Building on Opportunities in Cancer Research
 

NATIONAL CANCER INSTITUTE 

AN ANNUAL PLAN AND 

BUDGET PROPOSAL FOR 

FISCAL YEAR 

2016

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES 

National Institutes of Health 

National Cancer Institute 
Table of Contents 

1 Foreword 

4 The Changing Cancer Landscape

4 Lower Death Rates & More Survivors 

6 Improved Prevention, Screening & Treatment 

14 Rapid Progress Depends on Long-Term Support 

16 Building on the National Cancer Program 

16 New Approaches to Funding Researchers 

20 NCI-Designated Cancer Centers 

22 NCI’s National Clinical Trials Enterprise 

25 Overcoming Cancer Health Disparities 

28 NCI’s Intramural Research Program 

30 Bioinformatics to Accelerate Research 

32 Frederick National Laboratory for Cancer Research 

34 Opportunities in Cancer Research 

34 Building on Discoveries in Cancer Genomics 

38 Advancing Precision Medicine Trials 

40 Harnessing the Promise of Immunotherapy 

43 Making Progress against Childhood Cancers 

46 Developing Therapies for RAS-Driven Cancers 

50 Finding New Strategies to Prevent Cancer 

58 The Future 

61 Budget

61 NCI Professional Judgment Budget Recommendation 
An Annual Plan and Budget Proposal for Fiscal Year 2016 1 

NATIONAL CANCER INSTITUTE 

SCOPE OF OUR WORK 

Basic Science 

Risk Factors 

Detection 

& Diagnosis 

Prevention 

Control 

Survivorship 

Treatment 

Causes 

www.cancer.gov 

Foreword 

This is a time of remarkable opportunity

in cancer research. Armed with broad knowledge 

about how various kinds of cancer arise and with powerful 

new research tools, the cancer research community, under the 

leadership of the National Cancer Institute (NCI), is poised to 

reduce the burden of cancer in this country and around the 

world at an accelerated pace. 

The NCI’s goal is to support research that ultimately leads to 

important clinical outcomes: improvements in prevention, 

diagnosis, and treatment that can reduce the incidence, 

morbidity, and mortality of all types of cancer. Making sustained 

progress, however, requires a wide range of research disciplines 

that span the continuum from basic science to clinical research 

to research on implementation and cancer care delivery. 

They include a variety of basic sciences, 

such as genetics, genomics, cell biology, 

immunology, and nanotechnology; 

translational and clinical sciences, 

such as drug development and testing, 

diagnostics, and the discovery and 

development of molecular markers, 

advanced imaging technologies, and 

new radiotherapy techniques; population 

sciences, such as population genetics, 

epidemiology, and environmental 

sciences; and behavioral sciences. Virtually 

all major advances toward the goal of 

improving the prevention, diagnosis, 

and treatment of cancer depend on 

many kinds of science. Cancer research 

is also cumulative. Today’s investments 

in basic science will provide tomorrow’s 

opportunities in clinical research. 
2 National Cancer Institute 

The NCI seeks to manage 

its resources to take 

advantage of the most 

promising scientific 

opportunities. Photo of 

NCI researchers Olga 

Nikolaitchik, Ph.D., 

Wei-Shau Hu, Ph.D., and 

Jianbo Chen, Ph.D. 

Photo by Rhoda Baer 

The NCI’s broad responsibilities for supporting research are 

severely tested during fiscally austere times that require a 

delicate balancing of its resources. This is especially true during 

long periods when budgets do not keep pace with inflation, 

as has occurred over the past decade. (The temporary budget 

increases in 2009 and 2010 associated with the American 

Recovery and Reinvestment Act [ARRA] were exceptions 

to this trend.) NCI-supported activities include funding 

thousands of grants to individual scientists and teams in 

many fields; supporting a national infrastructure for clinical 

research; training the next generation of researchers in diverse 

disciplines; and maintaining the NCI-Designated Cancer 
An Annual Plan and Budget Proposal for Fiscal Year 2016 3 

Today’s investments in basic science 

will provide tomorrow’s opportunities 

in clinical research. 

Centers and the NCI intramural research program. The NCI is 


attuned to the changing understanding of cancer and seeks to 


manage its resources to take advantage of the most promising 


scientific opportunities. Yet, despite careful management, 


current budget limitations mean that many meritorious 


research proposals, including some proposing bold concepts, 


must still go unfunded each year. 


The following pages provide examples of the scientific 


opportunities before us. You will see that exciting progress 


is being made. But, for the many Americans diagnosed with 


cancer each day, progress is not being made quickly enough. 


Harold Varmus, M.D.
 

Director, National Cancer Institute
 

Photo by Matthew Septimus 
Source: SEER Cancer Statistics Review 1975-2011

THE OVERALL CANCER DEATH RATE 

IN THE UNITED STATES FELL BY 

22%

FROM

1990 2011 

Source: SEER Cancer Statistics Review 1975-2011. 

4 National Cancer Institute 

The Changing Cancer Landscape 

Lower Death Rates & 

More Survivors 

T

prognosis, and outcome. Before 1990, overall age-adjusted cancer 

rends in cancer-related mortality are an important 

measure of the impact of cancer research, because they 

provide an overall assessment of what is happening 

to the combination of cancer incidence, treatment, 

mortality rates increased for several decades. Since 

the mid-1990s, however, they have dropped steadily. 

Part of this sustained success in reduced cancer 

mortality is attributable to recognition of the harms 

caused by tobacco, which has led to reductions 

in tobacco consumption in the United States. This 

reduced consumption has lowered the overall risk of 

and deaths from tobacco-related diseases, including 

the most common forms of lung cancer, which claim 

more lives among both men and women than cancers 

in any other organ. Mortality rates are also decreasing 

for most other cancers, including those occurring 

at the three most common sites: the breast, colon/ 

rectum, and prostate. 

These improvements in mortality rates have been accompanied 

by a substantial increase in the number of cancer survivors. The 

number of people living beyond a cancer diagnosis in the United 

States doubled during the 20-year period between 1992 and 2012, 

from 7 million to 14 million, and is expected to rise to 18 million 

by 2022. Thus, whereas cancer survivors accounted for about 2.5 

percent of the U.S. population in 1992, it is estimated that cancer 

survivors will account for more than 5 percent of the population 

in 2022. Importantly, many of these cancer survivors will return to 

live active and productive lives following their cancer diagnosis. But 

for many of these survivors, long-term effects, both physical and 

psychological, may remain. Recognizing this, survivorship research 

remains a key component in the research portfolio of the NCI. 

It is estimated that cancer survivors 

will account for more than 5 percent 

of the population in 2022. 
Source: de Moor, JS et al.

Cancer Epidemiol Biomarkers Prev.

2013 Apr;22(4):561-70

An Annual Plan and Budget Proposal for Fiscal Year 2016 5 

MORE PEOPLE SURVIVE CANCER 

WHERE WE WERE 

7 million in 1992 

14 million in 2012 

18 million in 2022 

HOW FAR WE’VE COME 

WHERE WE WILL BE 

Despite these advances, too many people still face 

a cancer diagnosis, and far too many are still dying 

from the disease. It is estimated that more than 

600,000 people in the United States will die from 

cancer in 2014 and that there will be more than 

1.6 million new cases. In addition, our progress in 

preventing, diagnosing, and treating cancers is not 

universal for all forms of the disease. The mortality 

rates for some cancers have actually increased. For 

example, death rates from liver cancer increased 

by about 20 percent between 2001 and 2010. 

Thus, much work remains. 

Because older age is a major risk factor for 

developing cancer, improved life expectancy by 

itself will lead to a rise in the total number of 

cancer cases in the United States. Therefore, 

although the age-adjusted rates at which cancer 

develops are expected to continue to decline, 

the aging of the U.S. population means that the 

total number of cancers will increase. Between 

2012 and 2025, the estimated number of cancer 

cases will increase by 31 percent, from 1.6 million 

to 2.1 million; the estimated number of cancerrelated deaths will increase even faster, by 37 

percent, from 620,000 to 850,000. These projected 

increases imply that intensive and sustained research efforts against 

cancer will continue to be critical. The NCI continues to employ 

every aspect of its portfolio to better prevent, diagnose, and treat 

cancer, but these efforts must be enhanced to keep up with the 

changing demographics of our society. 

Over the past few decades, the incidence of obesity has risen 

markedly in the United States and in many other countries around 

the world. Although the so-called “obesity epidemic” has been 

most commonly linked to the rising incidence of diabetes and 

related conditions, it also has substantial implications for cancer 

research and cancer control, since obesity is associated with 

increased risks of developing cancer at many sites. These sites 

include the esophagus, endometrium (uterus), colon/rectum, 

pancreas, breast, and liver. In the liver, nonalcoholic steatohepatitis, 

which can develop in obese individuals, is associated with an 

increased risk of developing liver fibrosis and liver cancer. It is 

important to refine our understanding of the associations between 

Source: de Moor JS, et al. Cancer survivors in the United 

States: prevalence across the survivorship trajectory and 

implications for care. Cancer Epidemiol Biomarkers Prev. 

2013; 22(4):561-570. 
6 National Cancer Institute 

WORLDWIDE CANCER CASES 

WORLDWIDE CANCER DEATHS 

WILL INCREASE BY 

WILL INCREASE BY 

37%

39%

FROM IN 2012

2025

14.1 million 

TO 19.3 million IN

8.2 million 

11.4 million 

FROM IN 2012

TO IN 2025

Source: Ferlay J, et al. GLOBOCAN 2012 v1.0, Cancer Incidence 

and Mortality Worldwide: IARC CancerBase No. 11. Lyon, 

France: International Agency for Research on Cancer; 2013. 

obesity and specific cancers, determine the mechanisms 

underlying these associations and their potential 

reversibility for people who lose weight, and support 

behavioral research to help overcome obesity at the 

individual and population levels. 

Improvements in nutrition, health care, and other factors 

are increasing life expectancy for most of the world. 

However, this benefit is accompanied by an increase 

in many diseases associated with an aging population, 

including cancer, and this trend is being exacerbated by 

greater tobacco consumption in many low- and middleincome countries. The International Agency for Research 

on Cancer, part of the World Health Organization, 

estimates that there will be 19.3 million cases of cancer 

worldwide in 2025, a 37 percent increase over the 

14.1 million cases in 2012. During that time span, the 

estimated number of cancer-related deaths worldwide 

will increase by 39 percent, from 8.2 million 

to 11.4 million. 

To help address this expanding global burden of cancer, 

the NCI established its Center for Global Health (CGH) 

in 2011. The center facilitates global collaboration by 

leveraging research resources with U.S. government 

agencies, foreign governments, nongovernmental 

organizations, and pharmaceutical and biotechnology companies 

to support clinical trials and device development appropriate for 

low- and middle-income settings. 

Improved Prevention, Screening 

& Treatment 

Basic science: Uncovering clues for tomorrow’s cancer 

prevention and treatment. Cancers are disorders of cell 

growth, cell survival, and other cell behaviors, fueled largely by 

changes in cell chromosomes. Therefore, the NCI has traditionally 

made substantial investments in many fundamental aspects of cell 

biology and genetics, recognizing that basic biological science is 

essential in efforts to understand this set of diseases. 

That premise has not changed, and the NCI continues to put 

resources toward many exciting areas of basic science under 

investigation. For example, we have known for several decades 
An Annual Plan and Budget Proposal for Fiscal Year 2016 7 

that much of a cell’s RNA comprises the messengers 

that instruct the cell to make its proteins, but 

unexpected developments in just the past decade 

have demonstrated compellingly that the cell has 

other forms of RNA that cannot be translated to 

make proteins. Instead, they directly regulate the 

expression of many, if not all, genes that do encode 

proteins. Many of these regulatory “non-coding” RNAs 

can influence the behavior of cancer cells. Their roles 

in cancer, as well as the roles of other regulators, such 

as proteins that govern gene expression, are still under 

intense investigation. The dividends of that research 

may be a more profound understanding of how a 

normal cell becomes a cancer cell, as well as new 

ways to classify and treat cancers. 

Abnormalities of metabolism, which have been identified in 

many tumors, also represent an important area of basic and 

applied research. The affected genes, which are fundamental 

regulators of the normal energy balance of the cell, are mutated 

in several forms of cancer. One class of these mutant genes has 

been identified in several forms of brain tumors and in acute 

myeloid leukemia. Another class has been found in hereditary and 

nonhereditary forms of kidney cancer. These changes in energy 

metabolism, which contribute to the abnormal growth properties 

of the cancer cells, are being intensively studied to better define 

their mechanism of action and their role in cancer to determine 

whether their inhibition might be clinically beneficial. 

From the earliest days of cancer research, much of our knowledge 

about this set of diseases has come from studies in experimental 

models, using cells grown in Petri dishes and animals that develop 

cancer naturally or after experimental manipulation. Over the 

past couple of decades, novel genetic methods have been used 

to create mice that develop cancer in a predictable way in a 

variety of tissues under the influence of mutant genes also found 

in human cancers of the same type. Refinements in the methods 

used to generate mouse models of cancer are making them more 

closely related to human disease, and technological advances 

are making it easier to study the consequences of specific gene 

mutations and potential therapies in these models. The evaluation 

of tumors that are taken directly from patients and placed 

immediately in mice (patient-derived xenografts) is enabling the 

study of these tumors in the context of an experimental animal. 

In addition, three-dimensional methods for growing cancer cells 

DNA sequencing results 

from an automated DNA 

sequencing machine. 
8 National Cancer Institute 

A researcher analyzing 

DNA sequencing results. 

in culture enable researchers to 

study tumor architecture that more 

closely mimics that found in the 

tumor environment in living animals 

or patients than that provided 

by traditional two-dimensional 

culture methods. These advances 

have considerable potential to 

provide additional insight into the 

development of cancer, the role of 

the extracellular matrix in which 

tumors grow, and responses to new 

therapeutic interventions. 

It is generally agreed that cancers 

arise from single cells that continue 

to accrue mutations during the 

course of a multiyear process of 

tumor evolution. Thus, it was not 

unexpected when the analysis of 

tumor genomes from different parts 

of a cancer, either metastatic growths 

or cells from different locations in the 

primary tumor, revealed significant 

heterogeneity and important aspects 

of the cancer’s evolutionary process. 

