancer types are indistinguishable when first diagnosed, but are clinically very different 

as the disease progresses: 40 percent of patients respond 

well and exhibit prolonged survival while 60 percent 

do not. Led by Louis Staudt, M.D., Ph.D., head of NCI’s 

Molecular Biology of Lymphoid Malignancies Section, a 

team of researchers from several institutions used molecular profiling to show that there is significant diversity 

among the tumors of DLBCL patients. They identified two 

molecularly distinct forms of DLBCL and associated each 

form with a clinical outcome. These profiles were then 

used to develop mathematical predictors, which accurately 

divided patients into two categories—those with good and 

those with poor prognoses—and proved to be a more powerful tool than the standard methods for the identification 

of high-risk patients. 

The potential of molecular profiling is not limited to leukemia and lymphoma; progress is being made with molecular profiling of many solid tumors as well. However, much 

research still needs to be done before this tool can be used 

routinely in the clinic. 
N A T I O N A L C A N C E R I N S T I T U T E 41 | C A N C E R P R O F I L E S : A C U T E M Y E L O I D L E U K E M I A 

A C U T E M Y E L O I D L E U K E M I A

More than 12,000 Americans 

were diagnosed with AML 

in 2010, and nearly 9,000 

died from the disease. Following 

diagnosis, patients with AML have 

an overall five-year survival rate of 

23 percent. 

AML is a cancer of the bone 

marrow that develops when a type of 

precursor cell, the myeloblast, proliferates unchecked and fails to differentiate, resulting in accumulation 

of myeloblasts in the bone marrow 

and blood. AML is characterized 

by a high degree of genetic alterations—about half of patients with 

AML have chromosomal changes or 

rearrangements that can be seen by 

special staining procedures and visualized under the microscope (karyotyping). AML illustrates the key 

role of NCI support in untangling 

Light micrograph of large 

numbers of white blood cells in 

a patient with AML. 

the myriad mutations that underlie 

cancer. Discovering these mutations 

is the first step in the development of 

new treatments. 

Recent advances in understanding the genetics of AML have moved 

diagnosis beyond karyotyping to 

molecular profiling (see molecular 

profiling box), resulting in improved 

classification and stratification of 

cancer subtypes. Molecular profiling 

refers to a series of high-throughput 

techniques that scientists use to measure many characteristics of the cell, 

essentially giving a snapshot of the 

cell at the moment of the test, which 

includes extensive characterization 

of DNA through sequence analysis, 

determination of whether there are 

extra copies of some genes, and assessment of other changes to DNA or 

DNA-associated proteins that may 

influence gene expression (sometimes 

called epigenetic changes). In addition, it is possible to gain insight 

into pathways that are active in a 

cell by measuring levels of proteins 

and messenger RNA (the templates 

from which proteins are formed), as 

well as looking at patterns of expression of microRNAs, which are small 

RNA molecules capable of regulating 

gene expression. Piecing together the 

information provided by molecular 

profiling will provide the map that 

eventually may guide us to new 

therapies for AML. 

In 2003, Timothy Ley, M.D., 

professor of genetics at Washington University in St. Louis, and his 

colleagues applied for an NCI grant 

to sequence all of the genes in the 

normal and leukemic cells of patients 

with AML. At the time, sequencing 
42 N A T I O N A L C A N C E R I N S T I T U T E | 

the entire genome of cancer patients 

was an extremely expensive and ambitious concept. Despite debate as to 

what might be learned, NCI supported the proposed research. Ultimately, 

Ley’s team identified a mutation in 

the gene for DNA methyltransferase 3A (the DNMT3A gene) in the 

tumor cells of AML patients who did 

not exhibit any large-scale chromosomal changes. DNA methyltransferases add molecules called methyl 

groups to DNA, which can influence 

DNA structure and activity. High 

levels of methylation in regions of 

DNA that control expression of specific genes often result in lower levels 

of expression of those genes. 

This particular DNMT3A gene 

mutation is associated with poor 

outcomes for AML and can be used 

to make treatment decisions: for 

patients with a DNMT3A gene mutation, chemotherapy is not the best 

treatment option. These data suggest 

that molecularly informed therapies 

will be selected for a patient’s individual cancer, resulting in a therapy 

that would likely have the highest 

efficacy. 

Subsequently, in 2009, Ley’s 

team linked mutations in isocitrate 

dehydrogenase 1 and 2 (IDH1/2 

genes), which had previously been 

found in glioblastoma, to AML. 

