National Agendas for Disease-Specific Research

Unlike the common belief of 30 or 40 years ago, we know today that there are more than 100 distinct types of cancer. We are also learning that many diseases have subtypes with unique molecular characteristics that influence how they develop and progress and how they can be effectively prevented, detected, and treated. For these reasons, NCI carries out an ambitious program of research on specific types of cancer. These efforts along with the broad-based programs described in this document provide the framework for national agendas for cancer disease-specific research.

NCI leads the development and pursuit of disease-specific research by assessing the current understanding of specific cancers, the funded research, our ability to prevent and treat the disease, and the extent of our success. We chart the course primarily through advice from expert Progress Review Groups(PRGs) who work with us to evaluate the state of the science for specific types of cancer or groups of related cancers, identify research gaps and resource needs, and develop recommendations for future priorities. NCI's planning and evaluation process for disease-specific research involves three distinct phases:

1. Developing recommendations through the PRGs.
2. Planning for and implementing those recommendations with advice from internal implementation working groups.
3. Reporting on progress.

This comprehensive and integrated approach to planning helps us demonstrate our progress and the wise use of resources to the scientific community and the public. Through these and other crosscutting efforts, NCI establishes a framework for accountability that is in keeping with the President's Management Agenda and the Congressionally mandated Government Performance and Results Act.

The Progress Review Group Process

Developing Recommendations

PRGs are panels of 20 to 30 prominent members of the scientific, medical, private sector, and advocacy communities who are selected to assess the state of the science and recommend future research-related priorities for one type of cancer or a group of closely related cancers. The deliberations of each PRG are informed by a larger group of more than 100 leaders from diverse disciplines and the advocacy community who assemble for a Roundtable Meeting to discuss their understanding of the disease, barriers to progress, and key research and resource priorities for the next five years. PRGs use the input from these Roundtable groups to develop comprehensive and widely distributed reports and recommendations for national research agendas.

For example, recently assembled PRGs have identified some specific initiatives they believe are needed to speed research progress.

• The Gynecologic Cancers PRG has identified a need to develop a virtual shared specimen resource that will improve timely access to high quality tissue and body fluid samples and enable gynecologic cancer researchers to exploit emerging genomics, proteomics, and informatics technologies. This critical tool would support the discovery of new and urgently needed early detection methods and new prevention and treatment targets.
• The Lung Cancer PRG believes faster progress against the difficult problem of lung cancer will be achieved with scientifically integrated, interdisciplinary, multi-institutional consortia organized around the disease, rather than around scientific disciplines. Among its other top recommendations, this PRG has underscored the need for continued research on the genetic, social, and biobehavioral aspects of tobacco control and the need to better elucidate the contributions of injury, inflammation, and infection on lung cancer development.
• The Kidney and Bladder Cancers PRG has identified and prioritized research questions across the full spectrum of fundamental research, intervention development, and delivery that will advance progress against these cancers over the next five years. One priority area identified by this group focuses attention on our need to better understand the tumor microenvironment, which likely plays an important role in tumor development and growth in bladder and kidney cancers. Most studies to date have examined only the characteristics of the cancer cells. Expanding the scope of research to include analysis of interactions between the cancer cell and its immediate surroundings and cancer-associated changes in the tumor microenvironment will help researchers to understand the role of cellular communication in tumor development and maintenance. This recommendation aligns with NCI's new thrust to explore how the interaction between the cancer cell and its microenvironment enables and even promotes tumor growth.

A number of common themes have emerged across PRG recommendations that parallel priority initiatives identified in this document. For example, the following were emphasized in more than one PRG recommendation and are closely tied to the capacity building initiatives for supporting research collaborations or development of and access to research resources.

• Cross-disciplinary collaborations such as additional Specialized Programs of Research Excellence (SPOREs) and consortia focused on disease-specific research
• Enhanced bioinformatics to enable better researcher access to data and analytic tools
• Training on emerging technical developments and career development opportunities related to specific types of cancer, to attract new investigators
• More extensive, higher quality, and more fully documented tissue resources
• Preclinical models that more faithfully reflect the behavior of specific tumors in humans

Other recommendations may be addressed through our initiatives for supporting research on genes and the environment, signatures of the cancer cell and its microenvironment, molecular targets, cancer imaging, survivorship, and cancer communications.