This heterogeneity has important implications for understanding 

the biology and evolution of tumor development and progression, 

as well as for treatment with conventional therapies, targeted 

drugs, and immunotherapies. 

Our understanding of the tumor microenvironment, which is 

composed of the noncancerous cells and other materials that 

surround cancer cells in a tumor mass, has recently increased. 

We now recognize the importance of immune cells, blood vessels 

that support tumor growth, and other factors, such as hormonal 

mediators of cell growth and extracellular matrix proteins that 

influence tumor cell migration and tumor architecture. Additional 

study of the components of the microenvironment and their 

interactions with the tumor has considerable potential for 

improving our understanding of the interplay between tumors 

and their hosts. These interactions are likely to be complex 

but profound and may hold clues for future efforts at prevention 

and treatment. 
An Annual Plan and Budget Proposal for Fiscal Year 2016 9 

Cancer: Genetics plus environmental exposures. 

A wealth of research, much of it supported by the NCI, has 

determined that cancer develops through a complex interplay 

of genetic and environmental factors. In some cases, the risk of 

developing cancer is strongly influenced by inheriting a mutation 

in a single gene, such as BRCA1 or BRCA2. Mutations in these 

genes confer a high risk of familial breast and ovarian cancer. 

More commonly, however, the genetic background of individuals 

plays a more subtle role in the risk of cancer. Although their 

genes can make important contributions to cancer susceptibility, 

the sum of their exposures to various environmental factors 

is believed to account for the development of most cancers. 

Many environmental factors can contribute to cancer risk, 

including tobacco use, some types of infection, exposure to 

ultraviolet light, and lifestyle factors, such as obesity, lack of 

exercise, and eating an unhealthy diet. 

Once these risks and exposures are identified and understood, 

we can frequently develop effective preventive interventions. 

Interventions may include reducing cancer risk in the general 

population or identifying high-risk individuals who can be 

screened for signs of precancers or early cancers, which can often 

be treated more effectively than advanced disease. Reducing 

exposure to an environmental carcinogen, such as tobacco, 

asbestos, or ultraviolet light, is one approach. Another is to 

reduce the consequences of exposure to the carcinogen. This 

approach includes vaccinating against hepatitis B virus (HBV) 

and human papillomavirus (HPV), and using sunscreens that 

block ultraviolet light. Reducing exposure can also be employed 

in some instances of familial predisposition to cancer. In women 

who have an abnormal BRCA1 or BRCA2 gene, preventive 

removal of the breasts, ovaries, and fallopian tubes decreases 

their risk of developing cancer at these sites. Tailored screening 

approaches may also be employed. For example, individuals who 

are considered to be at high risk of colorectal cancer because of a 

familial genetic abnormality are recommended to start colorectal 

cancer screening at an earlier age than people in the general 

population. 
10 National Cancer Institute 

Tumor cells have 

undergone irreversible 

changes in one or 

more genes. This 

graphic visualization 

shows the genetic 

alterations in a human 

rhabdomyosarcoma 

tumor. 

Image by Javed Khan, M.D. 

Cancer: A disease of abnormal genes and their 

activities. At the level of the tumor, cancer is often described as 

a “genetic disease” because the tumor cells have undergone one 

or more irreversible changes in some genes. These changes may 

arise from mutation of the genes, which increases or decreases 

their activity; an increase in the number 

of copies of certain genes, which often 

increases their activity; deletion of parts or 

all of some genes, which usually abolishes 

their activity; or rearrangements between 

two genes, which lead to the production 

of fusion proteins that have increased 

activity. These genetic changes are critical 

to the development of the tumor, and they 

continue to be important as the tumor 

grows. Changes designated as “epigenetic” 

also contribute to cancer, usually by 

increasing or decreasing the expression of 

specific genes by chemically modifying DNA 

or the proteins associated with DNA. These 

changes are called “epigenetic” because 

the chemical modification and consequent 

alterations in gene expression are potentially 

reversible, in contrast to the irreversible 

nature of changes in the sequence or 

organization of genes. 

At the level of the tumor, cancer is often 

described as a “genetic disease” 

because the tumor cells have undergone 

one or more irreversible changes in 

some genes. 

At least two types of functional genetic and epigenetic changes 

contribute to the progression of a normal cell into a cancer cell. 

One involves genes with the natural capacity to prevent the 

development of cancer; many of these genes are referred to as 

tumor suppressor genes, whereas others in this category promote 

the repair of damaged DNA. Changes that affect this class of genes 

reduce the cell’s ability to block abnormal growth. The second type of 
An Annual Plan and Budget Proposal for Fiscal Year 2016 11 

change involves genes that have the capacity to promote 

the development of cancer. Many of these genes are 

referred to as oncogenes, and their alterations in cancer

increase their activity. Both types of changes occur in 

the vast majority of malignant tumors. 

It is also recognized that a person’s inherited genes may

contribute to tumor susceptibility. An unfortunate, but 

dramatic, example of this situation is seen in individuals 

whose inherited DNA has a mutation that inactivates 

one of the two copies of the RB1 tumor suppressor 

gene. When this happens, all of the individual’s cells 

have one copy of this inactivated version. The patients 

are usually healthy when born because they have 

one fully functioning copy of the gene in their cells, in 

addition to the inactivated copy. During early childhood, however, 

these individuals have a high risk of developing retinoblastoma 

if their one normal copy of RB1 in a retinal cell also becomes 

inactivated. This inactivation process may arise independently in 

more than one retinal cell, leading to the development of separate 

tumors in each eye. If the inactivation occurs in some other cells 

elsewhere in the body, tumors may develop at these locations. 

Targeting specific genes in cancer treatment. 

Understanding the molecular changes in cancer has 

stimulated efforts to develop drugs that specifically target key 

proteins involved in the development of a given cancer type. 

This therapeutic approach is often referred to as precision 

medicine. Although surgery, radiation therapy, and standard 

chemotherapeutic drugs continue to have an important role 

in cancer treatment, our increased understanding of the 

genetic and epigenetic changes in cancer, together with our 

A molecular model of a 

dimer of the p53 tumor 

suppressor protein 

bound to DNA. 

Image by Thomas Splettstoesser 

Understanding the molecular changes 

in cancer has stimulated efforts 

to develop drugs that specifically 

target key proteins involved in the 

development of a given cancer type. 

This therapeutic approach is often 

referred to as precision medicine. 
12 National Cancer Institute 

evolving ability to intervene, present the opportunity to provide 

treatments that are potentially less toxic and more effective than 

previous therapeutic approaches. Another aspect of precision 

medicine is the development of assays, often called companion 

diagnostics, that can predict which patients are most likely to 

benefit from a particular targeted therapy. For example, the 

Food and Drug Administration (FDA) approval of vemurafenib 

(Zelboraf) for patients with advanced melanoma whose tumors 

harbor a frequent mutation in the BRAF oncogene came with a 

requirement that the mutation be identified by an FDA-approved 

companion diagnostic test before the drug is used. 

Most targeted drugs are directed at inhibiting the proteins encoded 

by oncogenes because it is currently technically easier to inhibit 

these proteins than it is to replace the missing activities of tumor 

suppressor genes. Thus far, most of the successful monoclonal 

antibodies and small molecule drugs inhibit the activities of 

oncogene-encoded proteins. Examples include erlotinib (Tarceva), 

which targets the epidermal growth factor receptor (EGFR), for the 

treatment of lung adenocarcinoma; trastuzumab (Herceptin), which 

targets ERB-B2 (also known as HER2), a receptor that is similar to 

EGFR, for breast cancer treatment; and imatinib (Gleevec), which 

targets a fusion protein resulting from a rearrangement between 

two genes, for the treatment of chronic myelogenous leukemia. In 

contrast to therapeutic approaches that target specific abnormalities 

in the cancer cell, an alternative successful approach is to harness 

the potential of the patient’s own immune system to seek and 

destroy the cancer cells. This approach is discussed in the section 

titled Harnessing the Promise of Immunotherapy. 

The genomic analysis of tumors, which examines the genes 

in tumor cells and may compare the differences between the 

patient’s normal cells and changes found in the tumor cells, 

has revealed a potential challenge for therapy, namely, that the 

spectrum and number of changes that can lead to cancer are 

so great that it is difficult to identify the specific genetic and 

epigenetic changes responsible for driving the abnormal growth of 

the tumor cells. Fortunately, however, changes in some oncogenes 

have been found to occur repeatedly in a given type of cancer, 

and abnormalities that involve the same gene often occur in more 

than one cancer type. Therefore, if drugs that target a particular 

abnormal gene are useful in one form of cancer, they will often 

be useful in the treatment of other types of cancer that have the 

same abnormal gene. 
An Annual Plan and Budget Proposal for Fiscal Year 2016 13 

Classifying cancers according to their genomic profiles. 

Effective cancer treatment can be directed against the specific 

genetic abnormalities in a tumor. Therefore it is more and more 

important to determine the genomic profile of a cancer and to 

classify the cancer according to that categorization, rather than 

just by the organ site where it developed or by its appearance 

under a microscope. Such categorization is important both for 

cancer treatment today and for research that can lead to new 

treatments that will improve the outcome for patients with cancer 

in the future. For example, genomic profiles can be used in basic 

research that seeks to understand which genetic abnormalities are 

most critical to a tumor, and these findings can help to prioritize 

efforts aimed at identifying drugs that target specific genes. 

This analysis can also deepen our basic understanding of how 

specific combinations of abnormal genes collaborate in cancer. 

Such understanding is likely to lead to improved combinations of 

targeted treatments for cancer and to help prevent and overcome 

drug resistance, which, unfortunately, occurs commonly with 

targeted treatment by a single drug. 

Illustration of the DNA 

double helix and the 

genetic code. 

Image from the National Human 

Genome Research Institute 

It is more and more important to 

determine the genomic profile of 

a cancer and to classify the cancer 

according to that categorization, 

rather than just by the organ site 

where it developed. 
14 National Cancer Institute 

Important gains 

made over 

the last four 

decades have 

occurred as the 

cancer research 

enterprise has 

expanded in 

talent, facilities, 

and ideas. 

Rapid Progress Depends on 

Long-Term Support 

Supporting research improves health. The NCI is committed 

to answering the most pressing questions about each type of cancer 

and to continuing the pursuit of fundamental knowledge about 

the inner workings of cancer cells, so that we can eventually prevent 

and control cancers of all types. As indicated previously, investigators 

and, increasingly, patients with cancer are benefitting from new—but 

often costly—research methods used in genomics and informatics. 

These approaches include drug screening and development; cancer 

detection, diagnosis, and monitoring; and immunologically and 

genetically based therapeutics. The NCI is committed to bringing 

improved, less-toxic, and less-debilitating treatment to patients, based 

on the molecular abnormalities of their disease. 

Increased funding is associated with faster progress. 

Important gains made over the last four decades have occurred 

as the cancer research enterprise has expanded in talent, facilities, 

and ideas. The rapid escalation of the NCI budget following the 

National Cancer Act of 1971 and the doubling of the National 

Institutes of Health (NIH) budget over a 5-year period that began in 

the late 1990s contributed to these gains. These two periods of rapid 

growth were remarkably fruitful. The first period of growth launched 

the pursuit of cancer genes and the molecular basis of oncogenesis, 

laying the foundation for the transformation of clinical oncology 

that is now occurring. The second period of growth accelerated 

completion of the human genome project, which led to current 

genomic analyses that now help guide the study and control of 

many diseases, including cancer. 

Cancer research also benefitted significantly from the American 

Recovery and Reinvestment Act (ARRA) of 2009. The NCI saw an 

infusion of approximately $1.25 billion from ARRA, allowing the 

expansion of initiatives such as The Cancer Genome Atlas (TCGA) 

project, a joint effort by the NCI and the National Human Genome 

Research Institute (NHGRI) to catalog all of the genetic changes in 

more than 10,000 cancer cases involving more than 30 different 

types of cancer. TCGA and projects like it are providing a foundation 

for further discovery by the research community and stimulating 

new approaches to preventing, diagnosing, and treating cancer. 

Without the leadership and financial investment of the NCI, projects 

such as these would likely not occur or would be of smaller scale 

and progress at a slower pace. 
An Annual Plan and Budget Proposal for Fiscal Year 2016 15 

Source: NCI Office of Budget and Finance 

Flat budgets threaten short-term and long-term 

progress. Since 2003, with the exception of the funding received 

through ARRA, there has been a decade-long hiatus in financial 

growth in the nation’s investment in research. Coupled with the 

increased expense of research and the loss of nearly 25 percent 

of the NCI budget in constant dollars since 2003 due to inflation, 

our ability to exploit some promising opportunities and to sustain 

rapid momentum in preventing, diagnosing, and treating cancer 

is being compromised. The current financial status of the cancer 

research enterprise has created an unhealthy, hypercompetitive 

atmosphere for both experienced and new investigators, who are 

vying for part of a progressively shrinking budget. In this climate, 

because the success rate of grant applications has dipped so 

low, substantially more time must be devoted to preparing grant 

applications and to keeping laboratories afloat, which reduces 

scientific productivity and threatens promising careers. A larger 

sustained budgetary commitment to cancer research would be 

a visible step to attracting and retaining the scientists we need to 

pursue the many opportunities before us. 

Without the

leadership

and financial

investment of the

NCI,projects such

as [TCGA] would

likely not occur

or would be of

smaller scale

and progress at

a slower pace.

THE DECLINING PURCHASING POWER OF THE NCI BUDGET 

$0

Fiscal Year

1998

$1

2000

2002

2004

2006

2008

2010

2012

2014

2015

$2

$3

$4

$5

$6

NCI Budget ARRA Funding (Public Law 111-5)

ARRA in 1998 Dollars

Dollars (in billions)

The dashed line at $2.9 billion shows that the current 

NCI budget, adjusted for inflation, is essentially the 

same as the NCI budget in FY 1999.

NCI Budget Adjusted for Inflation (FY 1998 dollars)
16 National Cancer Institute 

Building on the National Cancer Program 

The NCI supports the National Cancer Program in various 

ways, both financially and intellectually. It provides 

resources to individual investigators and to institutions, 

provides leadership to national infrastructures that care 

for patients and that develop new methods to prevent and treat 

disease, and conducts research in especially challenging areas. 

Over the last 10 years, the core support that the NCI has been able 

to provide to the nation’s cancer research enterprise has eroded. 