Within a year of the IDH1/2 gene 

mutation discovery in AML, studies conducted by a group partly 

funded by an NCI specialized cooperative center grant designed to 

bring together physical scientists, 

engineers, cancer biologists, and 

oncologists in collaboration with a 

pharmaceutical company, revealed 

“It’s an amazing time 

in cancer research. 

I’m convinced that 

some of the findings 

are so clear and 

so informative and 

have such a tremendous potential to 

change things that 

I think it’s possible 

only to be optimistic 

about the future.”

 — Tim Ley, M.D., Professor of 

Genetics, Washington 

University in St. Louis 

that these mutations resulted in the 

excess production of the cellular 

metabolite, 2-hydroxyglutarate 

(2HG). Studies suggest that IDH1/2 

gene mutations may not be the first 

step in development of either AML 

or glioblastoma but are potential 

drivers for tumor progression. As 

this profile illustrates, understanding 

the molecular changes underlying 

cancer can provide the foundation 

for ultimately improving the way we 

deliver therapy and identifying new 

targets for therapy.
 N A T I O N A L C A N C E R I N S T I T U T E 43 | C A N C E R P R O F I L E S : A C U T E M Y E L O I D L E U K E M I A 

 

 

 

 

 

 

 

 

 

 

 

EPIGENETICS

Looking back on discoveries made in just the last decade 

or two, it’s easy to see the hope—and promise—that the 

future holds. For example, we know much more about 

both genetic alterations (changes to the DNA sequence, 

changes in gene copy number, and rearrangements of 

chromosomal DNA) and epigenetic changes (persistent 

changes in gene activity that result from the addition or 

removal of chemical tags and DNA-associated proteins to 

DNA that affect how and when genes are turned on or off) 

and how these changes lead to initiating development 

and spread of cancer. 

The initiation and progression of cancer are controlled by 

both genetic and epigenetic changes; however, unlike 

genetic alterations, epigenetic changes are potentially 

reversible. Following the approval of several drugs that 

target specific molecules involved in the epigenetic regulation of gene expression, the use of epigenetic targets is 

emerging as a valuable approach to chemotherapy as 

well as chemoprevention of cancer. 

Normal epigenetic modifications encompass two major 

types of changes: DNA methylation and modifications to 

the components that make chromosomes, or chromatin, 

each of which is altered in many cancer cells. As a result, 

cells cannot appropriately control gene expression (genes 

are repressed when they should be activated or activated 

when they should be silent) and thus cell proliferation 

can occur at inappropriate times, augmenting cancer 

development. 

Conceptual DNA helix showing regions silenced due to 

addition of a methyl group 

or active due to absence of 

a methyl group. 

Methyl group 

No methylation 

Methylation 

Active gene 

Silenced gene 

The potential reversibility of epigenetic modifications 

suggests that they are viable targets for the treatment of 

cancer, and a small number of drugs that target epigenetic 

changes have been developed over the years. An NCI 

developmental research grant supported the development 

of vorinostat (Zolinza), which targets histone modifications 

and it, along with a second inhibitor for histone modifications, romidepsin (Istodax), has been FDA approved for the 

treatment of T-cell lymphoma. A recent study suggested 

that vorinostat also possesses some activity against recurrent glioblastoma multiforme, resulting in an improved 

median overall survival of 5.7 months. Decitabine (Dacogen) and azacitidine (Vidaza), which target DNA methylation, have been approved for the treatment of myelodysplastic syndrome—a pre-cancerous state that frequently 

leads to deadly cancer of the bone marrow. A few years ago, 

the latter diagnosis was a death sentence. Today, patients 

have a good chance of remission with fewer side effects 

than offered by conventional chemotherapy. These drugs 

offer the potential for chemoprevention, by reversing 

epigenetic changes before they lead to full-blown cancer. 
44 N A T I O N A L C A N C E R I N S T I T U T E | 

N E U R O B L A S T O M A

Each year about 700 children 

in the U.S. are diagnosed 

with neuroblastoma (which 

comprises about 7 percent of pediatric cancers), and approximately 

200 children die of the disease. Little 

is known about risk factors for 

neuroblastoma, though 1 percent to 

2 percent of patients have a family 

history of neuroblastoma. The rarity 

of the disease makes NCI’s involvement in funding research and developing new therapies particularly 

critical, as pharmaceutical companies 

are unlikely to invest in diseases 

for which there is a small potential 

market. 

As we have been learning for 

many cancers, neuroblastoma is not 

a single disease. Researchers have 

identified three biologically distinct 

types of neuroblastoma. The three 

risk categories for neuroblastoma— 

low, intermediate, and high—which 

indicate patient prognosis, are based 

in part on these biological types. 

