Previous

NIH 1998 Almanac/The Organization/NCI/      

National Cancer Institute: Research Programs


There are four fundamental goals of cancer research: understanding cancer biology; identifying who is at risk for cancer and why; developing interventions to prevent, detect, diagnose, treat, and enhance survivorship from cancer; and translating research discoveries to the public and to medical practice.

Cancer Biology

The most remarkable progress in the past 25 years has been in the knowledge of cancer biology. NCI is dramatically extending the understanding of what is required to turn a normal cell into a cancer cell. Cancer arises when a single cell changes so that it divides continuously, released from the controls that constrain the replication of normal cells. This transformation results from changes in the function and activity of genes, which are segments of DNA containing the information that directs a cell to make a particular protein product. Of the 100,000 genes found in the human genome, the altered activities of only a small number of genes are responsible for transforming a normal, well-behaved cell-- whether in the breast, brain, blood, colon, prostate, or other organ--into a cancer cell. Identifying these "cancer genes" defines the central scientific hunt in cancer biology, and opens an unprecedented window into the nature of cancer.

Scientists now realize that many processes are dysregulated in cancer cells. For example, cancer cells often lose their normal primary function and start behaving like rapidly growing embryonic cells rather than fully mature skin or liver or breast cells, in which growth is slow and regulated. They replicate without regard to the signals that normally indicate when it is appropriate to divide. These cells have damaged mechanisms for repairing DNA errors and often have even lost the fail-safe mechanisms that normally eliminate highly damaged cells.

DNA changes can occur due to chemicals, viruses, radiation, and mistakes made each day in the course of duplicating 3 billion units of DNA each time a cell divides. DNA is very vulnerable to damage, but each cell has the remarkable ability to recognize damage and correct it. When a normal cell recognizes DNA damage, it stops the process of growth and division called the cell cycle. A normal cell either repairs its damage or, if it fails, undergoes programmed cell death (apoptosis). In cancer, these checkpoint controls are lost and the cell continues to divide, transmitting its damaged DNA to its descendants.

No one genetic alteration, however, is enough to make a normal, healthy cell a cancer cell. Rather, an accumulation of changes in a relatively small number of genes during the lifetime of a cell is required. NCI has learned that some individuals carry a very high lifetime risk of developing cancer because fewer successive changes in DNA are required to take place in one of the trillions of cells in their bodies to transform that cell into a cancer cell. This understanding has allowed the institute to begin describing the evolution of specific cancers from predisposition to precancer to cancer.

Each cancer is ultimately defined by its particular pattern of altered and normal gene activity. This unique pattern determines the cancer’s rate of growth, tendency to spread, responsiveness to hormones and therapies, and also predicts the ability of a person’s immune system to recognize and respond to the cancer. Moreover, cataloging these molecular patterns will ultimately tell us how many different cancers exist and enable researchers to distinguish each cancer from its normal counterpart. Advances in the ability to detect, diagnose, and treat each cancer will most likely be found in these differences.

Cancer Risk

Cancer risk is the probability that the disease will occur in a given population. Research on cancer risk seeks to identify populations with a significant probability of developing cancer. By identifying populations with different probabilities of developing cancer, researchers can identify and quantify risk factors. Moreover, since cancer is a multistage process, risk factor analysis leads to the development of prevention and control strategies, early detection methods, and in some cases, more precise clinical intervention and management regimens.

Epidemiology is the principal discipline used to study cancer patterns, identify populations at risk, and establish cancer risk factors. Epidemiologists have uncovered distinct cancer patterns among various groups and continue to pinpoint previously unrecognized risk factors. For example, women in Asian countries have some of the lowest rates of breast cancer in the world, while women in the West have among the highest.

But when Asian women migrate to the U.S., their breast cancer risk rises over several generations until it matches that found in women in the United States. Upon further investigation, institute scientists discovered that the increase in breast cancer risk was related predominantly to weight changes, particularly weight gain during the decade preceding breast cancer diagnosis. This finding incriminated certain aspects of American lifestyles such as dietary and exercise patterns. Moreover, it illuminated a major public health implication--that weight maintenance or reduction as an adult, accompanied by specific changes in diet and physical activity, may have a significant and rapid impact on breast cancer incidence. Studies such as these demonstrate NCI’s commitment to address the burden of cancer in all population groups in America and ensure that all benefit from research.