Years of trimming around the edges have resulted in an NCI that 

funds too few grants. The grants that are funded are too small to 

adequately cover the costs of clinical trials and sufficiently support 

essential elements of the enterprise, such as the NCI-Designated 

Cancer Centers. In short, we are underserving the cancer research 

community. 

Years of trimming around the edges 

have resulted in an NCI that funds too few 

grants. The grants that are funded are 

too small to adequately cover the costs 

of clinical trials and sufficiently support 

essential elements of the enterprise. 

New Approaches to Funding Researchers 

The NCI continues to develop new funding opportunities 

that adapt to changes in the way that science is 

conducted. Support for the best science underpins 

everything the NCI does; therefore, supporting the best 

scientists is paramount. Today, attracting the best minds to the field 

of cancer research is challenging. Retaining talent is also difficult. 

The uncertainty of a successful career in cancer research due to a 

lack of funding opportunities is a significant barrier to embarking 

on, and remaining in, this career path. The NCI is committed to 

supporting the training and development of a strong workforce 

of cancer researchers that spans the career continuum. However, 

in the current hypercompetitive culture of biomedical science, 

the early careers of graduate students, postdoctoral fellows, and 
* Numbers do not include students and postdoctoral fellows supported by NCI research project grants, cancer center grants, and other nontraining mechanisms

† Does not distinguish between summer research experiences and part­ or full­time appointments

TRAINING THE WORKFORCE

NATIONAL CANCER INSTITUTE

An Annual Plan and Budget Proposal for Fiscal Year 2016 17 

3,590

Individuals supported 

by NCI training, career 

development grants, 

and intramural research 

experiences 

392 221 784 1,681 112 400
 High-School Pre- & Post- Graduate & Postdoctoral & Clinical Early-Career
 

Students† Baccalaureates Medical Students Research Fellows Fellows Scientists
 

 

                   

NATIONAL CANCER INSTITUTE 

Training the Workforce 

In FY 2013, NCI supported 3,590 emerging cancer researchers through training and career development grants and intramural 

research experiences.* 

*

 Numbers do not include students and postdoctoral fellows supported by NCI research project grants, cancer center grants, and other non-training mechanisms 

†

 Does not distinguish between summer research experiences and part- or full-time appointments 

young investigators may be hampered by low salaries, many years 

spent in training positions, and still more years in an independent 

research position, before they obtain NIH funding for their 

research. For most of the past 50 years, at least 30 percent of grant 

applications were funded, dipping to 25 percent during periods 

of lean budgets. Today, the percentage of successful applications 

hovers in the mid-teens, far lower than at any other time. Although 

the NCI is actively building a cancer research workforce for the 

future, these efforts will appear hollow without strong support for 

funding these young scientists. This infrastructure problem is not 

limited to cancer research. 

Even established researchers are forced to devote too much time 

to securing funding rather than conducting research or training 

the next generation of scientists. To partially address this problem, 

the NCI recently established the Outstanding Investigator Award. 

This new R35 funding mechanism is designed to provide longerterm support—7 years—and more than twice the dollar amount 

The NCI is 

committed to 

supporting the 

training and 

development of a 

strong workforce 

of cancer 

researchers 

that spans 

the career 

continuum. 
18 National Cancer Institute 

Examples of 

NCI Grants 

R01: Research Project 

These grants are awarded 

to institutions to allow a 

Principal Investigator to 

pursue a scientific focus 

or objective in his or 

her area of interest and 

competence. Applications 

are accepted for healthrelated research and 

development in all areas 

within the scope of the 

NIH’s mission. 

R21: Exploratory/ 

Developmental Grants 

These grants encourage 

the development of 

new research activities 

in categorical program 

areas. Support generally 

is restricted in level of 

support and duration. 

R35: NCI Outstanding 

Investigator Award 

This new award supports 

investigators with 

outstanding records of 

productivity and allows 

them to embark on longterm projects of unusual 

potential in cancer 

research. 

of an average R01 investigator-initiated grant to experienced 

investigators who are likely to continue to conduct seminal cancer 

research as well as to mentor the next generation of cancer 

researchers. With this support, investigators may pursue research 

that might be viewed as too high-risk to be funded through 

regular grant mechanisms. In addition, through mechanisms such 

as R21 exploratory grants, the NCI seeks to help investigators 

conduct other potentially new and exciting but high-risk studies. 

R21 grants are not substitutes for the main investigator-initiated 

grants, the R01 awards, because R21 grants are given for fewer 

years and have a lower level of annual funding. However, when 

used appropriately, the R21 awards can be useful for investigators 

who need additional data to successfully compete for larger 

grants. The need to maintain the vitality of the cancer research 

workforce cannot be overstated, and the NCI takes its leadership 

role in this domain very seriously. 

Although traditional single-investigator-driven approaches 

remain preferable for a range of scientific endeavors, coordinated 

teams of investigators with diverse skills and knowledge have 

proven to be helpful in many areas of cancer research. As part of 

its commitment to improve the quality of cancer research, the 

NCI supports a variety of “team science” approaches, including 

those used in a large proportion of cancer genomics and cancer 

epidemiology research. This support of team science has 

yielded important discoveries but has also identified barriers 

to broader collaborations. Authorship of journal articles and 

the acknowledgment required for tenure decisions are two 

examples of issues that must be addressed to fully achieve 

the potential of team science. The NCI has led in this effort to 

appropriately recognize the contributions of individuals involved 

in interdisciplinary research. The NCI spearheaded a change in 

the NIH biosketch, which accompanies grant applications and 

documents the qualifications of the investigators applying for the 

grant. Instead of merely listing their most relevant publications, the 

new biosketch takes a narrative form that emphasizes individual 

accomplishments and their significance by asking investigators 

to enumerate their most important research accomplishments, 

the significance of the accomplishments, and their specific 

contributions to the research. The NCI has also created an online 

resource, the Team Science Toolkit (www.teamsciencetoolkit. 

cancer.gov), to help investigators support, conduct, and study 

team science. Professionals from many disciplines can connect 
An Annual Plan and Budget Proposal for Fiscal Year 2016 19

through the website, which provides a forum for sharing 

knowledge and tools to maximize the efficiency and effectiveness 

of team science initiatives.

The Provocative Questions initiative is another approach 

developed by the NCI to stimulate the research community 

and provide a new form of funding. This initiative has brought 

together researchers to identify questions in specific areas 

of cancer research that have been understudied, neglected, 

paradoxical, or difficult to address in the past. To encourage 

the NCI’s research communities to use laboratory, clinical, and 

population sciences in especially effective and imaginative ways to 

answer some of these questions, select questions were advertised 

in requests for applications (RFAs), with a set-aside budget to 

fund the most meritorious applications. The selected questions 

have been categorized into five themes: cancer prevention 

and risk; mechanisms of tumor development or recurrence; 

tumor detection, diagnosis, and prognosis; cancer therapy and 

outcomes; and clinical effectiveness. To date, 168 grants have 

been funded with $63.9 million dollars to address the identified 

Provocative Questions. 

Source: NCI Center for Strategic Scientific Initiatives

THE PROVOCATIVE

HAS FUNDED

THE INITIATIVE

HAS IDENTIFIED QUESTIONS IN CANCER 

RESEARCH THAT HAVE BEEN UNDERSTUDIED,

NEGLECTED, PARADOXICAL, OR DIFFICULT TO

ADDRESS IN THE PAST.

GRANTS

168

WITH A TOTAL OF

MILLION

$63.9

QUESTIONS INITIATIVE

Source: NCI Center for Strategic Scientific Initiatives

NCI researcher Joseph 

Ziegelbauer, Ph.D. (second 

from left), has teamed 

with the Trans-NIH RNA 

Interference Screening 

Facility and colleagues 

in the NCI HIV and AIDS 

Malignancy Branch to 

study the Kaposi sarcomaassociated herpesvirus.

Photo by Rhoda Baer
DESIGNATED CANCER CENTERS

NATIONAL CANCER INSTITUTE

promising laboratory discoveries into new treatments for cancer patients. There are 20 cancer centers, 41 

comprehensive cancer centers, and 7 research centers.

20 National Cancer Institute 

The 68 NCI-Designated Cancer Centers are at the forefront of NCI-supported efforts at universities and cancer research 

centers across the United States. The centers are developing and translating scientific knowledge from promising laboratory 

discoveries into new treatments for cancer patients. There are 20 cancer centers, 41 comprehensive cancer centers, and 

7 research centers. For more information, visit www.cancer.gov/researchandfunding/extramural/cancercenters/about. 

NCI-Designated Cancer Centers 

The NCI-Designated Cancer Centers program is one 

of the anchors of the nation’s cancer research effort. 

The 68 cancer centers, which are located in 35 states 

and the District of Columbia, form the backbone of the 

institute’s programs for studying and controlling cancer. Together, 

they represent the nation’s single most important source of new 

insights into the causes of cancer and strategies for prevention, 

diagnosis, and treatment; the research proposals from their 

investigators account for about three-quarters of the successful 

investigator-initiated grants that are awarded, after stringent 

peer review, by the NCI. 

NCI-DESIGNATED CANCER CENTERS 

Source: NCI Office of Cancer Centers 
An Annual Plan and Budget Proposal for Fiscal Year 2016 21 

At any given time, hundreds of research studies are under way at 

NCI-Designated Cancer Centers, ranging from basic laboratory 

research to clinical assessments of new treatments. Many of these 

studies are collaborative and may involve several research centers 

and other partners in industry and the community. In addition to 

conducting meritorious basic and applied research, the cancer 

centers deliver quality cancer care to patients and their families, 

including in communities with underserved and understudied 

populations. 

Each NCI-Designated Cancer Center receives a core support 

grant from the NCI that funds the critical research infrastructure 

of the center, in addition to the funding received from individual 

competitive research grants and contracts with the NCI. The 

funding provided by the core grants is essential for the efficient 

conduct of research at the centers and for maintaining the 

nation’s progress against cancer. The size of the core grants is 

relatively small in comparison with the return on investment 

and with the size of other NIH center grants, such as those that 

support the approximately 60 institutions that receive Clinical and 

Translational Science Awards (CTSAs). The specific amount for 

each cancer center has depended on a variety of factors, including 

the budget cycle, resulting in awards that do not entirely reflect 

the scientific quality or quantity of the research performed at the 

center or the size and complexity of the center itself. To address 

this inequity, the NCI plans to adjust the size of the core grants 

and to provide a closer link between these more appropriate 

parameters and the size of the grants. 

The funding provided by the core grants 

is essential for the efficient conduct 

of research at the [NCI-Designated 

Cancer Centers] and for maintaining 

the nation’s progress against cancer. 
Source: NCI Cancer Therapy Evaluation Program

22 National Cancer Institute 

IN 2014, NCI’S NATIONAL CLINICAL

INVESTIGATORS

TRIAL PARTICIPANTS

TRIALS NETWORK INCLUDED

14,000 19,000+

3,100

INSTITUTIONS

NCI’s National Clinical Trials Enterprise 

Clinical trials are supported by industry, private 

philanthropy, and through public funding. Each of these 

mechanisms can make important contributions to 

improved interventions for cancer control. The NCI has 

a long history of supporting both small early-phase trials as well 

as large-scale trials, many of which have led to changes in the 

standard of care. The NCI’s National Clinical Trials Network (NCTN) 

includes an active network of researchers, cancer centers, and 

community physicians. The program enrolled between 19,000 and 

20,000 participants in clinical trials in 2014. With the involvement 

of more than 3,100 institutions and 14,000 clinical investigators, 

the NCI’s clinical trials enterprise has changed the face of clinical 

oncology, establishing the safety and efficacy of many therapies 

now commonly used to treat patients with cancer. 

People with cancer now live longer lives in part because of 

strategies that have come from the NCI’s clinical trials program. 

For example, this year a clinical study found that adults with lowgrade glioma, a type of brain tumor, who received chemotherapy 

following the completion of radiation therapy lived significantly 

longer than patients who received radiation therapy alone. In 

addition, early results from another clinical trial showed that 

men with hormone-sensitive metastatic prostate cancer who 

received the chemotherapy drug docetaxel (Taxotere) at the start 

of standard hormone therapy lived longer than patients who 

received hormone therapy alone. These trials and their clinical 

findings were possible only because of the nation’s investment, 

through the NCI, in a national clinical trials network. 

Conducting a new generation of 

clinical trials requires sophisticated 

and expensive technologies and 

clinical processes, including 

carefully annotated tissue collection, 

advanced DNA and RNA sequencing 

methods, and complex analytic 

algorithms to distinguish normal 

genetic variants from tumor-specific 

changes. These, in turn, entail new 

expenses for surgery, interventional 

radiology, molecular pathology, and 

Source: NCI Cancer Therapy Evaluation Program 
An Annual Plan and Budget Proposal for Fiscal Year 2016 23 

bioinformatics that have not typically 

been a part of most clinical trials. 

In response to recommendations 

made in an Institute of Medicine 

report requested by the NCI, the 

national clinical trials enterprise has 

been transformed, building on the 

success of the NCI’s Clinical Trials 

Cooperative Group Program to create 

a system that can respond more 

rapidly to scientific opportunities, 

particularly in conducting genomically 

based clinical trials. The NCI is now 

providing a higher percentage of cost 

reimbursement to the physicians who 

are treating participants enrolled in 

clinical trials. Flat budgets, together 

with the increased cost of conducting 

state-of-the-art trials, are making it 

necessary to decrease the number of 

people participating in clinical trials, 

which will slow our rate of progress. 

Many of the new trials now planned 

through the NCTN depend on new 

drugs, genetically based diagnostics, 

and immunotherapies, which have 

great promise for patients with cancer 

and are direct outgrowths of the 

NCI’s commitment to basic and early 

translational science. Some specific 

trials that are evaluating targeted 

treatments are described in the 

section titled Building on Discoveries 

in Cancer Genomics. 

This new clinical trials enterprise is a 

national resource. Although the NCTN 

is designed to carry out all aspects 

of advanced clinical trials, the NCI is 

unable to fully support the network 

and must rely on the partnership of 

the institutions and others involved in 

NATIONAL CANCER INSTITUTE 

National Clinical Trials Network 

The National Clinical Trials Network (NCTN) has four U.S. adult 

cooperative groups (Alliance, ECOG-ACRIN, NRG Oncology, and SWOG) 

and one pediatric cooperative group (COG). The NCTN also includes 

a Canadian Network Group because the NCI has had long-standing 

collaborations with Canadian investigators in clinical trials. Sites that 

are part of the NCI Community Oncology Research Program (NCORP) 

can also participate in NCTN clinical trials. 