High-risk neuroblastoma accounts 

for about half of all cases and is the 

most challenging to treat. Most cases 

of high-risk neuroblastoma occur in 

children one year of age and older. 

Five-year survival rates in children 

one year of age or older have improved, increasing from 35 percent in 

the period from 1975 to 1978 to 65 

percent from 1999 to 2002. Despite 

improvements in survival, current 

therapy is not adequate for about half 

of children with high-risk disease. 

of chemotherapy and radiation 

therapy. Other cancers are informing 

potential therapies for neuroblastoma, as some mutations are shared 

across disease types. 

Developing new therapies for 

high-risk neuroblastoma has posed a 

significant challenge; until recently, 

these children had few treatment 

options other than escalating doses 

Just this past year, results from 

an NCI-funded Children’s Oncology 

Group (COG) clinical trial demonstrated that ch14.18, an antibody that 

binds to a cell surface protein called 

GD2, is effective for children with 

high-risk neuroblastoma when given 

in conjunction with other immuneboosting drugs. An approximately 10 

percent increase in two-year survival 

(which went from 75 percent to 86 

percent) was observed among patients who had been treated with the 

antibody and immune-boosting drugs 

compared with those who had been 

treated with standard therapy. The 

initial discovery that most neuroblastoma cells express GD2 on their 

surfaces was made in the 1980s, 

but translation of this finding into a 

successful therapy took nearly two 

decades. Because GD2 is not found in 

more common cancer types, pharmaceutical companies exhibited little 

interest in making the ch14.18 antibody. Instead, NCI manufactured and 

provided the antibody for the phase 

III trial that demonstrated efficacy 

and continues to manufacture the 

A neuroblastoma cell 

viewed with a scanning 

electron micrograph; the 

cell has a rough surface 

with many finger-like 

cytoplasmic projections. 
 N A T I O N A L C A N C E R I N S T I T U T E 45 | 

“NCI’s role in the 

success of this trial 

went far beyond 

funding. The COG 

team that led the 

clinical trial had 

access to a unique 

and outstanding 

resource: NCI’s 

drug production 

facility, where NCI 

scientists manufactured the antibody 

because no privatesector company was 

willing to do so. ” 

C A N C E R P R O F I L E S : N E U R O B L A S T O M A 

— John Maris, M.D., Director, 

Center for Childhood Cancer 

Research, Abramson Family 

Cancer Research Institute 

Wells of neuroblastoma 

cells in culture, used to 

test the effects of potential therapeutic agents on 

the cells.
�

antibody for ongoing COG trials. 

The translation of ch14.18 from 

discovery to the clinic took 20 to 

25 years; however, under the right 

circumstances, development of new 

therapies can occur more rapidly. 

In 2008, an NCI-funded laboratory 

discovered that mutations in the 

anaplastic lymphoma kinase (ALK) 

gene cause the majority of hereditary 

neuroblastoma cases. In addition, the 

ALK gene is mutated or amplified in 

approximately 7 percent of sporadic 

neuroblastoma cases. While many 

genetic discoveries are heralded as 

promising targets for screening or 

therapy, the ALK’s gene potential 

as a therapeutic target was quickly 

exploited. The ALK gene is also mutated, through a different mechanism 

(fusion with another gene by chromosomal rearrangement), in about 

3 percent to 5 percent of non-small 

cell (NSCLC) lung cancers (see lung 

cancer profile). The potential of the 

ALK gene as a target for NSCLC in 

addition to neuroblastoma resulted 

in increased interest in developing 

drugs against the ALK gene and 

quickly led to the launch of a COG 

phase I clinical trial of crizotinib, an 

ALK inhibitor that had demonstrated success in a lung cancer phase I 

trial—just one and a half years after 

the initial genetic discovery in neuroblastoma. 

Much attention has been focused 

on genetic discoveries such as the 

ALK gene findings, but understanding basic biology can also lead to new 

interventions. Researchers in NCI’s 

intramural program observed that 

retinoids (derivatives of vitamin A) 

imposed growth control and induced 

differentiation in neuroblastoma cells 

grown in the laboratory. By investigating the mechanisms leading to differentiation, scientists discovered that 

retinoic acid was inducing chemoresistance through a cellular survival 

signaling pathway involving the AKT 

family of protein kinases. Inhibition 

of AKT with a small molecule called 

perifosine slowed cell growth and 

sensitized tumors to chemotherapy. 