• Discovery of genetic and environmental factors and interactions that lead to cancer
• Definition of molecular pathways and cellular interactions involved in cancer initiation, progression, and metastasis
• Molecular profiling for the detection of precancerous conditions and early cancers and for monitoring treatment response
• Development and testing of molecular targeted therapy
• Improved imaging for early detection, guided therapy, and real time monitoring of treatment response
• Treatment side effect and quality of life outcomes studies, including establishing registries and cohorts for study
• Education of medical providers and patients about cancer risk, prevention, detection, treatment, follow-up, and end-of-life care

Implementing Strategies to Address PRG Recommendations

Formal implementation plans that respond to PRG recommendations are now being developed under the leadership of disease-specific research working groups at NCI. The Brain Tumor Working Group proposed the application of new concepts in developmental neurosciences to understand the unique organ-specific mechanisms of gliomas biology in both pediatric and adult patients. The Leukemia, Lymphoma, and Myeloma Working Group suggested convening a meeting of leaders from academia, industry, the advocacy community, and government to examine models for establishing public-private partnerships for drug discovery. This could lead to a concept for the funding of planning grants and eventually drug development centers. The Pancreatic Cancer Working Group encouraged the funding and training of new investigators, imperative in advancing research on pancreatic cancer.

NCI does everything in its power to expedite progress against all types of cancer. We implement as many of the proposed initiatives in the disease-specific strategic plans as possible, and encourage and enable other organizations to take leading roles on those initiatives where additional collaboration is needed. PRG recommendations are implemented through ongoing NCI initiatives, new or expanded research programs, infrastructure support, partnerships, or a combination of these approaches. Our ability to implement any new initiative is dependent on:

• Determining that the initiative is vital, feasible, and sound
• Availability of funds
• Receipt of high quality applications or proposals

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Reporting on Progress

We close our accountability feedback loop by providing details to the community on actions we have taken to address PRG recommendations. Recognizing that some actions take longer to demonstrate results, NCI monitors implementation and collects progress data for several years and then prepares a progress report. This report is shared with a reassembled PRG. Based on NCI's assessment of progress and PRG input, implementation strategies are revised, retired, or added as needed, and NCI continues to monitor progress.

By 2003 we will publish progress reports for prostate cancer and breast cancer, in follow-on to the first two PRG reports issued in 1998. NCI will also complete an evaluation of the PRG process itself before the end of this year. The chart below indicates the current status of reports and plans related to the PRGs established to date.

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NCI Programs Support Disease-Specific Research

A number of NCI's existing programs support research focused on specific types of cancer.

• Specialized Programs of Research Excellence (SPOREs) have proven to be highly effective channels for disease-specific translational research. The scope of the SPOREs is expanding to establish research hubs for additional cancers so that by the end of Fiscal Year 2002, 40 disease-specific SPOREs will be supported, with further expansions planned. Much of this expansion has been in response to PRG recommendations. Increasingly, SPOREs are partnering with Cancer Centers and NCI-sponsored research networks and consortia to build synergism and share resources to speed progress against specific cancers. Current SPORE Programs exist for brain, breast, gastrointestinal, genitourinary, head and neck, lung, lymphoma, ovarian, pancreatic, prostate, and skin cancer sites. Future SPOREs will be established for gynecological, leukemia, and myeloma cancers.
• Early Detection Research Network (EDRN) participants develop, evaluate, and validate markers for earlier cancer detection and risk assessment. The Network includes academic and private collaborations and resources for basic, translational, and clinical research. EDRN collaborative groups include those focused on breast, gynecologic, gastrointestinal, lung and upper aerodigestive tract, prostate, and urologic cancers.
• NCI's Innovative Molecular Analysis Technologies (IMAT) program focuses on developing and applying technologies that identify the expression of genes and gene products, the function of major cellular communication pathways involved in cancer, the role of infectious agents in specific cancers, and the significance of other molecular alterations that distinguish normal cells from cancerous ones.
• The Mouse Models of Human Cancers Consortium (MMHCC) develops new preclinical models that will enable investigators to better understand specific human cancers and predict the effects of promising targeted therapies. New models continue to be developed for sarcomas and for lung, prostate, mammary, skin, cervical, ovarian, nervous system, blood system, and gastrointestinal cancers. The MMHCC fosters collaboration in these efforts with industry partners and other research institutions.

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Stalking a Silent Killer - Pancreatic Cancer

Pancreatic cancer is often called a "silent" cancer because it has no clear symptoms until it is advanced. This malignancy metastasizes early, with many tumors as small as 1 or 2 centimeters in diameter spreading beyond the pancreas, and it is resistant to both chemotherapy and radiation treatment. Most patients live six months or less after diagnosis. In 2002, approximately 30,300 new cases will be diagnosed. Experts estimate that 29,700 people will die from this disease in the same time period. Finding better ways to detect, diagnose, and treat pancreatic cancer is absolutely critical.