ALLIANCE

CANADIAN

NETWORK

GROUP

SWOG

COG

(PEDIATRIC)

ECOGACRIN

NRG

ONCOLOGY

NCTNCENTRALIZED

FUNCTIONS

NCORP

SITE

PARTICIPATION

Centralized Functions: 

• Centralized Institutional

Review Board 

• Cancer Trials Support Unit 

• Imaging and Radiation 

Oncology Core (IROC) Group 

• Common Data Management 

System Central Hosting 

(

30 Lead Academic 

Participating Sites 

LAPS) 

www.cancer.gov/clinicaltrials/nctn 
24 National Cancer Institute 

NCI’s National Clinical 

Trials Network enrolled 

between 19,000 and 20,000 

patients in clinical trials 

in 2014. Informed consent 

is an important part of the 

enrollment process. 

the network to cover some costs. For example, a large number of 

biotechnology and pharmaceutical companies are collaborating 

with the NCTN on a series of precision medicine trials for some 

types of lung cancer and other tumor types. Although these 

partnerships are highly effective and appropriate for some trials, 

there are some clinical questions for which there are no obvious 

partners. It is the NCI’s responsibility to pursue these trials, 

especially in the case of rare cancers, but funding levels remain 

problematic. 

In addition, the institute recently launched the NCI Community 

Oncology Research Program (NCORP). This community-based 

initiative builds on the scope and activities of the NCI’s previously 

supported community networks—the NCI Community Clinical 

Oncology Program, the NCI Minority-Based Community 

Clinical Oncology Program, and the NCI Community Cancer 

Centers Program—to bring clinical trials, as well as cancer 

care delivery research, to people in their 

own communities. This effort enhances 

patient and provider access throughout 

the country to clinical trials in prevention, 

screening, diagnosis, and treatment. It also 

facilitates the participation of minority and 

underserved populations in clinical research 

and accelerates knowledge transfer into 

clinical practice and health care systems and 

organizations. Cancer care delivery research 

is conducted to improve outcomes for 

patients by translating approaches developed 

in controlled clinical trials to the community 

NCI’S COMMUNITY ONCOLOGY PROGRAMS 

IN THE PAST HAVE CONTRIBUTED APPROXIMATELY

25%

OF THE PATIENTS ENROLLED IN 

NCI COOPERATIVE GROUP TREATMENT TRIALS 

Source: NCI Division of Cancer Prevention
An Annual Plan and Budget Proposal for Fiscal Year 2016 25 

setting and measuring the success of these efforts. The NCORP 

provides an important connection to community-based cancer 

care, ensuring that people have access to the benefits of the 

latest research regardless of where they live. This is a foundational 

tenet of the NCI. 

The NCORP provides an important 

connection to community-based cancer 

care, ensuring that people have access 

to the benefits of the latest research 

regardless of where they live. 

Overcoming Cancer Health Disparities 

As with many diseases, cancer affects some racial and 

ethnic groups more than others. In addition, because 

cancer is a constellation of diseases, a given group may 

be more susceptible to some cancers but not to others. 

Access to health care may also be associated with the stage at 

which cancer is diagnosed and, often, with its outcome. 

The NCI Center to Reduce Cancer Health Disparities (CRCHD) 

is a major component of the institute’s efforts to overcome the 

unequal burdens of cancer in our society. The CRCHD (and 

all of the NCI) supports research to understand the biological 

differences of cancer among different ethnic and racial groups; 

identify and overcome barriers to equitable health care; and 

develop effective, culturally appropriate interventions. Cancer 

health disparities also represent a major focus of the NCORP. In 

addition, NCI-supported researchers are evaluating the potential 

of patient navigation to increase cancer screening rates, improve 

appropriate follow-up care, and enhance cancer outcomes. 

The NCI also monitors trends in incidence and mortality from 

cancer by race and ethnicity. One notable disparity is a higher 

overall incidence of cancer among black men (601 per 100,000 

men) compared with white men (532 per 100,000 men). Black 

men also have a higher mortality rate (269 versus 210 per 100,000 

men, respectively). Several cancers contribute to these disparities, 
26 National Cancer Institute 

The NCI Center 

to Reduce 

Cancer Health 

Disparities 

(CRCHD) is a 

major component 

of the institute’s 

efforts to 

overcome the 

unequal burdens 

of cancer in our 

society. 

including cancers of the lung, colon/rectum, prostate, stomach, 

and liver. The NCI supports a range of relevant research, from 

genomic studies of cancer in black men, to efforts to reduce 

their tobacco consumption, to evaluating and improving 

decision making when faced with a lung cancer or prostate 

cancer diagnosis. Improvements have been seen in reducing the 

disparities in mortality for some of these cancers. For example, 

from 2001 through 2010, the mortality rates for lung and prostate 

cancers among black men fell by 3.3 percent and 3.8 percent 

per year, respectively. In comparison, during the same time 

period, the lung cancer mortality rate among white men fell 

by 2.4 percent per year and the prostate cancer mortality rate 

fell by 3.3 percent per year. 

Another important disparity is seen with breast cancer among 

black women. Although the overall incidence of breast cancer 

among black women (123 per 100,000 women) is lower than that 

for white women (128 per 100,000 women), the mortality rate for 

breast cancer is higher for black women (31 versus 22 per 100,000 

women, respectively). Some of this difference can be attributed 

to the fact that black women are more likely to have subtypes 

of breast cancer for which treatment is less effective. One such 

subtype, triple-negative breast cancer, tests negative for the 

estrogen and progesterone receptors, as well as for overexpression 

of the HER2 oncoprotein. Overall, compared with white women, 

black women are also screened less frequently for breast cancer, 

are more likely to have advanced disease when a diagnosis is 

made, have a poorer prognosis for a given stage of disease, and 

Michael Jackson is a 

teacher...and a survivor 

of prostate cancer. He 

delayed seeing a doctor 

before being diagnosed. 

Michael is now outspoken 

with his peers about 

putting their health 

first. See his story in 

the “Patient Voices” 

video series on NCI’s 

YouTube channel, 

www.youtube.com/ncigov. 
An Annual Plan and Budget Proposal for Fiscal Year 2016 27 

have less access to medical care. The NCI supports many kinds 

of research on breast cancer among black women, including 

epidemiologic studies examining the role of obesity and other 

risk factors, basic science studies of genomics and molecular 

mechanisms, and studies of treatment access and outcomes. 

The mortality rates for breast cancer have been falling for both 

black and white women, but the rate of decline from 2001 through 

2010 was slower for black women (1.6 percent per year) than for 

white women (2.0 percent per year). 

Improvements in cancer mortality rates have been even slower 

for American Indians and Alaska Natives. While overall cancer 

mortality rates from 2001 through 2010 decreased by 1.4 percent 

per year among whites and by 2.1 percent per year among 

blacks, they decreased by only 0.7 percent per year among 

American Indians and Alaska Natives. Among those cancers 

for which population-wide screening is recommended—cervix, 

breast, and colon/rectum—American Indians and Alaska Natives 

are screened less frequently, and the improvements in their 

mortality rates for these cancers have been smaller than those 

among whites or blacks. The NCI supports research for American 

Indians and Alaska Natives to encourage greater use of cancer 

screening, introduce culturally tailored programs to reduce 

tobacco consumption, and improve treatment and outcomes from 

cancer for this population. 

The NCI is also working to increase the proportion of 

underrepresented minorities in the cancer research workforce. 

For example, the Partnerships to Advance Cancer Health Equity 

(PACHE) program enables institutions that serve communities 

with cancer health disparities, including NCI-Designated Cancer 

Centers, to train scientists from diverse backgrounds in cancer 

research and the delivery of cancer care to racially and ethnically 

diverse communities. 

The NCI is also working to increase 

the proportion of underrepresented 

minorities in the cancer research 

workforce. 
28 National Cancer Institute 

NCI’s Intramural Research Program 

S

ome of the NCI’s budget supports the research of scientists 

who work at the NIH Clinical Center and in offices and 

laboratories located in Bethesda, Rockville, and Frederick, 

Maryland. These intramural investigators conduct basic, 

clinical, and population-based research, including the study of 

rare cancers, and are encouraged to explore the translation of 

relevant findings from the laboratory to the clinic. At the NIH 

Clinical Center, the largest clinical research hospital in the world, 

intramural researchers are able to quickly test new approaches 

to cancer prevention and treatment. Clinical studies can be 

developed in close collaboration with researchers from extramural 

institutions and the findings extended by extramural investigators. 

The ability of the NIH Clinical Center to treat patients from all 

over the world facilitates expeditious clinical research on rare 

cancers, which may help patients with these diseases and 

produce insights relevant to more common cancers. 

For example, the use of immunotoxins that target a protein 

expressed in mesotheliomas has produced long-term responses 

in patients with this relatively uncommon cancer and is leading 

to clinical trials of this approach in patients with more common 

tumors. In another, recent advance, adult patients with a type 

of cancer known as Burkitt lymphoma had excellent long-term 

Intramural researchers are 

able to quickly test their 

new approaches to cancer 

prevention and treatment 

at the NIH Clinical Center, 

the largest clinical research 

hospital in the world. 

Photo of the Mark O. 

Hatfield Clinical Research 

Center. 
An Annual Plan and Budget Proposal for Fiscal Year 2016 29 

survival rates—upwards of 90 percent—following 

treatment with low-intensity chemotherapy 

regimens. Standard treatment for Burkitt 

lymphoma involves high-dose chemotherapy, 

which is highly toxic and, historically, cures 

only 60 percent of adult patients. 

The NIH Clinical Center does not come 

without expense. The NCI and the other NIH 

institutes and centers support, financially and 

professionally, the operations of the clinical 

center, with the NCI covering more of the 

costs than any other institute. 

The intramural program also conducts 

population and multidisciplinary research 

to discover genetic and environmental 

determinants of cancer and new approaches 

to cancer prevention. Over the years, research 

by this group of epidemiologists, geneticists, 

and biostatisticians has influenced public health 

policy in the United States and around the 

world. NCI researchers, together with colleagues 

at the National Institute for Occupational Safety and Health, 

recently completed the first study to show that heavy exposure to 

diesel exhaust among miners was associated with an increased 

risk of developing and dying from lung cancer, even after adjusting 

for other lung cancer risk factors, such as cigarette smoking. The 

findings, which took years to develop, played a pivotal role in the 

recent classification of diesel engine exhaust as carcinogenic to 

humans (a group 1 carcinogen) by the International Agency for 

Research on Cancer. The conclusions have implications not just 

for miners but also for the 12 million American workers and tens 

of millions more worldwide who are exposed to diesel exhaust in 

the workplace and for people who live in cities with high levels of 

diesel exhaust. 

The activities of the NCI intramural research program complement 

those of other aspects of the National Cancer Program. With both 

academic and private sector partners, intramural researchers 

can undertake longer-term projects that may be difficult, if not 

impossible, through traditional funding mechanisms. For example, 

NCI researchers studied immunotherapy during long periods 

when it was not in vogue. 

Melinda Merchant, 

M.D., Ph.D., of the NCI 

Pediatric Oncology 

Branch, and Ewen 

Raballand navigate the 

hallways of the NIH 

Clinical Center, where 

Ewen participated in 

a clinical trial testing 

natural killer cells to 

treat his osteosarcoma. 

Photo by Daniel Sone 
30 National Cancer Institute 

Researchers Bruce 

Shapiro, Ph.D. (left), 

and Kirill Afonin, Ph.D., 

of the NCI intramural 

program’s Basic 

Research Laboratory 

study RNA structure, 

RNA folding, and RNA 

nanobiology. 

Photo by Rhoda Baer 

However, the findings from this long-term research made 

important contributions to the current widespread efforts to 

develop immunotherapy as a standard of care for a range of 

cancers. In addition, some public health issues, as exemplified 

by the diesel exhaust study, take many years and would be very 

difficult to conduct without government support. 

Bioinformatics to Accelerate Research 

Bioinformatics, which enables the management and use of 

very large sets of molecular and clinical data, has become 

a core component of the NCI’s research enterprise. 

The National Cancer Informatics Program (NCIP), part 

of the NCI Center for Biomedical Informatics and Information 

Technology (CBIIT), is the institute’s main bioinformatics initiative. 

The collection, analysis, storage, retrieval, and distribution of 

“big data” are essential for many aspects of cancer research— 

especially for cancer genomics, in which millions of data points 

are frequently collected on each patient—and the monitoring of 

clinical trials. 

The NCI’s efforts in this area include ensuring the availability 

and usability of cancer research data to the broader cancer 

community. For example, a new study details how a suite of 

web-based tools provides the research community with greatly 

improved capacity to interrogate data derived from large 

collections of genomic information against thousands of drugs. 

By comparing drugs and genetic targets, researchers can begin 
An Annual Plan and Budget Proposal for Fiscal Year 2016 31 

to identify pharmaceuticals that may be effective against different 

forms of cancer. In addition to furthering research itself, this 

information may be used in patient diagnosis and treatment. 

Part of the current effort involves the use of “cloud computing” to 

manage the vast amounts (about 20 petabytes; 1 petabyte = 1015 

bytes = 1 million gigabytes) of genomic data generated by TCGA 

for adult tumors and the Therapeutically Applicable Research to 

Generate Effective Treatments (TARGET) initiative for pediatric 

tumors, and to assemble and, ultimately, integrate clinical data 

in manageable forms. Researchers anticipate that, in the near 

future, genomic analyses of tens of thousands of cancers will be 

shared with the research community. Keeping up with the pace 

of acquisition of new information and ensuring that it remains 

retrievable in useful ways for basic researchers and clinical 

investigators requires continual upgrading of the bioinformatics 

infrastructure, systems, and software, which is critically important 

and expensive. 

Keeping up with the pace of acquisition 

of new information...requires continual 

upgrading of the bioinformatics 

infrastructure, systems, and software, 

which is critically important and 

expensive. 

Paul Meltzer, M.D., Ph.D. 

(foreground), directs the 

NCI Clinical Molecular 

Profiling Core, which 

facilitates the collection 

of biological data on 

tumors. 