Identification of leads for testing in future clinical trials likely 

will stem from continued efforts to 

understand the basic biology that 

drives tumor formation. One aspect 

of neuroblastoma that intrigues 

researchers is the fact that many lowrisk tumors resolve spontaneously, 

suggesting that the body is capable 

of eliminating at least some cells that 

go awry. Uncovering the mystery of 

spontaneous regression might have 

implications for the prevention and 

treatment of neuroblastoma and 

other cancers in the future. 
46 N A T I O N A L C A N C E R I N S T I T U T E | 

L U N G C A N C E R

An estimated 220,000 individuals were diagnosed with some 

form of lung cancer in 2010. It 

is the leading cause of cancer-related 

death, with more than 157,000 

predicted deaths in 2010. Smoking is 

far and away the most important risk 

factor for lung cancer. It is evident 

that risk increases with the number 

of cigarettes smoked per day and the 

duration of smoking. Deaths from 

lung cancer have been decreasing in 

men since 1990, but have been stable 

in women since 2003 after continuously rising for several decades. 

These trends reflect historical differences in smoking between men and 

women, and the decrease in smoking 

rates over the past 40 years. 

The cancer community is poised 

to take advantage of the convergence 

of genetic information, appropriate 

screening techniques (see section on 

NLST on page 14), and new targeted 

therapies for lung cancer. For the 

enormous number of individuals 

who will face a diagnosis of lung 

cancer this year, any brighter outlook 

is most welcome. 

When we say lung cancer, we 

are actually referring to four different subtypes. Three subtypes are 

non-small cell lung carcinomas, or 

NSCLC: adenocarcinoma, squamous 

cell carcinoma, and large cell carcinoma; the fourth subtype is small cell 

carcinoma. This first-level classification is likely to be the start of solving 

a complicated challenge of linking 

diagnostic characteristics to the most 

effective treatments. NCI-supported 

researchers are beginning to uncover 

genetic drivers of these four subtypes 

and applying this molecular knowledge for clinical benefit. However, 

it is clear that the best in diagnostic 

technologies and therapeutic advances will be needed to make significant 

progress in treating this very complex collection of diseases. Ideally, 

this will be complemented by downward trends in smoking rates, which 

is the most effective way to reduce 

the burden of lung cancer. 

There are currently several mutations that are known to exist in lung 

cancer, including EGFR and RAS 

gene mutations in non-small cell lung 

Scanning electron micrograph image of a small 

cancerous tumor inside 

an alveolus, or air sac, 

in a lung. 
 N A T I O N A L C A N C E R I N S T I T U T E 47 | C A N C E R P R O F I L E S : L U N G C A N C E R 

cancer. As with melanoma and some 

other cancers, BRAF gene mutations 

have also been found in lung cancers. Last year, researchers identified 

a genetic target known as a gene 

translocation, or movement of a gene 

fragment from one chromosomal 

location to another. The translocated 

gene, EML4-ALK—found in 5 percent of NSCLC patients—can be acted on by crizotinib, a promising new 

drug with minimal side effects. Crizotinib acts by blocking the ALK kinase, 

believed to promote tumor growth. 

Results from this phase I trial showed 

that more than half of treated patients 

experienced tumor shrinkage while 33 

percent had their tumors stabilize. The 

development of crizotinib was made 

possible through molecular tumor 

characterization that was conducted at 

NCI-designated Cancer Centers. The 

drug was first tested against anaplastic 

large-cell lymphoma as well as on neuroblastoma and NSCLC cells grown 

in the laboratory. Preliminary results 

of the phase I trial were so promising 

that a trial testing crizotinib in children 

with neuroblastoma was launched less 

than six months after the release of the 

results (see neuroblastoma profile). 

While efforts to further decrease 

smoking rates are critical, there is 

also great opportunity to utilize 

molecular and genetic information to 

significantly improve the treatment 

options available to patients diagnosed with lung cancer. This will require continued investigation into the 

biology of the various types of lung 

cancer and coordination between 

laboratory and clinical researchers to 

optimize existing treatment strategies 

and develop new ones.

 “I think it’s an exciting 

time now, because 

if we can influence 

early diagnosis and 

prevention of lung 

cancer, and care of 

discovered lung cancer, we could actually 

make a major change 

to total cancer mortality in the United 

States. [Already] the 

total cancer mortality 

has gone down over 

the past five to ten 

years mainly due to 

decreases in cigarette smoking.” 