The epidemiologic approach has been successful in identifying many factors that increase cancer risk; most of these are related to environment and lifestyle, while others are part of a person’s genetic makeup. With the exception of a few genetic conditions, however, it is still not possible to predict with any degree of certainty that a person having one or more of these factors will develop cancer. This uncertainty is related to the very nature of cancer, and the need for many specific alterations to accumulate in the DNA of a single cell for that normal cell to be transformed to a malignant state.

Molecular epidemiology, a recent advance in molecular biology, enables scientists to combine biological markers (i.e., measurements of carcinogenic exposure, biologic response, and individual susceptibility) with traditional epidemiologic methods. Recent molecular research has provided evidence that environmental factors contribute to human cancers and that their risks are strongly influenced by inherited and acquired genetic susceptibility.

As this research continues, it remains true that the single most important exposure that increases cancer risk is the use of tobacco products, particularly cigarette smoking. Smoking is believed to contribute to more than 30 percent of all cancer deaths. In addition, certain aspects of the diet, particularly diets lacking in fruits and vegetables or high in certain fats, seem to be important contributors to cancer risk. Greater than average cancer risk also has been linked to alcohol consumption; exposure to radiation (for example, ultraviolet and x-rays), certain occupational agents such as asbestos, and environmental pollution (for example, arsenic); consumption of some pharmaceutical agents (for example, estrogenic drugs); infection with viruses such as the human immunodeficiency virus (HIV) or the human papillomavirus (HPV); and hormonal factors.

Cancer Interventions

Ultimately, the purpose of understanding tumor biology and cancer risk is to discover more effective ways of preventing, detecting, diagnosing, and treating cancer. Although the full realization of this process lies ahead, important advances achieved over the past quarter century give ample reason for optimism.

The ability to prevent cancer depends on identifying, removing. and/or reversing the effects of specific risk factors. Approximately 90 percent of skin cancers expected to occur this year could have been avoided through the use of protective measures against sunlight. Avoidance of smoking and use of other tobacco products could reduce the incidence of lung cancer by 80 percent and significantly reduce the rate of other cancers, including cancers of the pancreas, kidney, and head and neck. The adoption of diets containing less fat and more fruits and vegetables could diminish the incidence of some cancers, and physical activity may be associated with a lesser risk of several common forms of cancer, most notably colon and breast cancers.

NCI conducts and supports research into behavioral aspects of cancer prevention, such as smoking cessation and dietary interventions, including trials of dietary modification to reduce cancer incidence, dietary fat reduction to reduce recurrence of breast cancer, and high-fiber, low-fat, high fruit and vegetable diets to reduce recurrence of large intestine polyps. The institute also supports research into chemoprevention, including clinical trials of tamoxifen and raloxifene to prevent breast cancer, finasteride as a prostate cancer preventive, and aspirin to prevent recurrence of colorectal cancer.

In 1997, a new Division of Cancer Prevention was established to coordinate NCI’s prevention research. The new division will bring added visibility, prominence, and strength to the prevention research that NCI sponsors. In addition, an in-depth review of NCI’s prevention program was completed in summer 1997. The review group’s recommendations will be a guide for strengthening cancer prevention research.

Researchers have learned to see inside the bodies of living human beings and detect tumors with a precision that could not have been anticipated by a previous generation of physicians. Computed tomography, magnetic resonance imaging, and ultrasonography simply did not exist as useful clinical tools just over 25 years ago. Today, these technologies enable scientists to locate internal tumors with unprecedented accuracy, and to biopsy internal organs without the need for major surgery. There is every reason to believe that continued improvement in their powers of resolution will enable detection of small tumors even earlier than is possible with currently available methods, such as x-ray mammography. Invasive detection and diagnostic procedures such as colonoscopy and bronchoscopy are gradually giving way to "virtual" procedures that use data from MRIs, CT scans, and x-rays to generate a 3-D computerized image of an internal structure without invading the body with scopes.

Currently, the diagnosis of cancer depends principally on the microscopic appearance of tissue samples taken from growths or other suspicious lesions in the body. Advances in biological knowledge, however, have improved the ability to subclassify cancers into accurate categories. Classifying cancers more precisely is important because it will enable a better prediction of patients’ clinical outcome and refine therapies. For example, expanded understanding of normal immune system development and biology has led directly to molecular techniques for classifying immune system tumors (lymphomas).

