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I: hr 5 Z I. i «3‘ “; . :n- W' W'u-mpl WI National Cancer Institute 9 Division of Cancer Prevention >>>>>>a>>>>>>>»> for Chemoprevention Research at the National Cancer Institute Report of the Chemoprevention Implementation Group September 10, 1999 TABLE OF CONTENTS KC 7/ 7/ 11 13 13 14 14 14 14 14 14 15 15 15 15 15 15 15 15 17 17 18 18 19 21 21 22 23 23 24 25 26 27 29 29 32 45 QSNZM / “:7 if," L / {We ’ Executive Summary L Chemoprevention Implementation Group Organization: Division of Cancer Prevention Exhibit 1: NCI Division of Cancer Prevention Organization Chart Foundation Research Groups Chemopreventive Agent Development Community Oncology and Prevention Trials Nutritional Science Basic Prevention Science Cancer Biomarkers Early Detection Biometry Organ System Research Groups Breast and Gynecologic Cancer Prostate and Urologic Cancer Lung and Upper Aerodigestive Cancer Gastrointestinal and Other Cancer Office of Preventive Oncology Challenges for Chemoprevention Basic Science Chemopreventive Agent Development Clinical Chemoprevention Trials Developing Chemoprevention Expertise in the Research Community Progress and Plans to Address Challenges for Chemoprevention Expansion of Basic Science Programs New Programs for Chemopreventive Agent Development Continued Growth of DCP Clinical Chemoprevention Research Programs Perspectives from Current Large Clinical Chemoprevention Trials Clinical Trials Decision Process Exhibit 2: Decision Process for Chemoprevention Trials Exhibit 3: Cancer Prevention Trials Phase III Decision Committee: Operational Approach Exhibit 4: Cancer Prevention Trials Phase III Decision Committee: Dimensions of the Ranking Process Appendices Appendix 1: Roster of the Chemoprevention Implementation Group Appendix 2: Basic Science Implementation Subcommittee— Summary of Meeting January 21, 1999 Appendix 3: Basic Science Implementation Subcommittee Roster , Aw. Mmmmb gm "Executive nmmdi’y _ Cancer chemoprevention marked 1998 with a forerunner of its potential achievements—the now well-known success of tamoxifen in reducing breast cancer incidence in women at significant risk.‘ Besides this definitive result with tamoxifen and the development of even more selective antiestrogens for breast cancer chemoprevention, several other agents have shown promise in reducing cancer incidence. For example, the selective cyclooxygenase (COX)—2 inhibitor celecoxib caused regression of colorectal adenomas in patients with familial adenomatous polyposis (FAP), the synthetic vitamin A analog (retinoid) fenretinide decreased the number of second primary breast cancers in premenopausal women,2 and clinical study results (secondary or ancillary analyses) have suggested that vitamin E3 and selenium4 have chemopreventive potential against prostate cancer. The promise of cancer chemoprevention will continue to be realized through our ever-increasing understanding of carcinogenesis. Advances in the basic sciences, particularly genomics and proteomics, and in biomedical technologies such as imaging provide the tools for further growth. These advances lead to identifying molecular targets and pathways in carcinogenesis for agent discovery and risk assessment, and to better tissue visualization for early detection and diagnosis, as well as for quantifying histopathologic changes occurring as precancerous lesions progress to invasive disease. Also, including those already cited, more than 40 agents are already undergoing evaluation in clinical chemoprevention trials. The Chemoprevention Implementation Group (CIG) was convened under the auspices of the Division of Cancer Prevention (DCP) in mid-1998 as part of the National Cancer Institute (NCI)’s evaluation of the state of cancer research and restructuring to accelerate progress toward defeating cancer. The CIG is made up of extramural scientists working with NCI staff to identify resources and participate in interactive decision-making processes relevant to the direction of chemoprevention research at the NCI. During its first year, the primary mission of the CIG and the DCP staff has been to explore the challenges and opportunities for chemoprevention research defined in the NCI review process, and to make recommendations for new and restructured DCP programs to address these challenges. The four general recommendations elucidated by the CIG and DCP staff are as follows: Build Basic Science Program. Provide focus and support for basic science research in chemoprevention—sag, functional genomics leading to the development of molecular progression models of carcinogenesis, animal models that mimic human carcinogenesis, characterization of biomarkers of