— John Minna M.D., 

director of the Harmon Center 

for Therapeutic Oncology 

Research at the University 

of Texas Southwestern 

Medical Center 
48 N A T I O N A L C A N C E R I N S T I T U T E | 

O V A R I A N C A N C E R

I

n 2010, ovarian cancer was the 

fifth most common cause of 

cancer death in U.S. women. Each 

year more than 21,000 American 

women are diagnosed with ovarian 

cancer, and about 14,000 die from 

the disease, making ovarian cancer 

the most deadly cancer of the female 

reproductive tract. Though this 

cancer is diagnosed in adult women 

of all ages, the five-year survival rate 

of 57 percent for women under 65 

years of age is nearly twice that of 

women over 65. Ovarian cancer is 

particularly devastating because the 

disease frequently is not recognized 

until relatively late in its progression, due to the lack of early symptoms and effective screening tests. 

Currently, fewer than 20 percent of 

ovarian cancers are diagnosed early, 

when treatment is most effective. 

Prognosis is particularly discouraging for patients with advanced-stage 

disease—only about one-third live 

five years past their diagnosis. 

Although ovarian cancer continues to be a major problem, cancer 

researchers are making headway 

in improving diagnosis and treatment as well as advancing our basic 

understanding of this disease, and 

NCI is mounting several major 

efforts to push progress in these 

areas. For example, the most aggressive type of ovarian cancer was one 

of the three cancer types analyzed 

during the pilot phase of The Cancer Genome Atlas. In early studies, 

significant heterogeneity was observed among the nearly 500 ovarian 

tumors that underwent molecular 

characterization. While virtually all 

of the tumors had mutations in the 

well-characterized tumor suppressor 

gene p53, there were other mutations 

present in smaller subsets of tumors, 

including mutations in BRCA1 and 

BRCA2 (genes also associated with 

hereditary breast cancer). 

Another finding from the ovarian 

cancer characterization has exciting therapeutic potential. There are 

many DNA copy number changes— 

large regions of DNA whose number 

of copies are increased or decreased, 

Ovarian cancer cells 

viewed with a scanning 

electron micrograph; 

these are pleomorphic 

epithelial cells covered in 

microvilli. 
 N A T I O N A L C A N C E R I N S T I T U T E 49 | 

compared with normal DNA— 

consistent with a high level of genomic instability. There are some 

indications from studies on ovarian and other types of cancer that it 

may be possible to exploit genomic 

instability therapeutically. In addition, there may be recurring patterns 

to some regions of DNA whose copy 

number is increased or decreased. 

Areas of increased copy number 

found in a high proportion of ovarian cancers are likely to contain one 

or more oncogenes that contribute 

to the malignant properties of the 

cancer. Cancer biologists can analyze 

the candidate genes that lie within 

these regions to determine which 

are the most important for ovarian 

cancer. This type of analysis may 

identify new therapeutic targets with 

relevance to a high proportion of 

ovarian cancers. 

As with all TCGA data, the 

genomic information is being made 

freely available to the scientific community, providing opportunity for researchers from different backgrounds 

and with different perspectives to 

gain insight into the disease. In one 

example, the comprehensive molecular analysis carried out by TCGA is 

being used by systems biologists to 

develop computational models that 

aim to predict patient response to 

various therapeutic interventions 

based on a tumor’s molecular profile. 

These and other efforts eventually 

should help match patients with molecularly diverse ovarian tumors to 

the most appropriate treatments. 

Despite the challenges to treatment of advanced ovarian cancer, 

some progress is already being made. 

For example, bevacizumab (see 

glioblastoma profile) has demonstrated activity in women with recurrent ovarian cancer. In 2010, results 

from a phase III clinical trial studying the effect of adding bevacizumab 

to standard chemotherapy treatment 

in women with newly diagnosed, 

advanced ovarian cancer, found that 

addition of the drug extended survival by several months compared to 

standard chemotherapy alone. 

Technological advances in the 

areas of molecular diagnostics and 

imaging have potential to facilitate 

the development of effective and 

minimally invasive early-detection 

tests. Through its Early Detection 

Research Network and other mechanisms, NCI supports translational 

researchers at institutions across the 

country who are using varied approaches to identify potential screening biomarkers and conducting the 

necessary clinical and epidemiological research to confirm promising 

leads. Much of the work is focused 

on developing panels of biomarkers 

that can more accurately detect cancer at an early stage. Some progress 

is being made in this area, but it is 

clear that more work is needed to 

develop tests sufficiently sensitive 

to detect cancer early enough to 

improve patient outcomes. 

C a N C e r p r o f i l e s : o v a r i a N C a N C e r 
50 N A T I O N A L C A N C E R I N S T I T U T E | 

IMMUNOTHERAPY ADVANCES 

The pace of progress in immunotherapy has quickened 

in recent years, with some early-stage clinical trials of 

different therapies showing positive results for several 

different cancer types. In a recent large clinical trial, a 

monoclonal antibody called ipilimumab (also known as 

MDX-010), which treats cancer by binding to cells of the 

immune system and inhibiting their activity, became the 

first immunotherapeutic agent to show an increase in 

the survival of patients with advanced melanoma whose 

disease was no longer responding to other treatments. 