This experience with lymphoma is a model for what will very likely occur in a variety of malignancies, including neuroblastoma, a rare childhood cancer, which we now know has at least two forms--one that sometimes regresses and may need little treatment and one that advances rapidly and requires aggressive treatment. NCI expects that tumor diagnosis and classification will be revolutionized in the coming years as scientists apply emerging knowledge in molecular genetics. Some of this information will be gained through NCI’s new Tumor Gene Index, which will catalog the genetic characteristics of tumors at each stage of growth.

The past quarter century has seen major progress in the ability to treat certain cancers. In addition to well-publicized improvements in the cure rates for many uncommon types of cancer, such as Hodgkin’s disease, certain lymphomas, testicular cancer, and a variety of childhood cancers, combining chemotherapy with surgery and/or radiation has increased survival rates for patients with breast, colorectal, and non-small cell lung cancers. High-dose chemotherapy with stem cell rescue is effective treatment for leukemias and is undergoing definitive testing in breast and ovarian cancers.

The application of molecular biology to the drug discovery process has ushered in the era of biological therapy by permitting the large-scale production of so-called "recombinant" proteins; as a result, the availability of interferon alpha-2b has markedly improved the outlook for patients with a rare form of leukemia. Both interferon and interleukin-2 provide improved symptom control for some patients with kidney cancer. Bone-marrow stimulating agents have improved supportive care by reducing the toxicity of chemotherapy to the blood elements. Over the past 15 years, the formidable problem of treatment-related vomiting has been lessened dramatically by the development of truly effective new drugs.

NCI is committed to research to improve the quality of life for those who develop cancer. As treatment becomes increasingly effective, the population of cancer survivors will continue to grow; it can also be expected that problems associated with long-term survival will continue to emerge. Responding to these trends, NCI has established the Office of Cancer Survivorship to address the needs of cancer survivors and conduct research needed to answer important questions about quality of life and the development of secondary cancers. The first problem to be addressed is the challenge to an optimal quality of life posed by the effects of cancer treatment itself.

Although most acute side effects of treatment are rapidly reversible, some, such as the loss of a limb, have a lasting impact. The widespread use of techniques such as breast reconstruction, conservative surgery, and customized limb prostheses have greatly improved the emotional and functional outlook for survivors of breast and bone cancers. The knowledge, gained in a landmark clinical trial, that chemotherapy followed by radiation treatment is as effective as total removal of the voice box for cancer of the larynx has made natural speech preservation possible for many patients with this condition. FDA-approved drugs for protecting against the cardiac toxicity of the anthracycline antibiotics (used in the treatment of several types of cancer, including breast cancer and lymphoma) and the kidney toxicity of cisplatin (an important treatment for testicular and ovarian cancers) are expected to reduce the overall incidence of two particularly troublesome chronic effects of treatment.

The second problem to be addressed is the tendency of many cancer survivors to develop second cancers at the same or other body sites. In some cases, this too is a treatment effect, since many current therapies that effectively treat the patient’s primary cancer unfortunately promote the development of second cancers in a small fraction of people who receive them. For example, certain chemotherapy regimens are associated with late-appearing acute leukemia in some patients, often many years after treatment. Sometimes, however, second cancers are unrelated to cancer therapy. Patients who survive a first cancer of the lung or oral cavity, for instance, have a high incidence of subsequent tumors at those sites, probably because of the continued carcinogenic influences of tobacco.

Inherited risk may also play a role. Some breast, ovarian, and colorectal cancer patients have a genetic predisposition to those cancers and are likely to develop second primary cancers. The solution to these persistent problems is clearly to discover more targeted and less toxic treatments and to develop better surveillance and prevention strategies for people whose risk is elevated for reasons unrelated to treatment.

Psychosocial and behavioral research can make fundamental contributions to all aspects of cancer survivorship, improving the quality of life both for cancer patients and for those at increased risk of developing cancer. Psychosocial research investigates how cancer affects quality of life and finds ways to address survivors’ needs so they can meet the everyday demands of life and regain their productivity. NCI is committed to such research to complement its cancer prevention, detection, and treatment research programs. We expect that this research will be of growing importance as genetic advances pose difficult prevention and treatment choices

Pain control is one of the largest quality of life issues that face cancer patients as it can be one of the most debilitating side effects of the disease. NCI recognizes the need to expand its research into pain control methods and has several ongoing pain control-related clinical trials. In addition to these trials and currently available NCI patient publications on pain management, the Johns Hopkins University Oncology Center, through an NCI grant, has produced a patient/health professional resource, Controlling Cancer Pain. This resource includes a video and brochure, available in both English and Spanish, and a pain rating instrument. Johns Hopkins and NCI are now exploring a partnership for production of Web-based educational software to accompany the materials and distribution of the resource package. Finally, the Agency for Health Care Policy and Research has recently updated its guidelines for pain management for clinicians. A quick reference version for clinicians of Clinical Practice Guideline: Management of Cancer Pain can be found on the NCI Web site.