Photo by Rhoda Baer 
32 National Cancer Institute 

The Frederick National 

Laboratory for Cancer 

Research provides 

its researchers 

with scientific 

tools, services, and 

information to enable 

and expedite their 

investigations. 

Frederick National Laboratory for 

Cancer Research 

The only Federally Funded Research and Development 

Center (FFRDC) dedicated to biomedical research was 

established in 1971 under the National Cancer Act. 

This national resource, overseen by the NCI, provides 

rapid response capabilities and one-of-a-kind resources for the 

entire biomedical research community. Its scientists develop 

technologies and perform studies to support the NCI’s mission, 

as well as the work of other NIH institutes. Like Los Alamos, 

Brookhaven, Sandia Labs, and others, this FFRDC uses a unique 

contract mechanism to bring public and private partners together 

to solve difficult medical research challenges. 

A key component of this FFRDC is running the Frederick National 

Laboratory for Cancer Research (FNLCR). As part of its ongoing 

commitment to cancer researchers, the FNLCR provides scientific 

tools, services, and information to enable and expedite their 

investigations. These include: 

•	 The Biopharmaceutical Development Program (BDP) — This 

program produces novel antibodies and other proteins that 

require early development or are not ready for industry to 

take on. For example, when the Children’s Oncology Group 

wanted to test the therapeutic value of ch 14.18, a monoclonal 

antibody directed against the protein GD2, which is expressed 

on the surface of neuroblastoma tumor cells in children, the 

BDP produced the antibody for the clinical trial because there 

was no commercial producer. The findings of the trial indicated 

that ch 14.18 helped to reduce the risk of recurrence when 

given to children whose disease had responded favorably to 

standard chemotherapy. The monoclonal antibody, which the 
An Annual Plan and Budget Proposal for Fiscal Year 2016 33 

BDP has continued to produce as needed, has now become the 

standard of care for children with this type of neuroblastoma. 

Its production is being transferred to the pharmaceutical 

company United Therapeutics. 

•	 The Nanotechnology Characterization Laboratory (NCL) — 

This lab is part of the NCI’s Alliance for Nanotechnology in 

Cancer initiative, which is accelerating the development of 

nanotechnology for basic and applied cancer research. The 

NCL, which works together with the FDA and the National 

Institute of Standards and Technology (NIST), performs and 

standardizes the preclinical characterization of nanomaterials 

intended for cancer therapeutics and diagnostics developed 

by researchers from academia, government, and industry. By 

providing critical infrastructure and characterization services to 

nanomaterial providers, the NCL accelerates the transition of 

basic nanoscale particles and devices into clinical applications. 

The NCL has evaluated more than 200 nanoparticle 

formulations, many of which have gone forward into clinical 

testing. The lab has also helped to establish widely adopted 

standards for nanoparticles and contributes directly to the 

education of the next generation of nanotechnologists through 

biotechnology training courses in nanomedicine and an NCL– 

NIST postdoctoral training program in chemistry. 

•	 NCI’s Experimental Therapeutics (NExT) program — NExT 

advances breakthrough discoveries in basic and clinical 

research into new therapies to treat patients with cancer by 

safely shortening the timeline for new drug development. The 

program consolidates the NCI’s anticancer drug discovery and 

development resources in support of a balanced therapeutics 

pipeline, from the validation of new targets to evaluation in 

phase III clinical trials. For example, promising molecules, such 

as cediranib (AZD2171), an angiogenesis inhibitor, and olaparib 

(AZD2281), which inhibits the repair of DNA damage, are being 

used in combination to treat ovarian cancer and mesothelioma 

in clinical trials. Another promising therapeutic, selumetinib 

(AZD6244), which inhibits the activity of an enzyme called MEK 

in an important cancer growth pathway, is being developed to 

treat childhood brain tumors. 

•	 The RAS Initiative — This effort was initiated to develop effective 

therapies against tumors that contain mutations in members of 

the RAS family of oncogenes. The initiative is discussed in the 

section titled Developing Therapies for RAS-Driven Cancers. 

Photograph of two cells 

that have taken up drugbearing polyethylene 

glycol-coated nanoparticles 

(green). Inside the cells, 

the nanoparticles will 

degrade, releasing their 

drug payload. The cells’ 

skeletons are stained red, 

and the cells’ nuclei are 

stained blue. 

Photo by Omid Farokhzad, M.D. 
34 National Cancer Institute 

Opportunities in Cancer Research 

Today’s progress in cancer research creates opportunities 

to bring new approaches to cancer prevention, diagnosis, 

and treatment tomorrow. 

Thanks to investments made in understanding the interactions 

between genes and the environment and the changes that lead 

to cancer, we are poised to offer strategies for preventing and 

treating cancer that are tailored to these changes. Precision 

medicine offers the promise of being able to decrease the 

risks of disease and optimize treatment for individuals based 

on understanding the specific causes of cancer as well as the 

genomic profiles of cancer. The outcome of this research has the 

potential to prevent more cancers in the first place and, for those 

who receive a diagnosis, enable them to live longer lives. However, 

the current cost of research is substantially higher than it was even 

a decade ago, and maintaining the pace of this progress requires 

increased support. 

Building on Discoveries in 

Cancer Genomics 

S

cientists recognized that it would be necessary to decipher 

the genomes of many cancers to understand the extent 

of their complexity and diversity. This understanding led 

the NCI to launch two large research programs that have 

undertaken the comprehensive analysis of the DNA and RNA in 

approximately 10,000 tumors from more than 30 types of cancer. 

These programs are TCGA for adult tumors and TARGET for 

childhood cancers. 

TCGA is a joint project of the NCI and the NHGRI. This comprehensive 

program, made possible by advances in sequencing technologies 

beyond those used to sequence the human genome, has resulted 

in substantial progress in understanding the biology of cancer and 

has led to new approaches to cancer diagnosis and treatment. 

TARGET is a TCGA-like effort in children’s cancers that is managed 

by the NCI. Genomic technologies are being used to search 

for therapeutic targets in five cancers that are common in, but 

not always exclusive among, children: acute lymphoblastic 

leukemia (ALL), acute myeloid leukemia (AML), neuroblastoma, 

osteosarcoma, and high-risk Wilms tumor. 
An Annual Plan and Budget Proposal for Fiscal Year 2016 35 

TCGA and TARGET have brought together several hundred 

investigators to work on various cancer projects, which also 

required the development of an efficient infrastructure for 

organizing the many steps involved in processing and sequencing 

the DNA in each tumor and storing the large amount of generated 

data in a readily retrievable format for analysis. The technical 

resources, reagents, and personnel for these programs represent 

a considerable investment by the NCI and the NHGRI. Support 

for these large, ambitious programs was greatly facilitated by 

the increased funding associated with ARRA, which led to faster 

progress in completing the analyses of the various tumors. To 

build on this momentum, the extensive information developed by 

TCGA and TARGET is stored in databanks that can be accessed and 

analyzed by the entire cancer research community, even before 

papers arising from the data have been published. 

Analysis of the tumors in TCGA and TARGET has made it possible 

to organize each tumor type, often for the first time, into 

subsets that share particular genetic and epigenetic changes. 

The latter type of changes, unlike genetic changes, are potentially 

reversible, which makes it possible to consider treatment to reexpress epigenetically silenced genes in the tumor or to silence 

genes that have been aberrantly activated epigenetically. The 

targeting of some of the identified genetic abnormalities can be 

evaluated by using drugs that have already been approved by 

Technical advances in DNA 

and RNA sequencing have 

resulted in substantial 

progress in understanding 

the biology of cancer. A 

technician operates a DNA 

sequencing machine. 

Photo by the National Human Genome 

Research Institute 
36 National Cancer Institute 

TCGA analysis of 

stomach tumors 

identified Epstein-Barr 

virus (EBV) as the 

CIN 

• Intestinal histology 

• TP53 mutation 

• RTK-RAS activation 

TCGA analysis of 

stomach tumors 

identified Epstein-Barr 

virus (EBV) as the 

probable cause of a 

GS 

• Diffuse histology 

• CDH1, RHOA mutations 

• CKDN18-ARHGAP fusion 

• Cell Adhesion 

TCGA analysis of 

stomach tumors 

identified Epstein-Barr 

virus (EBV) as the 

probable cause of a 

MSI 

• Hypermutation 

• Gastric-CIMP 

• MLH1 silencing 

• Mitotic pathways 

TCGA analysis of 

stomach tumors 

identified Epstein-Barr 

virus (EBV) as the 

probable cause of a 

distinct subset of st 

EBV 

• PIK3CA mutation 

• PD-L1/2 overexpression 

• EBV-CIMP 

• CDKN2A silencing 

• Immune cell signaling 

Source: Cancer Genome Atlas Research Network. Comprehensive molecular 

characterization of gastric adenocarcinoma. Nature 2014; 513 [7517]: 202-209. 

TCGA analysis of stomach 

tumors identified EpsteinBarr virus (EBV) as the 

probable cause of a 

distinct subset of stomach 

cancers and suggested 

new approaches for 

its treatment. This 

illustration lists some of 

the features associated 

with each of the four 

molecular subtypes 

of gastric cancer. 

the FDA or experimental drugs that 

are in clinical trials. In addition, 

there are efforts to develop specific 

inhibitors to target other identified 

abnormalities, once they have been 

validated as key drivers of the tumor 

types in which they are found. 

In one example, TCGA investigators 

reported that many squamous cell 

lung cancers have abnormalities in 

enzymes called protein kinases for 

which experimental drugs are in 

development. This finding has led 

the NCI to develop the Lung-MAP 

trial, a master protocol for patients 

with this form of lung cancer, who 

will receive experimental targeted 

treatments as determined by the 

molecular abnormalities present in 

their tumors. 

In another example, TCGA analysis of stomach tumors identified 

Epstein-Barr virus (EBV) as the probable cause of a distinct 

subset of stomach cancers and suggested new approaches for its 

treatment. EBV had been identified previously in some stomach 

cancers, but the significance of this finding remained uncertain. 

However, TCGA analysis indicated that a wide range of tumor 

suppressor genes are epigenetically silenced in EBV-positive 

stomach cancers and, in addition, that most of the tumors have 

mutations in a particular protein kinase for which experimental 

inhibitors are currently in clinical trials. It should therefore be 

possible to test whether reactivating these silenced tumor 

suppressor genes and/or inhibiting the mutated protein kinase 

can help patients with this cancer. 

In acute myeloid leukemia, TCGA investigators identified at least 

one key mutation in every case, a finding with both short- and 

long-term clinical implications. 

In glioblastoma multiforme, an aggressive form of brain cancer, 

reactivation of the tumor was found to occur through epigenetic 

changes, an observation with potential implications for 

preventing reactivation. 
An Annual Plan and Budget Proposal for Fiscal Year 2016 37 

Although it is recognized that cancers at a given organ site may 

have several subtypes, some important characteristics may be 

shared among cancers that arise at different sites. For example, 

TCGA researchers identified four genomic-based subtypes 

of endometrial cancer and, in addition, uncovered important 

similarities between endometrial, ovarian, and breast cancers. 

Recognizing the value of comparing genomic data from diverse 

types of cancer, TCGA investigators developed a formal project for 

cross-tumor analysis called the Pan-Cancer project. This effort has 

brought together more than 250 collaborators from 30 institutions 

to analyze the same dataset. It is leading to a deeper appreciation 

of features common to several cancer types. Some of the results 

point to potential new uses for existing drugs based on shared 

molecular targets across cancer types. 

Recognizing the value of comparing 

genomic data from diverse types of 

cancer, TCGA investigators developed a 

formal project for cross-tumor analysis 

called the Pan-Cancer project. This 

effort has brought together more than 

250 collaborators from 30 institutions 

to analyze the same dataset. 

A recent analysis of 12 cancers by TCGA investigators identified 

11 major subtypes based on their molecular profiles. Although 

some types were specific to their organ site of origin, others, 

such as squamous cell lung, head and neck, and a subset of 

bladder cancers were found to have many shared molecular 

characteristics between organ sites. Such analyses are leading 

to a potentially new classification of tumors according to their 

molecular abnormalities, which would go beyond the traditional 

histologic classification according to the site of origin. A molecular 

classification may have therapeutic implications in addition to 

highlighting similar pathogenetic features between cancers of 

different origins. Finding that a particular targeted treatment is 

beneficial in one form of cancer may indicate that it could also be 

clinically useful in other tumor types that share similar molecular 

abnormalities. 
38 National Cancer Institute 

Advancing Precision Medicine Trials 

The advances in cancer genomics achieved by TCGA, 

TARGET, and other molecularly oriented cancer research 

projects are leading to new clinical trials for patients 

whose tumors will be extensively genomically tested 

and whose treatment will be based on the identified molecular 

abnormalities. These include the Lung-MAP, ALCHEMIST, and 

MATCH trials. 

The Lung-MAP trial is evaluating patients with squamous cell 

lung cancer that does not respond to first-line therapy. The 

study divides patients into multiple treatment arms based on 

the molecular profiles of their cancers, uses targeted drugs and 

standard chemotherapeutic agents from several pharmaceutical 

companies, and compares these new approaches to standard 

second-line treatment. Promising results in any arm can lead to 

testing the drugs in that treatment arm in more patients, with 

the goal of more rapidly determining whether the new treatment 

represents a substantial advance over the standard treatment. 

This trial is a public–private partnership between the NCI, several 

pharmaceutical companies, the Foundation for NIH, and Friends 

of Cancer Research. 

ALCHEMIST will test the benefits of molecularly targeted 

adjuvant (post-surgical) treatment of patients with early-stage 

lung adenocarcinomas whose tumors have either an EGFR 

gene mutation or an anaplastic lymphoma kinase (ALK) gene 

rearrangement. Depending on the genetic abnormality in a tumor, 

the patient will receive the EGFR protein kinase inhibitor erlotinib 

(Tarceva) or the ALK protein kinase inhibitor, crizotinib (Xalkori). 