carcinogenesis, exploration of biological characteristics of carcinogenesis (such as stromal—epithelial interactions), understanding the biological mechanisms underlying putative associations between diet and cancer incidence, and elucidating the role of viral and bacterial factors in carcinogenesis. Strengthen Agent Development Eflort. Support more effective and efficient agent development by providing programs to assist individual investigators in the early development process, increasing interaction with the FDA and industry, developing cell and animal models for evaluating chemopreventive efficacy, and validating biomarkers as endpoints for chemoprevention studies. Establish Infiastructure and Planning Process for Clinical Chemoprevention Trials. Develop strategies and resources for conducting clinical chemoprevention studies. Ensure the existence of a well-defined process of decision—making about target organ sites, appropriate populations, credible endpoints, candidate chemoprevention agents for human trials, and strategies for recruiting appropriate study populations, particularly healthy high—risk subjects. Increase size of DCP scientific staff to address these issues. Establish a decision process for chemoprevention trials including both DCP staff and extramural scientists. Report oft/7e Chemoprevention Implementation Group 7 Develop Chemoprevention Expertise in the Research Community. Increase chemoprevention expertise in the research community by developing funding mechanisms to attract young investigators, attracting medical disciplines besides oncology (precancers, which are primary chemoprevention targets, are most often seen and treated by target—organ—based medical specialists such as urologists, gynecologists, gastroenterologists, and dermatologists), and promoting chemoprevention research at NCI—designated cancer centers. Develop programs that bring modern science (e.g., in genetics, cell biology, toxicology, epidemiology, psychology, and statistics) to bear on questions of diet in chemoprevention. Develop strategies to assess multiple endpoints related to cancer prevention interventions. As a first and major step, strongly supported by the CIG, to address these challenges and opportunities in chemoprevention, the DCP has been reorganized into a matrix structure incorporating core research functions (agent development, biometry, large trials, basic science, biomarkers, early detection, and nutritional science) at a division—wide level, along with specific target-organ—centered research groups to develop and follow clinical studies. Integration of functions among all groups and with the CIG and its subcommittees is provided by a coordinating unit comprising the chiefs of the foundation research and target—organ—centered groups, and led by the DCP Director. The coordinating unit evaluates and prioritizes projects requiring integration of the various groups, convening project teams to carry forth the efforts. Additionally, the CIG and DCP staff have initiated new programs and made plans addressing specific aspects of basic science, agent development, and clinical trials relevant to chemoprevention studies and expansion of the chemoprevention research community, which are outlined briefly below: Basic Science ° Four foundation research groups have been created within the DCP to foster basic science aspects of chemoprevention. These are the Basic Prevention Science, Cancer Biomarkers, Nutritional Science, and Early Detection Research Groups. ' The Early Detection Research Network (EDRN) initiative addresses the challenge of developing and validating biomarkers for early detection and risk assessment. 8 National Cancer Inrtitute 0 Division of Cancer Prevention Chemopreventive Agent Development ' The Rapid Access to Preventive Intervention Development (RAPID) program will provide NCI expertise and resources to the research community for the preclinical and early Phase I clinical development of potential chemopreventive agents. 0 Additional initiatives are planned on animal model development, agent discovery using technology arising from cancer genetics research, and validation of surrogate endpoints for evaluating chemopreventive efficacy. Clinical Cbemoprevention Trials ' To realize the full potential of large clinical chemoprevention studies, the CIG has recommended that ancillary studies and provisions for tissue and serum collection to accommodate this research be incorporated into study planning, along with provision for long—term follow-up of participants after intervention is completed. Clinical Trials Decision Process 0 The CIG recognizes the need for selection criteria for agents considered, trial design guidelines for Phase I/ II as well as Phase