Researchers are pursuing a number of avenues in search of answers about pancreatic cancer:

• Risk factors. Old age, cigarette smoking, genetic history, chronic pancreatitis, and diabetes are established risk factors for pancreatic cancer. A recent study indicates that obesity increases susceptibility. People who have first-degree relatives who have had the disease have a threefold higher risk compared with the general population. Researchers are now trying to learn more about other suspected and corollary risk factors such as chemical exposures and nutrition in hope of developing effective preventive measures.
• Biomarkers and therapeutic targets. One important avenue of research is to find genes or gene products that influence the tumor's development or progression and could serve as early detection or diagnostic indicators, or targets for better therapies. Research is uncovering a growing number of such genes.
• Hereditary susceptibility. Several hereditary syndromes and their related genes (such as p16, BRCA2, STK11/LKB1, hMSH2, hMLH1, PRSS1) have been identified, but these probably account for no more than 5-10 percent of cases.
• Genetic changes. Known non-hereditary genetic alterations include activation of the K-ras cancer gene, inactivation of a number of tumor suppressing and DNA repair genes, and overexpression of several growth factors and receptors.
• Gene-environment interactions. Researchers in the United States and abroad are looking for genes that are influenced by environmental exposures. For example, a recent NCI-funded study demonstrated that a specific deletion in the GSTT1 gene combined with heavy smoking increased pancreatic cancer risk significantly among Caucasian study participants, with the effect greater in women than in men.

NCI's Pancreatic Cancer Progress Review Group emphasized in its 2001 report that insufficient research funding and the limited number of researchers dedicated to studying the disease have hampered progress against this silent killer. NCI is taking specific steps to help increase volume of research on this highly fatal disease and to encourage researchers to commit to improving care for patients and those at risk for pancreatic cancer.

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Targeting a Tumor on the Rise - Kidney Cancer

The incidence of kidney cancer has been increasing about two percent per year for the past several decades. For African Americans, it is rising more rapidly than any other cancer - about four percent per year. Kidney cancer, including tumors of the main part of the kidney and the lower renal pelvis, is now diagnosed in nearly 32,000 people each year in the United States. About 200,000 people are living with kidney cancer. Mortality from the disease is also high and rising, with an estimated 11,600 deaths expected in 2002. Median age at diagnosis is 65 for men and 68 for women.

Four main types of kidney cancer have been identified. Clear cell renal tumors are the most common type, accounting for about 75 percent of cases. The reasons for the increase in incidence are not fully understood.

• Smoking is the most well established risk factor.
• Obesity, hypertension, occupational exposures, and heavy, long-term use of the pain medication phenacetin have also been linked to greater risk.
• A small percentage of kidney cancers are hereditary.

More than 40 percent of kidney cancers are not diagnosed until advanced stages. Five-year survival of patients who present with advanced kidney cancer is nine percent. By contrast, approximately 90 percent of patients diagnosed with Stage I disease survive at least five years. Scientists are actively exploring the growing field of proteomics to identify growth factors and other circulating proteins that may be indicators of disease and that can serve as biomarkers for early detection.

Currently, for localized kidney cancer, surgery is the only effective treatment. Minimally invasive and kidney-sparing surgical techniques are becoming more widely used. For metastatic kidney cancer, Interleukin-2 (IL-2) is the only approved treatment. Though highly toxic, IL-2 cures about 10 percent of patients. Scientists are investigating several important molecular pathways as potential targets for less toxic treatments. For example, anti-angiogenesis agents may prove beneficial against clear cell renal tumors, which are known to secrete several proteins that spur the blood vessel development required for the cancer to continue to grow.

In a recent NCI-funded Phase II clinical trial, high doses of the antibody bevacizumab, that neutralizes one such protein, vascular endothelial growth factor (VEGF), slowed tumor growth considerably in patients with metastatic kidney cancer. More than 20 other trials are now underway to evaluate this antibody as a treatment for various types of cancer. Phase III trials in breast and colorectal cancer are underway, as are Phase II trials for prostate, breast, colorectal, cervical, ovarian, pancreatic, and lung cancers, as well as for mesothelioma and several types of leukemia.

In 2001, NCI convened a Kidney and Bladder Cancer Progress Review Group to assess our understanding and treatment of these diseases and identify research priorities and supporting infrastructure needs to accelerate progress over the next 5 to 10 years. An NCI implementation planning group has been convened to analyze the recommendations contained in the 2002 PRG report and begin the process of determining how the recommendations can be implemented.

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