These molecularly targeted therapies are FDA approved for 

Promising results in any arm [of the LungMAP trial] can lead to testing the drugs 

in that treatment arm in more patients, 

with the goal of more rapidly determining 

whether the new treatment represents 

a substantial advance over the standard 

treatment. 
An Annual Plan and Budget Proposal for Fiscal Year 2016 39 

advanced lung adenocarcinoma in patients 

with the relevant genetic changes. The trial 

will test whether treating patients earlier 

in the course of the disease may give even 

better results. If patients develop resistance 

to these drugs, as eventually happens with 

most advanced tumors, the resistant tumors 

will be biopsied to identify the causes of 

resistance and to see whether, in future trials, 

the resistance might potentially be overcome

or prevented by alternative treatment 

approaches. It is expected that most 

patients with early lung adenocarcinoma 

who are screened will not be eligible for 

the therapeutic portion of this trial because 

their tumors will not have the necessary 

mutations. However, the tumor samples 

from these patients will be saved, and, if 

they relapse while on standard treatment, 

their tumors will be biopsied again and 

analyzed for insight into the progression of 

their disease and for potential therapeutic 

approaches suggested by this analysis. 

Although most trials study cancers arising at 

a particular anatomic site, the MATCH trial 

changes this paradigm by emphasizing the 

molecular abnormality and by testing a large 

number of chemotherapeutic agents in virtually any tumor type 

in which appropriate abnormalities are identified. This umbrella 

protocol will examine between 20 and 25 drugs, including those 

that have been FDA-approved for the treatment of cancer at 

another tumor site or experimental agents that have shown 

activity against a known target at one or more tumor sites. If the 

response rate to a particular agent is high, the number of patients 

evaluated with that treatment will be expanded to further explore 

whether the targeted treatment represents a substantial advance 

over standard chemotherapy. If a tumor becomes resistant to 

the first test drug, it will be re-biopsied to see if another targeted 

therapy might be effective and to understand the basis for 

resistance to the initial treatment. By studying multiple agents at 

the same time, a higher proportion of patients will be eligible for 

the trial, and efficient progress can be made in the assessment of 

clinical benefit. 

Researcher preparing 

tissue specimens for 

molecular analysis. 

Photo from the NCI Biorepositories and 

Biospecimen Research Branch 
40 National Cancer Institute 

Harnessing the Promise of 

Immunotherapy 

I

monoclonal antibodies such as trastuzumab (Herceptin) have 

n contrast to therapeutic approaches that target the 

abnormalities in cancer cells with small-molecule inhibitors, an 

alternative successful approach is to harness the potential of 

the immune system to seek and destroy cancers. Therapeutic 

been in use since the 1990s. However, their function is analogous 

to that of the small-molecule drugs, in that these antibodies bind 

to and inhibit cancer cell proteins that drive abnormal growth. 

In contrast, therapeutic monoclonal antibodies that modulate 

immune system activity do so by targeting proteins that normally 

restrict the strength of immune responses. This approach is based 

on the hypothesis, from fundamental studies of the immune 

system, that inhibiting one or another of these “checkpoint” 

proteins should enable the immune system to help destroy a 

tumor. The clinical validity of this approach has been confirmed: 

A monoclonal antibody, ipilimumab (Yervoy), that interferes with 

the activity of one of these proteins, called CTLA4, was approved 

by the FDA in 2011 for the treatment of advanced melanoma. 

This success is now leading to efforts to improve the effectiveness 

of anti-CTLA4 antibody treatment in melanoma, identify other 

tumors where this treatment can have clinical value, and test 

whether interfering with other immune 

Electron microscope 

image of a human T 

lymphocyte. Stimulating 

the activity of these white 

blood cells is one focus of 

immunotherapy. 

Image from the National Institute of 

Allergy and Infectious Diseases 

checkpoints may also have clinical 

benefit. Such antibody-based inhibitors 

in development include those that target 

the proteins PD-1 and PD-L1, which binds 

to PD-1. Clinical responses in several 

forms of cancer have been reported with 

antibodies that target either protein. 

The FDA has given its “breakthrough 

therapy” designation to several candidate 

antibodies, which has facilitated their 

use in clinical trials and led to the recent 

FDA approval of the first PD-1 inhibitor, 

pembrolizumab (Keytruda). 

Another antibody-based approach 

involves fusing a specific monoclonal 

antibody to a bacterial toxin, which 

creates an “immunotoxin” that selectively 
An Annual Plan and Budget Proposal for Fiscal Year 2016 41 

kills cancer cells because the 

antibody binds to a protein 

that is highly expressed on 

the cancer cells but not on 

normal cells. Immunotoxins 

developed by NCI researchers 

have induced remissions in 

patients with several cancer 

types, including late-stage 

mesothelioma, triple-negative 

breast cancer, hairy cell 

leukemia, and childhood 

acute lymphoblastic 

leukemia. Immunotoxins 

will soon be tested in lung 

adenocarcinoma, pancreatic 

cancer, and ovarian cancer. 

Directly engineering the 

patient’s own immune cells 

to recognize and attack their 

cancer is yet another form 

of immunotherapy. This 

approach is called chimeric 

antigen receptor T-lymphocyte adoptive cell transfer. In this 

therapy, T lymphocytes from the patient’s immune system are 

genetically engineered to express proteins on their cell surfaces 

Directly engineering the patient’s own immune 

cells to recognize and attack their cancer is [a 

form of immunotherapy] called chimeric antigen 

receptor T-lymphocyte adoptive cell transfer. 

Phineas Sandi, shown here on 

his first day of kindergarten, 

participated in an NCI clinical 

trial that tested genetically 

engineered T cells to treat 

acute lymphoblastic leukemia. 

He was in remission within 11 

days of starting the trial and 

remains free of cancer. 

Photo from Kristina Sandi 

that enable the cells to recognize and destroy cancer cells. 

Next, the engineered cells are grown in the laboratory to greatly 

expand their numbers before they are infused into the patient. 

The expressed proteins are hybrids of a receptor on the outside 

of the T lymphocytes that can recognize and bind to a protein 

on the surface of cancer cells and stimulatory molecules. When 

the receptor binds to the cancer cell, the stimulatory molecules 

activate the T lymphocytes to multiply and kill cancer cells. 
42 National Cancer Institute 

Long-term responses have been obtained using this approach 

in adult and pediatric patients with various forms of leukemia 

and lymphoma. The technology for this promising therapy is still 

cumbersome and expensive. However, it could have the potential 

for use in a large number of patients, if appropriately automated 

cell culture systems can be developed. 

Therapeutic vaccines that induce clinically beneficial immune 

responses are an alternate approach. Some target nonmutated 

proteins expressed by the tumor, while others target mutant 

proteins in the tumor. An experimental prostate cancer vaccine 

against a nonmutated protein (prostate-specific antigen, PSA) has 

produced long-term responses and is in late-phase clinical trials. 

Targeting mutant proteins, which is often called neo-antigen 

vaccination (neo = new; antigen = a part of a protein that induces 

an immune response), has thus far been successful in animals. It 

has the theoretical appeal of being directed against proteins whose 

mutations have been identified by genomic analysis of the tumor.

The journal Science designated “immunotherapy of cancer” its

Breakthrough of the Year in 2013, thanks to the recent progress made 

in patients. These clinical advances have come from long-term basic

research on the immune system and studies in the NCI intramural

approach could lead to lasting remissions. It is notable that this

research was done during a time of considerable skepticism about 

the clinical value of immunotherapy. We still need to understand 

what enables this approach to work in some patients but not others 

through systematic analysis of their immune systems and their

tumors. Improved understanding will make it easier to administer

this type of treatment to those patients who are most likely to benefit

from it. It could also help researchers develop ways to use this

approach to help patients for whom it is not yet beneficial.

We still need to understand what enables 

[immunotherapy] to work in some patients

but not others through systematic analysis 

of their immune systems and their

tumors. Improved understanding will 

make it easier to administer this type of

treatment to those patients who are most 

likely to benefit from it.
An Annual Plan and Budget Proposal for Fiscal Year 2016 43 

Making Progress against 

Childhood Cancers 

The NCI recognizes the importance of research that 

addresses pediatric cancers and has an extensive research 

portfolio that is directly or indirectly related to cancers 

in children. The institute’s support ranges from the 

conduct of basic science to improve our understanding of the 

mechanism of disease to the testing of new therapies, including 

those abandoned by industry. Although significant reductions in 

pediatric cancer death rates continue to occur each year, about 

2,000 children still die annually from cancer, and cancer remains 

the leading cause of death from disease among children. 

The TARGET program uses genomic approaches to catalog the 

full range of molecular changes in several childhood cancers to 

increase our understanding of their pathogenesis, improve their 

diagnosis and classification, and identify new candidate molecular 

targets for better treatments. The related Cancer Genome 

Characterization Initiative includes genomic studies of various 

pediatric cancers that often do not respond well to treatment. 

TARGET has identified many new mutations and chromosomal 

abnormalities associated with pediatric cancers; these studies 

have already led to two clinical trials with new drugs against 

childhood tumors. 

The Children’s Oncology Group (COG) is part of the NCTN. It 

develops and coordinates pediatric cancer clinical trials that are 

available at more than 200 member institutions, including cancer 

centers throughout the United States and Canada. In addition to 

The Children’s Oncology Group (COG) is part 

of the NCTN. It develops and coordinates 

pediatric cancer clinical trials that are 

available at more than 200 member 

institutions, including cancer centers 

throughout the United States and Canada. 
44 National Cancer Institute 

conducting traditional latephase clinical trials, COG has 

established its Phase 1 and 

Pilot Consortium to conduct 

early-phase trials and pilot 

studies so that new anticancer 

agents can be rapidly and 

efficiently introduced into the 

pediatric setting. COG will 

also conduct a new Pediatric 

Molecular Analysis for Therapy 

Choice Program (Pediatric 

MATCH) trial, which will provide 

opportunities to test molecularly 

targeted therapies in children 

with advanced cancers and 

few other treatment options. 

This precision medicine trial is 

modeled on the adult MATCH 

trial discussed in the section 

titled Advancing Precision 

Medicine Trials. The Pediatric 

MATCH trial will enroll children 

with cancers that have 

Karen Kinahan, M.S., 

R.N., (left), director 

of the STAR program 

at Northwestern 

University’s Lurie 

Comprehensive Cancer 

Center, which provides 

long-term care for adult 

survivors of childhood 

cancers, and Julia 

Stepenske, childhood 

cancer survivor and 

stem-cell transplant 

nurse, at an event 

celebrating the 

STAR program’s 

10th anniversary. 

Photo from Karen Kinahan 

progressed on standard therapy. DNA sequencing of their tumors 

will be used to identify children whose cancers have a genetic 

abnormality for which either an approved or investigational 

targeted therapy exists. Immunotherapeutic approaches will 

be considered for those children for whom no molecularly 

appropriate therapy is available. 

Childhood cancer survivors are at increased risk of developing 

secondary cancers and many other long-term health conditions 

commonly referred to as “late effects” of cancer treatment. 

The Childhood Cancer Survivor Study (CCSS) evaluates a longterm retrospective cohort with the twin goals of increasing our 

understanding of these late effects and improving the quality of 

life for survivors. The CCCS is studying the long-term effects of 

cancer and cancer therapy in approximately 35,000 survivors 

of childhood cancer diagnosed between 1970 and 1999 and 

approximately 8,000 siblings of survivors. 
An Annual Plan and Budget Proposal for Fiscal Year 2016 45 

As noted in the section titled Frederick 

National Laboratory for Cancer Research, the 

NCI has provided strong support for cancer 

immunotherapy. The FNLCR’s manufacturing of 

the ch 14.18 monoclonal antibody and COG’s 

successful testing of ch 14.18 in children with 

advanced-stage neuroblastoma are major 

successes. Moreover, the experimental approach 

of treating patients with their own T lymphocytes 

after they have been modified in the laboratory 

to express chimeric antigen receptors that 

recognize specific targets on cancer cells is 

currently being tested in children with several 

types of cancer. They include B-cell leukemia or 

lymphoma, synovial sarcoma, osteosarcoma, and 

other non-neuroblastoma solid tumors. 

The NCI supports research to develop treatments 

specifically for children because children are 

not just small adults. At the same time, we are 

actively pursuing drugs that have been effective 

in treating adult cancers and show promise for 

certain childhood cancers. To that end, the Pediatric Preclinical 

Testing Program (PPTP), which identifies new candidate agents 

for treating childhood cancers, has collaborated with more than 

50 companies to undertake the preclinical evaluation of more than 

80 therapeutic agents. To date, several PPTP-tested agents have 

moved into clinical testing. 

To take advantage of new information about pediatric cancer, 

especially in genomics, the NCI plans to convene a workshop 

in 2015 to discuss the opportunities for future improvement in 

detection, diagnosis, prevention, and treatment that build on 

recent genetic discoveries. The workshop participants will include 

representatives from the pediatric cancer advocacy community, 

as well as those from philanthropic foundations with an interest in 

pediatric cancer research. 

Harrison McKinion (right) 

was diagnosed with B-cell 

acute lymphoblastic 

leukemia in which the 

genes EBF1 and PDGFRB 

were rearranged. Brent 

Weston, M.D., of the UNC 

Lineberger Comprehensive 

Cancer Center, reports that 

Harrison has responded 

well to imatinib therapy 

and is expected to complete 

treatment in the spring 

of 2015. 

Photo from Ginger McKinion 

The NCI supports research to develop 

treatments specifically for children 

because children are not just small adults. 
46 National Cancer Institute 

Developing Therapies for RAS-Driven 

Cancers 

The NCI has recently initiated a project to develop 

effective therapies against tumors that contain mutations 

in members of the RAS family of oncogenes. Despite 

advances made with targeted treatments directed 

against the proteins produced by several other oncogenes that 

drive cancer, researchers have not yet succeeded in developing 

effective treatments against proteins produced 

by RAS oncogene family members. It has 

been known for many years that RAS genes 

are mutated in approximately one-third of 

all cancers, including the vast majority of 

pancreatic adenocarcinomas, about 45 percent 

of colorectal cancers, and about 35 percent of 

lung adenocarcinomas. As a group, cancers that 

carry mutations in a RAS gene tend to respond 

poorly to standard chemotherapy and carry with 

them a poor prognosis. It would therefore be 

extremely beneficial if there were effective drugs 

against these cancers. Although there has been 

considerable progress made in understanding the 

proteins produced by mutant RAS genes, these 

insights have not been translated into effective 

drugs, and many properties of these proteins 

have not been fully explored. 

RAS proteins serve as molecular switches that 

are activated by a specific group of proteins and 

inactivated by another group of proteins. The 

majority of mutant RAS proteins are constitutively 

activated primarily because they are resistant 

to the proteins that normally inactivate them. 