Given the paucity of effective treatments for patients 

with advanced melanoma, this finding represents a 

significant therapeutic advance. In late March, the FDA 

 approved that drug, which will be marketed under the 

 name Yervoy, to treat late-stage melanoma.

Immunotherapy using a syringe 

to remove purified lymphocytes 

from a blood bag, prior to 

addition of Interleukin-2 (IL- 2). 

Other forms of immunotherapy also hold promise. Last 

year FDA approved the first therapeutic cancer vaccine. Sipuleucel-T (Provenge) is designed for men with 

advanced prostate cancer. A different therapeutic vaccine developed by NCI investigators to treat advanced 

prostate cancer is moving into a phase III, or advanced, 

clinical trial. 

Other potentially promising immunotherapy approaches 

include inducing the immune system to target so-called 

tumor stem cells—or tumor-initiating cells, which are 

thought to be a chief cause of cancer recurrences—or to 

attack normal cells in the tumor microenvironment that 

cooperate with tumor cells to help them survive and 

spread to other parts of the body. 

Despite the progress we have made, more therapies to 

effectively stimulate the immune system to destroy cancer cells and promote destruction of tumors are urgently 

needed. The development of reliable animal models of 

cancer that more closely mimic how the human immune 

system responds to tumors will provide invaluable tools 

for developing future immunotherapy agents and vaccines for cancer. 

As of early 2011, there were nine such immunotherapeutic agents that are FDA-approved, including 

trastuzumab. Many other such agents, for many types 

of cancers, are being tested in clinical trials.
 N A T I O N A L C A N C E R I N S T I T U T E 51 | 

SYNTHETIC LETHALITY 

Finding drugs that kill cancer cells while leaving normal 

cells unscathed has been a major challenge in cancer 

treatment. However, there have been considerable advances in genomics in the last decade that have revealed 

a novel and promising approach: synthetic lethality. The 

concept is simple—a compound targeting a particular 

gene or pathway is selectively lethal to cells that harbor 

a cancer-causing mutation in a complementary pathway. 

Healthy, noncancerous cells are spared. In this method, 

two genes are said to be in a synthetic lethal relationship 

if disruption of either gene alone is not lethal, but changes 

in both genes—either by mutation or chemical inhibition— 

causes cell death. 

The approach tailored for cancer biology is based on the 

premise that oncogenic mutations often cause cancer 

cells to develop secondary dependencies on other genes 

that are not inherently oncogenic. Chemical inhibitors that 

disrupt these latter genes result in an oncogene-specific 

synthetic lethal interaction, and thus cell death. Healthy, 

noncancerous cells are spared. 

As an example, an exciting new class of drugs, called PARP 

(poly adenosine-disposphate-ribose polymerase) inhibitors, is being tested in a number of clinical trials in cancer 

patients with BRCA gene mutations. The BRCA and PARP 

genes, which have a synthetic lethal relationship, play 

different, but complementary, roles in DNA repair. Loss of 

either of these genes allows the cell to survive; but when 

PARP activity is blocked in cells with BRCA gene mutations, the cells lose their ability to repair themselves, 

resulting in cell death. Equally important, PARP inhibition, 

which kills cancer cells, spares cells that have at least one 

normal copy of the BRCA gene. 

Results from a recent phase I study using olaparib, a PARP 

inhibitor, showed that nearly 60 percent of patients who 

were BRCA gene mutation carriers and had ovarian 

cancer, breast, or prostate cancer, had some measure 

of clinical benefit. More than one-third of patients had 

tumor shrinkage in phase II studies of olaparib (AZD2281) conducted in women with BRCA1 or BRCA2 gene 

mutations and advanced chemotherapy-refractory breast 

or ovarian cancer. A second PARP inhibitor, iniparib (BSI201), appears to be even more promising. In combination 

with conventional chemotherapy, iniparib improved the 

duration of overall and progression-free survival in women with metastatic triple-negative breast cancer nearly 

40 percent compared to those who received chemotherapy alone. Iniparib did not cause additional toxicities. 

Cancer patients with BRCA1 and BRCA2 gene mutations 

are not the only candidates for PARP inhibition therapy. 

The Cancer Genome Atlas has revealed numerous other 

tumors with defects in DNA repair, creating opportunities 

for more types of synthetic lethality-based therapies. 