Cancer Control

Cancer control is the application of cancer research results and interventions to decrease the burden of cancer. Just as biology and epidemiology provide a foundation for intervention research, all three research areas provide a foundation for cancer control. The enormous challenges inherent in the effective application of research results are illustrated by the fact that despite decades of research, education, and outreach, more than one-third of high school seniors--and over 20 percent of eighth graders--currently smoke.

The science of cancer control is necessarily multidisciplinary and involves behavioral research, epidemiology, health services research, and communications research. A cross-cutting theme is to identify the environmental, genetic, physiological, and psychosocial determinants of health in order to devise interventions that result in behavior changes that can reduce cancer risk and improve prognosis for people with cancer.

Behavioral research is central to cancer control because a large proportion of cancer is caused by or linked to specific, identifiable behaviors. Through behavioral research, interventions can be developed that encourage individuals and health care professionals to adopt or promote healthy practices, such as smoking cessation, adopting a low-fat, high-fiber, balanced diet, and undergoing recommended cancer screening.

Recognizing the importance of behavioral research, the NCI sponsored a Working Group on Behavioral Issues in Cancer Prevention and Control to identify research priorities for the Institute. Target areas identified by the working group include preventing tobacco use by children and teenagers, enhancing cancer risk communication and comprehension, integrating prevention and early detection services into health delivery systems, and improving accuracy and counseling related to genetic testing for cancer susceptibility.

Another important aspect of cancer control research is identifying the economic, social, and cultural factors that facilitate or discourage adoption of recommended screening regimens. For example, more than one-half of women over age 50 do not get regular screening mammograms for breast cancer, despite clear scientific evidence that such screening saves lives. Since 1993, NCI has used a unique geodemographic database to identify the geographic locations and racial, social, and economic groups in which mammography rates are lowest. NCI uses this information to develop media and interpersonal outreach strategies targeted specifically to those groups.

Cancer control research often begins by studying cancer patterns in populations through epidemiological studies or through NCI’s cancer surveillance system that monitors cancer incidence, mortality, and survival. Evaluating cancer patterns provides insight into who is developing cancer and what factors may have contributed to their disease. Researchers examine not only the changing burden of cancer, but also the knowledge, attitudes, and practices of the public and health professions related to cancer prevention, early detection, treatment, and rehabilitation.

All of this information is essential for designing and evaluating interventions that may reduce the cancer burden. For example, surveillance data show that the incidence of non-Hodgkin’s lymphoma (NHL) has risen steadily over several decades. Some of the recent rise can be attributed to the spread of AIDS, but most of the increase is occurring in the general population. This suggests the possible influence of an environmental agent, and ongoing research at NCI has suggested several factors that may be contributing to this increase: environmental exposure to herbicides and other pesticides, exposure to organochlorines, and nitrates in drinking water. NCI will soon begin a large-scale study to examine the role of these and other agents in the etiology of NHL.

Effective and widespread communication plays a critical part in applying the knowledge gained in biology, epidemiology, and intervention research. The NCI supports research on cancer communication and innovative programs to provide information on cancer to the public and to the Nation’s health care providers. The NCI’s communication systems provide Americans--patients, the public, and health professionals--with current and comprehensive information on cancer treatments and on effective prevention, early detection, and supportive care technologies.

New challenges for cancer control research abound. The evolving health care system poses the dual challenges of introducing cancer discoveries in rapidly changing health care delivery settings, and of finding ways that clinical cancer research can be integrated into health care coverage, regardless of payer. Developing cost-effective cancer interventions is an essential part of cancer-related health services research. Discoveries in genetics and clinical science pose special challenges for cancer control. For example, more precise and individualized methods of assessing a person’s risk of developing cancer have raised an array of new issues in living with and understanding risk. Cancer control research will be needed to help tailor prevention, detection, and treatment to individual needs.

Cancer control is the final step in carrying out the basic mission of the NCI: To understand the nature of cancer and to apply that knowledge to reduce the cancer burden--the deaths and disabilities--so that all Americans can lead healthier and longer lives.


Previous



National Institutes of Health