RAS proteins appear to lack places where 

an anticancer compound can bind, leading 

some investigators to consider these proteins 

“undruggable.” In addition, RAS proteins signal 

to several downstream targets that together 

account for RAS’s strong cancer-promoting 

activity. Interfering with just one of these targets 

does not appear to be clinically useful against 

tumors driven by mutant RAS genes. 
An Annual Plan and Budget Proposal for Fiscal Year 2016 47 

However, recent developments, such as improvements in imaging 

tools and new information about how RAS proteins interact with 

several other proteins, have suggested that this pessimistic view 

may not be correct and have fostered renewed interest among 

researchers in finding ways to target mutant RAS proteins or their 

signaling pathways with small compounds. 

To accelerate progress, the NCI recently launched the RAS Initiative, 

a large-scale collaborative effort to find vulnerabilities in cancers 

driven by mutant RAS proteins that may be exploited in efforts to 

seek therapeutic strategies for patients with RAS-driven cancers. 

This new initiative is based on a “hub and spoke” model, with 

the Advanced Technology Research Facility of the NCI’s FNLCR 

serving as the initiative’s “hub.” The project is being led by Frank 

As a group, cancers that carry mutations 

in a RAS gene tend to respond poorly to 

standard chemotherapy and carry with 

them a poor prognosis. It would therefore 

be extremely beneficial if there were 

effective drugs against these cancers. 

Structure of human 

KRAS protein. 
48 National Cancer Institute 

To accelerate progress, the NCI recently
�

launched the RAS Initiative, a large-scale
�

collaborative effort to find vulnerabilities
�

in cancers driven by mutant RAS proteins
�

that may be exploited in efforts to seek
�

therapeutic strategies for patients with
�

RAS-driven cancers.
�

McCormick, a highly respected RAS researcher who, until 

recently, was director of the NCI-Designated Comprehensive 

Cancer Center at the University of California, San Francisco. 

The hub at FNLCR interacts with the “spokes” of academia, 

the NCI’s intramural laboratories, and the biotechnology and 

pharmaceutical industries. This project highlights the NCI’s ability 

to bring together experts from across the research enterprise to 

address pressing scientific and clinical questions in cancer. 

Although it is hoped that a “universal” RAS inhibitor will be 

found, an alternative approach is to take advantage 

of the fact that there are several relatively 

common mutations that change the same 

amino acid (glycine at position 12) in the

KRAS protein to one of three different 

amino acids (cysteine, aspartic acid, 

or valine). RAS Initiative researchers

will test whether it may be possible

to develop inhibitors that work 

against one or two of these closely 

related mutant proteins rather than 

against all mutant RAS proteins. 

Even this accomplishment could 

have a substantial impact, because 

one of these three mutant KRAS 

proteins is present in more than 

100,000 new cancers per year in 

the United States, with each mutant 

accounting for more than 29,000 

cases. This project will also develop 

accurate structural models of mutant 

LABORATORY FOR 

CANCER RESEARCH 

INTRAMURAL LABS 

EXTRAMURAL 

NCI-SUPPORTED 

FREDERICK NATIONAL LABS 

CONTRACT PHARMA 

RESEARCH 

BIOTECH 
An Annual Plan and Budget Proposal for Fiscal Year 2016 49 

0

30,000

60,000

90,000

R

120,000

NUMBER OF NEW U.S. CANCER CASES PER YEAR 

ALL CODON 12 G12C G12D G12V 

MUTATIONS MUTATIONS MUTATIONS MUTATIONS 

KRAS CODON 12 MUTATIONS 

Colorectal 

Combined Total New Cases Per Year 

Lung 

Abbreviations: G=glycine; C=cysteine; 

Pancreatic D=aspartic acid; V=valine. 

RAS proteins and their interacting proteins, an advance that could 

lead to new approaches for developing drugs that interfere with 

these interactions. RAS Initiative researchers also plan to identify 

a range of key genes that cooperate with mutant RAS genes to 

drive cancer cells and to see whether inhibiting them singly or 

in combination might lead to an effective approach for targeting 

tumors with mutant RAS proteins. The information developed by 

the RAS Initiative will be fully available to the research community 

to further increase the likelihood of progress. In addition, the RAS 

Initiative is developing a resource of reference reagents for the 

research community. 

INCIDENCE OF KRAS CODON 12 MUTATIONS 

IN THREE HUMAN CANCERS 

A codon is a sequence of three nucleotides in a messenger RNA molecule that determines which amino acid will be used during 

each step of protein synthesis. Codon 12 of KRAS messenger RNA normally specifies insertion of the amino acid glycine at postion 

12 of the growing KRAS protein molecule, but mutations can cause this amino acid to be replaced with cysteine, aspartic acid, or valine. 

Adapted from Stephen AG, Esposito D, Bagni RK, et al. Dragging Ras Back in the Ring. 

Cancer Cell 2014; 25(3):272-281. 
50 National Cancer Institute 

Finding New Strategies to 


Prevent Cancer
 

P

reventing cancer remains a critical goal. Because 

there may be an interval of several decades from the 

initial exposure to an environmental carcinogen to the 

development of cancer, it often takes many years before 

a decrease in exposure results in a reduction in cancer incidence 

and mortality. However, a decrease in exposure during this long 

interval can eventually result in substantial long-term dividends, 

as seen, for example, with tobacco. The greatest benefit is usually 

seen if the exposure is eliminated. 

Many preventive efforts are directed at reducing or eliminating 

exposures to carcinogens or protecting the body from exposures. 

Other efforts may involve screening procedures, such as those 

for cervical and colorectal cancer, which can find premalignant 

lesions and lead to treatment of patients who are at high risk of 

developing cancer. Although the pharmaceutical industry regularly 

funds diagnostic and therapeutically oriented research, the 

majority of prevention-oriented research is funded by the public 

sector because the potential for commercial profit in this area is 

either substantially less than for treatment or may not exist at all 

in some instances. Nevertheless, prevention has the potential to 

save more lives from cancer than treatment—as is already true for 

tobacco and lung cancer—which underlines the importance of 

strongly supporting this research area. 

Prevention has the potential to save
�

more lives from cancer than treatment...
�

which underlines the importance of
�

strongly supporting this research area.
�

As in other areas of research, the cost of prevention research 

continues to increase, which seriously constrains the kinds 

of trials that are undertaken. For example, the National Lung 

Screening Trial (NLST) was started in 2002, during the period 

of the doubling of NIH funding. When this study of more than 

50,000 high-risk current and former smokers was completed 
Source: U.S. Department of Health and Human Services.

The Health Consequences of Smoking—50 Years of Progress:

A Report of the Surgeon General, 2014.

An Annual Plan and Budget Proposal for Fiscal Year 2016 51 

SMOKINGAND

SECONDHAND SMOKE CAUSE

87%

OF LUNG

CANCER

61%

OF PULMONARY

DISEASE

DEATHS

DEATHS

32%

OF CORONARY

DISEASE

HEART

DEATHS

8 years later, it had cost the NCI more than $250 million. However, 

NLST demonstrated for the first time in a randomized controlled 

screening trial for lung cancer that a screening approach—lowdose helical computed tomography (CT)—could reduce mortality 

from lung cancer by almost 20 percent. The findings from NLST 

have led low-dose helical CT to become the standard of care for 

screening high-risk current and former smokers. It is not clear 

whether such a trial, whose potential for success was viewed as 

very uncertain when it was started, would be initiated in today’s 

funding climate. 

Tobacco control. Tobacco use is the single most 

important known preventable cause of cancer. In 

addition to being the major cause of cancers in the 

lung, smoking contributes to cancers elsewhere 

in the body as well as to cardiovascular and other 

diseases. It is estimated that the typical smoker in 

the United States reduces his or her life expectancy 

by more than 10 years. More than 87 percent of 

lung cancer deaths, 61 percent of all pulmonary 

disease deaths, and 32 percent of all deaths from 

coronary heart disease are attributable to smoking 

and to exposure from secondhand smoke. If current 

trends continue, it is estimated that smoking will 

cause the premature deaths of 5.6 million American 

youths who are now under the age of 18. 

The serious health consequences of tobacco 

use were highlighted by the landmark 1964 U.S. 

Surgeon General’s Report on smoking and health, 

which laid the foundation for tobacco control 

efforts in the United States. Adult smoking rates 

in the United States declined from 42 percent in 

1965 to 18 percent in 2012, preventing serious 

disease for many Americans. However, more than 

42 million Americans still smoke. Epidemiologic 

research indicates that many of the negative 

health consequences associated with tobacco 

consumption are potentially reversible for smokers 

who quit. For example, compared with someone 

who continues to smoke, 35- to 44-year-olds who 

quit can gain about 9 years of life expectancy, 45- to Source: U.S. Department of Health and Human Services. 

The Health Consequences of Smoking—50 Years of 54-year-olds can gain 6 years, and 55- to 64-year-olds can gain Progress: A Report of the Surgeon General, 2014. 
52 National Cancer Institute 

Adapted from BeTobaccoFree.gov 

4 years. Ten years after quitting smoking, the risk of death from 


lung cancer declines by almost one-half, and at 15 years the risk 


of coronary heart disease is close to that of a person who never 


smoked. 


Other epidemiologic research has found that people in the 


United States who have more education are less likely to smoke. 


Although the smoking rate among college graduates is 10 percent, 


it is 24 percent among high school graduates and 45 percent 

Source: World Health Organization.

WHO Report on the Global Tobacco Epidemic, 2011

Source: World Health Organization.

WHO Report on the Global Tobacco Epidemic, 2011

-

80%

LOW- & MIDDLE INCOME COUNTRIES 

THE PERCENTAGE OF THOSE 8 MILLION

DEATHS THAT WILL OCCUR IN 

WHO Report on the Global Tobacco Epidemic, 2011

An Annual Plan and Budget Proposal for Fiscal Year 2016 53 

30%

2012 2025 

THE RISE IN THE NUMBER TOBACCO-RELATED

DEATHS WORLDWIDE BET WEEN 

8 million

THE NUMBER OF TOBACCO-RELATED

2030 

DEATHS WORLDWIDE IN 

among those with a general educational development (GED) 

certificate. High smoking rates are also associated with low socioeconomic status, mental illness, and being Native American. In 

addition, the states with the highest smoking rates have more 

than twice the number of adult smokers as those states with the 

lowest smoking rates. The NCI supports several studies that aim 

to develop and implement more effective approaches for these 

groups with high smoking rates to prevent more of them from 

starting to smoke and to help those who do smoke to 

stop smoking. 

As youth become more attracted to electronic cigarettes, the NCI 

is addressing this emerging trend and its relationship with tobacco 

consumption. The NCI recently co-sponsored the NIH Electronic 

Cigarette Workshop: Developing a Research Agenda. The goal 

of the meeting was to identify the key research gaps related 

to electronic cigarettes and their effects on human physiology 

and health, the potential for addiction to these products, as well 

as issues related to smoking cessation and other public health 

concerns. The NCI is using several grant mechanisms, including 

supplements to the NCI-Designated Cancer Centers, to support 

research evaluating this nontobacco form of smoking for its 

potential to increase, or decrease, tobacco consumption, as well as

for its possible direct effects on health. We are also working closely 

with the FDA, which has the major responsibility for regulating 

tobacco products. 

Global tobacco consumption is a serious and growing health 

problem. The World Health Organization estimates that the 

number of annual tobacco-related deaths worldwide will increase 

from almost 6 million today to more than 8 million by 2030, 

with 80 percent of those deaths occurring in low- and middleincome countries. The NCI and NIH’s Fogarty International Center, 

together with other partners, have launched the International 

Tobacco and Health Research and Capacity Building Program. 

This program supports transdisciplinary research and capacitybuilding projects that address the burden of tobacco consumption 

in low- and middle-income nations, among many other strategies. 

The program is designed to promote international cooperation 

between investigators in the United States and other high-income 

nations that conduct research on tobacco control with scientists 

and institutions in countries in which tobacco consumption is an 

urgent public health concern. 

Source: World Health Organization.
 Source: World Health Organization.

WHO Report on the Global Tobacco Epidemic, 2011.
 
54 National Cancer Institute 

The NCI and NIH’s Fogarty International 

Center, together with other partners, have 

launched the International Tobacco and Health 

Research and Capacity Building Program [to] 

address the burden of tobacco consumption in 

low- and middle-income nations. 

Preventing cancers caused by viral infections: 

HPV and HCV. Identifying an infectious agent as a cause of 

cancer carries with it the possibility of prevention, because we 

can try to reduce exposure to the agent, develop a vaccine that 

prevents the infection, or treat the infection before it causes 

cancer. Identification of hepatitis B virus (HBV) in the 1960s and 

the recognition that chronic HBV infection is an important cause 

of serious liver disease, including liver cancer, led to development 

in the 1980s of the first vaccine that can prevent cancer. Recent 

developments with two oncogenic viruses, human papillomavirus 

(HPV) and hepatitis C virus (HCV)—both of which cause cancer 

after many years of chronic infection—illustrate how a variety 

of research advances have the potential to substantially reduce 

cancers attributable to both viruses. 

 

HPV infection causes virtually all cases of cervical cancer and 

a substantial proportion of several other cancers. In the United 

States, the number of noncervical cancers attributable to HPV 

infection is similar to that of cervical cancers. Thanks to decades 

of Pap smear-based cervical cancer screening and treatment of 

identified premalignant lesions, there has been an approximately 

75 percent reduction in the incidence of and mortality from this 

cancer since the early 1950s. On the other hand, there have been 

substantial increases in HPV-associated anal and oropharyngeal 

cancers, two diseases for which population-based screening 

has not been determined to be useful. The vast majority of anal 

cancers are caused by HPV infection, and incidence of and 

mortality from this cancer increased by 22 percent and 17 percent, 

respectively, between 2001 and 2010. The incidence of HPVpositive oropharyngeal cancer increased more than threefold 

during a recent 25-year period, and it is estimated that by 2020 the 

number of HPV-positive oropharyngeal cancers will be higher than 

the number of cases of cervical cancer. 
PROPORTION OF CANCERS

Source: Schiller, JT and Lowry, DR. Nature Reviews Microbiology. 2012 Oct; 10: 681-692

CAUSED BY HPV

An Annual Plan and Budget Proposal for Fiscal Year 2016 55 

PROPORTION OF CANCERS CAUSED BY HPV IN THE UNITED STATES 

HPV infection causes virtually all cases of cervical cancer and a substantial 

proportion of several other cancers. 