Researchers are also using the concept of synthetic lethality in genome-wide and chemical searches to identify 

cancer-killing drug combinations and new gene-targets to 

kill lung cancer cells. An NCI-sponsored study identified 80 

new genes that were synthetically lethal in combination 

with taxol treatment of cancer cells. Inactivation of these 

genes killed lung cancer cells but not normal cells, and only 

in the presence of a very low dose of taxol. This type of synthetic lethal approach has enormous potential not only for 

the treatment of lung cancer but numerous other cancers 

as well. Through combining novel, synthetic lethal inhibitors with traditional chemotherapeutic drugs, unlimited 

numbers of genetically diverse cancers could potentially 

be treated with fewer side effects. These findings seem to 

have great potential, but they were made in cultured cells, 

and it has not yet been determined that they accurately 

predict therapeutic response 

in people with cancer. 

Depiction of a signaling pathway that could be affected by 

synthetic lethality. Shown are 

two types of transmembrane 

protein receptors, smoothened (red) and patched 

(blue) that could be targeted. 

C a N C e r p r o f i l e s : o v a r i a N C a N C e r 
52 N A T I O N A L C A N C E R I N S T I T U T E | 

Revitalizing the Nation’s Cancer Clinical Trials System

I

f today’s new understandings of cancer biology are to benefit cancer patients 

on a broad scale, they must be coupled with a modernized system for conducting cancer clinical trials. This system must enable clinical researchers across 

the nation to acquire tumor specimens and conduct genetic tests on each patient, 

to efficiently sequence the DNA from those samples, to manage and secure vast 

quantities of genetic and clinical data, and to identify subsets of patients with 

tumors that demonstrate changes in specific molecular pathways—pathways that 

can be targeted by a new generation of cancer therapies. And all of this must be 

done one patient at a time. 

As part of its effort to transform the cancer clinical trials system, NCI asked the 

Institute of Medicine (IOM) in 2009 to review the Clinical Trials Cooperative Group 

Program. This program involves a national network of 14,000 investigators 

currently organized into nine adult Cooperative Groups and one pediatric 

cooperative group that conduct large-scale cancer clinical trials at 3,100 sites 

across the U.S. The IOM report, issued in April 2010, noted that the current trials 

system—established a half-century ago—is inefficient, cumbersome, underfunded, and overly complex. Among a series of recommendations, the report 

urged that the existing adult cooperative groups be consolidated into a smaller 

number of groups, each with greater capabilities and the ability to function with 

the others in a more integrated manner. 
N A T I O N A L C A N C E R I N S T I T U T E 53 | 

In December 2010, NCI announced its intent to begin consolidating the current 

nine adult cooperative groups into up to four state-of-the-art entities that will 

design and perform improved trials of cancer treatments, as well as explore 

methods of cancer prevention and early detection and study quality-of-life issues 

and rehabilitation during and after treatment. The sole pediatric cooperative 

group was created by consolidating four pediatric cooperative groups a number of 

years ago, and that group will not be affected by the current consolidation effort. 

NCI also intends to consolidate nine existing tumor banks into three to give 

researchers improved access to a nationally integrated tissue resource. 

Currently, optimal use of tissue specimens from NCI-supported prospective 

trials is impeded by the lack of a national IT system for locating tissue, the lack 

of standard operating procedures, and the lack of a transparent process to 

prioritize the distribution of specimens on a national scale. 

The consolidation of the cooperative groups is also intended to improve the efficiencies of operations centers and data management centers, and to facilitate the 

training of investigators in applying molecularly based approaches to large-scale 

clinical trials. In addition, NCI envisions using the Cooperative Group Program as 

a means for preparing the oncology community, including community physicians, 

for the widespread introduction of molecularly-based therapies. 

The consolidation of the Cooperative Group Program is the most recent in a 

series of changes initiated by NCI, through its Division of Cancer Treatment and 

Diagnosis and the Coordinating Center for Clinical Trials, to revitalize the nation’s 

cancer clinical trials system. Other transformative changes introduced in recent 

years include those outlined in a working group report which can be found at 

http://ccct.cancer.gov/files/OEWG-Report.pdf: 

•	� Reduce by half the time to initiate new clinical studies and terminate studies 

not begun within 18 to 24 months of concept approval. 

•	� Revamp the prioritization process for large phase II and phase III treatment 

trials by creating disease-specific and modality-specific steering committees. 

•	� Improve the use and efficiency of the NCI Central Institutional Review Board, 

which reduced the average time for final sign-off on protocols for national 

trials from 150 days in 2007 to 42 days in 2010. 

•	� Increase reimbursement to clinical trials sites. 