CERVICAL 

ANAL 

VULVAR/VAGINAL 

PENILE 

OROPHARYNGEAL 

0 2,000 4,000 6,000 8,000 10,000 12,000

ANNUAL NUMBER OF CASES 

HPV CASES NON-HPV CASES 

Source: Schiller JT and Lowy DR. Understanding and learning from the success of prophylactic human 

papillomavirus vaccines. Nat Rev Microbiol 2012; 10(10): 681-692. 

A safe and effective vaccine that, in principle, can prevent most 

cases of cervical cancer as well as most of the noncervical 

cancers attributable to HPV infection was approved by the FDA in 

2006, followed in 2009 by the approval of a second vaccine. This 

approach, made possible by earlier work done by NCI researchers, 

is already having a major impact on reducing the incidence of 

high-grade cervical dysplasia in young women in Australia, where 

there has been high vaccine uptake. However, these vaccines are 

underused in the United States, as well as in low- and middleincome countries, where cervical cancer is frequently the most 

common cancer among women. As the President’s Cancer 

Panel noted in a recent report, the underuse of HPV vaccines is a 

serious but correctable threat to progress against cancer. Recent 

research strongly suggests that two doses, and perhaps even a 

single dose, of the current vaccines may be sufficient to induce 

long-term protection in young adolescents. If confirmed to 

provide long-term protection, reducing the number of doses could 

make vaccination logistically easier and less expensive. Second 

generation vaccines with the potential to protect against even 

more of the HPV-associated cancers are in development. 
56 National Cancer Institute 

The recognition of HPV as a cause of several cancers 

is also having an impact on research and practice 

beyond the vaccine, to preventing the cancers after 

infection. HPV DNA-based testing, which is more 

sensitive than traditional Pap smear screening for 

cervical cancer, has been approved by the FDA 

for use in cervical cancer screening, initially in 

conjunction with Pap smear screening, and in 2014 

as a primary screening method. This approach has 

the potential to further reduce the incidence of and 

mortality from this cancer. To reduce the incidence 

of anal cancer, the NCI has initiated a large screening 

trial to determine whether treatment of high-grade 

anal dysplasia identified by screening high-risk 

patients can reduce their likelihood of developing 

invasive anal cancer. 

HCV infection is a major cause of liver cancer in the 

United States and throughout the world. Much of 

the 20-percent increase in liver cancer mortality in 

the United States seen between 2001 and 2010 is 

believed to be attributable to this infection. The recognition that 

HCV is frequently transmitted by blood products led to effective 

screening methods that have dramatically reduced the incidence 

of transfusion-related HCV infection. Although efforts to develop 

a preventive vaccine have thus far been unsuccessful, there 

has been enormous progress in the development of effective 

approaches to the antiviral treatment of chronic HCV infection. 

Several direct-acting antiviral drugs that can induce sustained viral 

responses have been licensed by the FDA since 2011, and others 

with potentially promising efficacy profiles are currently in latephase clinical trials. Long-term follow-up of treated patients will be 

needed to verify that the treatment has reduced their risk of liver 

cancer and other serious liver disease. These advances in treatment 

led the United States Preventive Services Task Force in 2013 to 

recommend that all individuals born between 1945 and 1965 

In 2006, the FDA 

approved a safe and 

effective vaccine that 

can prevent infection 

with the HPV types that 

cause most cervical 

cancers. The underuse 

of HPV vaccines is a 

serious but correctable 

threat to progress 

against cancer. 

HPV DNA-based testing...has the potential to 

further reduce the incidence and mortality 

from [cervical] cancer. 
An Annual Plan and Budget Proposal for Fiscal Year 2016 57 

 

(a group at high-risk of acquiring the virus from contaminated 

blood products) be screened once for HCV infection. Further 

research might indicate that it is cost effective to expand the group 

of individuals who should be screened for HCV infection. 

Chemoprevention with aspirin. Evidence from several 

studies of people who have taken low-dose aspirin for many years 

shows a substantial reduction in the incidence of and mortality 

from several types of cancer, including colorectal and lung cancer. 

However, the adoption of long-term chemoprevention of cancer 

with aspirin has been limited by concerns about gastrointestinal 

side effects, such as bleeding, especially in older individuals. The 

NCI is collaborating with the National Institute on Aging on a 

5-year study of aspirin’s preventive attributes and side effects in 

19,000 people over the age of 65 in the United States and Australia, 

in hopes of providing information that will better guide the use of 

aspirin for chemoprevention. 

As in cancer treatment, the genomic methods of precision 

medicine may help to identify patients who are more and less 

likely to reduce their cancer risk by taking aspirin. A recent 

retrospective study suggests that some individuals, based on 

their genetic background, may benefit more than others from the 

chemopreventive effects of aspirin. In the study, individuals who 

had higher levels in their normal colon of a particular enzyme in 

a pathway affected by aspirin and who took aspirin regularly had 

a 50 percent lower risk of colon cancer than those who did not 

take aspirin. However, those who had lower levels of the enzyme 

and took aspirin had only a 10 percent lower risk of colon cancer. 

Another study reached similar conclusions for the level of a 

related protein in the urine. If these results are confirmed in other 

studies, the ability to differentiate between groups who will benefit 

the most from this approach and those who will not might help 

doctors and patients make informed decisions about aspirin for 

cancer prevention. 
The Future 

The NCI recognizes the need to ensure that the nation’s 

cancer research portfolio supports the continuum from 

basic to translational to clinical research. As in the past, 

unexpected basic science discoveries will lead scientists 

to new areas of cancer research. It also remains important to 

continue to identify new causes of cancer and to study established 

causes that we do not fully understand. For example, Merkel 

cell carcinoma, a relatively uncommon form of skin cancer 

that is associated with a higher mortality rate than melanoma, 

was recently found to be associated with infection by Merkel 

cell polyomavirus (MCPyV). This association has led to a rapid 

increase in our understanding of the genetics, molecular biology, 

and pathogenesis of this type of tumor and to new candidate 

approaches for its treatment. 

Chanelle Case Borden, 

Ph.D., is a post-doctoral 

fellow in the NCI 

Experimental Immunology 

Branch. Investigators like 

Dr. Borden are the future 

of cancer research. 

Photo by Daniel Sone 

58 National Cancer Institute 
In the clinic, it will be critical to continue to identify molecular 

signatures of subpopulations of tumor types that can be correlated 

with prognosis or response to drugs. Applying this knowledge for 

improved screening and diagnosis will help us to better distinguish 

cancers that are likely to be aggressive from those that are not, 

leading to the ability to tailor treatment to the disease and provide 

the patient a better outcome. 

The dependence of tumors on the mutation and aberrant 

expression of particular genes, or on signaling pathways and 

networks, has led to effective targeted cancer treatments directed 

at inhibiting these activities. However, the duration of effectiveness 

is often limited by the development of treatment resistance, which 

arises from new mutations in the tumor and other mechanisms. 

The future of cancer treatment with new molecularly targeted 

drugs will depend on understanding drug resistance, overcoming 

it, and preventing it through the development of effective 

combination therapies that address multiple genetic changes 

over time, as well as alternative treatments that can circumvent 

resistance. 

Thus far, cancer research has identified very few ways to 

replace the anticancer activities of tumor suppressor genes that 

are commonly inactivated by mutation or deletion in cancer. 

Theoretically, such replacements have enormous potential, 

because we know that most cancers remain susceptible to 

these genes when nonmutated versions of them are selectively 

re-expressed. However, the clinical utility of this approach has 

remained largely elusive because of technical and conceptual 

barriers. Breakthroughs that can overcome this bottleneck will 

only come from additional research. 

Today’s efforts to control cancer and its broad effects—through 

science, medicine, and social programs—are vast and are 

conducted by many people in many organizations. The NCI is 

committed to the continued investigation of the basic biological 

causes of cancer. Applying that knowledge to develop new 

prevention, screening, diagnostic, and therapeutic approaches will 

result in further reductions in cancer incidence and mortality. 

“We need to keep 

our eye on our own 

history, and what 

has been productive 

for the NIH has 

been supporting 

the most brilliant 

people to think 

freely about solving 

really difficult 

problems.” 

— Harold Varmus, M.D. 

 October 21, 2014, 

presentation to the 

NCI Council of Research 

Advocates 

An Annual Plan and Budget Proposal for Fiscal Year 2016 59 
60 National Cancer Institute 

Our understanding of cancer is expanding, 

together with our ability to prevent, 

diagnose, and treat it. But, fiscal realities are curtailing 

the speed at which advances can occur. Despite the NCI’s best 

efforts, too many good ideas are left on the table unfunded. The 

cancer research community has demonstrated the capacity to 

utilize additional funds in ways that can accelerate programs and 

move the increased understanding of cancer into the clinic. TCGA 

is just one recent example of this capacity. Advances against the 

worldwide scourge of cancer will depend on strong continued 

support of the research enterprise and integration of the various 

modes of research employed by many global partners. This 

commitment to cancer research will demonstrate the urgency of 

making progress for current patients and for the many at risk of 

developing cancer. 

They deserve nothing less.
An Annual Plan and Budget Proposal for Fiscal Year 2016 61

NCI Professional Judgment Budget 

Recommendation

As the promising research opportunities highlighted 

in this document demonstrate, the cancer research 

community—under the leadership of the NCI—is poised 

to accelerate the rate of discovery and reduce the 

burden of cancer in America. Achieving these important goals 

will require resources to support the full continuum of research 

sponsored by the NCI. Major advances in prevention, diagnosis, 

and treatment are clearly possible, but they require ample 

funding across a broad spectrum of science, including basic 

biological research.

To make rapid progress in cancer research, NCI funding must 

not only be strong, but also sustained. Yet, recent experience has 

been discouraging. Measured in inflation-adjusted dollars and 

excluding any one-time funding, the NCI suffered a 25 percent 

budget decline due to inflation during the past decade. This 

decrease represents a cumulative loss of $10 billion in cancer 

research funding since 2003. As a consequence, the NCI’s 

ability to exploit promising research opportunities and translate 

these opportunities into new cancer treatments and prevention 

strategies has been constrained and compromised.

The outlook for funding in the future appears equally 

discouraging. In the decade ahead, the NCI may experience a 

repeat of the budget environment that governed the past decade. 

Based on recent amendments to the Budget Control Act, overall 

spending on the federal government’s discretionary programs—

which includes biomedical research—will remain flat through 

fiscal year 2021, when adjusted for inflation. 

If this assessment proves true, and if the NCI budget faces the 

same constraints as other discretionary programs, then funding 

for cancer research at the NCI will have suffered nearly 20 

years of budget stagnation. During this period, a generation of 

Americans will grow older, and with their advancing age comes 

an increased risk of developing cancer. More than 30 million 

Americans will likely receive a cancer diagnosis during this 

period, but for too many of these Americans, the research that 

could have led to better prevention, diagnosis, or treatment of 

their cancers will not have gone forward or will have advanced at 

a slower pace than possible, as a result of funding constraints. 

Budget
62 National Cancer Institute 

The table that follows contains recommended funding increases 

based on the most promising opportunities identified in this 

document. Increased funding for these cancer research priorities 

represents a modest step toward restoring some of the funds that 

the NCI research budget lost during the fiscal erosion of the past 

decade. 

As a measure of how modest this funding recommendation is, 

consider the following: If the NCI’s annual budget had kept pace 

with inflation in the cost of biomedical research since fiscal year 

2003, NCI cancer research funding would total $6.76 billion for 

fiscal year 2016. Thus, the $5.75 billion recommended in the table 

that follows is $1 billion below the amount the NCI would have 

received if the budget had merely kept pace with inflation. In other 

words, a budget of $5.75 billion restores only 41 percent of the 

funding required for the NCI to recover its losses due to inflation.

A budget increase to support the priorities outlined below should 

not be a solitary event, however. Truly accelerating scientific 

discovery in ways that can significantly reduce the burden of 

cancer requires steady annual funding increases for research 

supported by the NCI. Steady and sustained budget increases 

will drive progress on preventing, diagnosing, and treating cancer 

and will measurably improve outcomes for patients with all types 

of cancer. 

Sustained, steady budget increases will also speed progress 

toward a promising new era of precision medicine, in which the 

medical community routinely uses detailed genetic information to 

identify the most effective patient- and tumor-specific approaches 

to treat cancer. With sustained funding, the NCI can broadly 

advance and successfully integrate the many disciplines (including 

genomics, informatics, pharmacology, and cancer biology) 

required to achieve this era of precision medicine. With sustained 

investments, the NCI can alter the landscape for the practice 

of cancer medicine, foster standards for molecular medicine in 

other domains (such as infectious disease, metabolic disease, 

cardiovascular disease, and pediatrics), stimulate development of 

important new therapies within our nation’s biomedical industries, 

and enlarge U.S. prestige for its public health leadership and for 

improving outcomes for cancer patients across the globe. 
An Annual Plan and Budget Proposal for Fiscal Year 2016 63

National Cancer Institute 

FY 2016 Professional Judgment Budget

(dollars in millions)

At a Glance 

Fiscal Year 2015 Estimate $4,931

Current Services Increase* 108 

Subtotal 5,039

Fiscal Year 2016 Recommended

Additional Resources Increase

Cancer Clinical Trials, including Pediatric Trials $100

Cancer Centers 90

Informatics & Computation 50

Research Project Grant Pool, including

 Provocative Questions Initiative & 

 Outstanding Investigator Awards 250

Genomics 50

Global Health 20

Biological & Clinical Research Reagents 30

Prevention & Early Detection 50

Intramural Research 25

Immunotherapy 25

Frederick National Laboratory for Cancer Research 25

Total Additional Resources 715

Total NCI $5,754

*The estimated current services inflationary increase is based 

on the Biomedical Research and Development Price Index (BRDPI) 

for FY 2015 of 2.2 percent.

See Details

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View this document online at:

www.cancer.gov/NCIresearchfuture 

For more information about the

National Cancer Institute, visit:

www.cancer.gov

Or call the NCI Cancer Information Service:

1-800-4-CANCER
NIH Publication No. 15-7957

Printed December 2014