Revitalizing a cancer clinical trials system must enable researchers across the nation 

to acquire tumor specimens and conduct genetic tests on each patient, efficiently 

sequence DNA, and identify subsets of patients with tumors that demonstrate changes 

in specific molecular pathways.
54 N A T I O N A L C A N C E R I N S T I T U T E | 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 Director’s Afterword

I

was sworn in as the new Director of the National Cancer Institute just nine 

months ago, so this is the first time that I have been privileged to voice my 

pride in NCI’s past accomplishments and the promise of future achievements 

in its annual report on budget needs and priorities. 

Although I am new to this position, I am not new to cancer research or to the 

NCI. I received my scientific training here more than 40 years ago, started to 

work on cancer-causing viruses shortly thereafter, and have been supported by 

NCI funds throughout my career. In these intervening years, I have witnessed 

profound changes in our knowledge about the biology of cancer. When I began to 

study animal models of cancer in the early 1970s, the collective understanding of 

the origins and progression of cancer was negligible; now we are able to describe 

such events in minute detail at the molecular level. This transformation has been 

accompanied by gradual—and occasionally dramatic—improvements in the 

control of human cancer. In an increasing number of cancers, new concepts about 

the biology of cancer are now driving beneficial changes in the ways we prevent, 

diagnose, and treat disease. 

The importance of the NCI throughout this rich history can best be appreciated 

by considering the amazing diversity of the approaches it has undertaken to 

control cancer—through basic research on normal cells, genes, and proteins; 

through studies of the pathogenesis of various forms of cancer; and through 

efforts to improve the prevention, diagnosis, and treatment of cancers. 

In the first half of this report, we have tried to convey the depth of these enterprises, while emphasizing at least three big ideas. First, cancer constitutes a complex 

set of diseases. It is not simply one disease that happens to afflict many organs 

of the body; it is, instead, many different disorders that display some common 

themes, including mutations in many important genes, alterations in essential cell 

functions, and novel interactions with the cellular environment in which tumors 

grow. Second, cancers can be controlled in many different ways. As reflected in 

their biological complexity, cancers invite several strategies to improve control. 

These include a number of approaches to prevention, multiple methods to 

screen for early stages of carcinogenesis, more precise diagnostic tests, and better 
 N A T I O N A L C A N C E R I N S T I T U T E 55 | 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

therapies. The improved treatments are based on knowledge of specific genetic 

changes in cancer cells, the functions of the immune system, the susceptibilities 

of cancer cells to various drugs and radiotherapy, and an understanding of the 

symptoms and complications of these diseases. 

Third, advances against cancer that benefit people depend on science of many 

kinds. Progress in the control of cancer has required new knowledge from the 

many fields of research that the NCI supports—from molecular and cell biology, 

genetics, virology, immunology, and chemistry; from animal models of cancer; 

from the behavior and biology of human beings; and from many other directions. 

In brief, cancer represents one of the greatest challenges to the strength of modern 

medical science. 

My colleagues and I have chosen to illustrate these ideas, and the complexity they 

embody, by describing recent progress made against six kinds of cancer, chosen 

somewhat arbitrarily from a much larger repertoire of successes. We acknowledge 

that none of these six stories is over; in all situations, we have much more to do. 

But each narrative reveals a promising path to further progress. 

The men and women who have achieved these successes and who are poised 

to extend them represent our greatest resource. With the additional funds 

requested here, their ambitions and talents can be unleashed, ensuring that the 

NCI can take the greatest possible advantage of the opportunities created by its 

remarkable history. 

Harold Varmus, M.D. 

Director, National Cancer Institute 
At a Glance (dollars in thousands)

 Fiscal Year 2011 Estimate $5,103,388 

Current Services Increase 207,869 

Subtotal 5,311,257 

Fiscal Year 2012 Additional Resources 

Support Individual Investigators 173,000 

Genomics 145,600 

Clinical Trials 125,000 

Translational Sciences 

Subtotal

Total NCI 

115,000 

 558,600 

$5,869,857 

The 2012 Budget Request

56 N A T I O N A L C A N C E R I N S T I T U T E | 

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 some 

minimal growth. Noncompeting Research Project Grants (RPGs) would 

be funded at committed levels, the 

number of competing RPGs would 

be maintained at the FY 2010 level, 

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 

funds to make critically needed 

capital repairs and improvements at 

the NCI-Frederick Federally Funded 

Research and Development Center. 

The additional funds requested 

reflect 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. 

National Cancer Institute 

Conceptual computerized 

image of DNA. 

NIH Publication No. 11-7760

Printed March 2011