III chemoprevention clinical trials, and clinical development plans for the promising agents. The DCP has proposed a decision process for developing and prioritizing clinical trials. Specific criteria and guidelines will be developed by project teams comprising Research Group staff, CIG members, and other extramural experts. Chemoprevention Research Community ' The size of the DCP Cancer Prevention Fellowship Program will be increased. This program trains young investigators in cancer prevention through course work, seminars, and internships at the NCI. 0 Young investigators will be encouraged to participate in ancillary studies to larger prevention studies. ' Young investigator career development awards in prevention will be established. ° DCP will provide research investigators with more access to NCI resources for chemopreventive agent development (i.e., the RAPID program). ° Experienced investigators will be provided with information on training grants. These investigators will be encouraged to send pre— and postdoctoral fellows to relevant training courses. Cancer prevention science at cancer centers will be strengthened by, for example, providing grants to develop core infrastructure for carrying out translational research. A cyber—conference series on chemoprevention will be developed for cancer centers and other sites. NCI publications on cancer prevention will be increased— e.g., a textbook on the basic science of chemoprevention will be developed. The NCI, DCP will continue to sponsor chemoprevention workshops with published proceedings. Visiting scientists will be brought to NCI to work with the DCP, and NCI scientists will be sent to do “hands— on” work in the extramural research community. Referral guidelines for chemoprevention grants are being revised to ensure that both basic science and applied research grant applications focusing on prevention studies are overseen by DCP. 1 Fisher, B., Costantino, ].P., Wickerham, D.L., Redmond, C.K., Kavanah, M., Cronin, WM,, Vogel, V., Robidoux, A., Dimitrov, N., Atkins, ]., Daly, M., Wieand, 5., Tan—Chiu, E., Ford, L., Wolmark, N. and other NSABP investigators. Tamoxifen for prevention of breast cancer: Report of the National Surgical Adjuvant Breast and Bowel Project P—l Study. ]. Natl. Cancer Inst. fl: 1371—1388, 1998. 2 De Palo, G., Camerini, T., Marubini, E., Formelli, E, Miceli, R., Mariani, L., Costa, A., Veronesi, U., Maltoni, C., Del Turco, M.R., Decensi, A., Boccardo, F. and D’Aiuto, G. Ongoing clinical chemoprevention study of breast cancer with fenretinide. Int. Cangr. Ser. fl: 249—254, 1996. 3 Heinonen, 0.1)., Albanes, D., Virtamo, J., Taylor, PR, Huttunen, J.K., Hartman, A.M., Haapakoski, J., Malila, N., Rautalahti, M., Ripatti, S., Maenpaa, 1-1., Teerenhovi, L., Koss, L., Virolainen, M. and Edwards, B.K. Prostate cancer and supplementation with 4—tocopherol and B—carotene: Incidence and mortality in a controlled trial]. Natl. Cancer Inst. fl: 440—446, 1998. 4 Clark, L.C., Dalkin, B., Krongrad, A., Combs, GF, Jr., Turnbull, B.\W., Slate, E.H., Witherington, R., Herlong, ].H., Janosko, E., Carpenter, D., Borosso, C., Falk, S. and Rounder]. Decreased incidence of prostate cancer with selenium supplementation: Results of a double-blind cancer prevention trial. Bx]. Urol. 5;: 730—734, 1998. Report Off/76 Chemoprez/ention Implementation Group 9 @% 92a 933%-Em ,a ,1, flaws: _ _ swag mmmwemmmma Eww gammy Wm .. 2.3% «whammy—h ammmmfimmm famwmmwe , mamaumsmma The C] G comprises extramural scientists working with NCI stafl to ia'entzfi/ resources and participate in interactive decision—maleingprocesre: relevant to the direction of chemoprevention research at N C]. During the past two years, the NCI has been evaluating the state of cancer research and planning for NCI’s role in accelerating progress. Groups of experts were commissioned by the Director of the NCI to review current NCI programs, identify challenges and research opportunities, and make recommendations for restructuring and refocusing NCI programs. The findings of several of the groups, namely the Prevention Review Group, the Breast Cancer Progress Review Group, and the Prostate Cancer Progress Review Group, have high impact on the direction to be taken by chemoprevention research at NCI. To address these important findings and to further define and guide chemoprevention research activities, the Director of the NCI, DCP convened the Chemoprevention Implementation Group (CIG) in July 1998. The CIG membership is based on recommendations of the NCI Prevention Review Group and NCI staff that extramural scientists be incorporated into an Chemoprevention open and interactive DCP decision-making process. The extramural CIG members represent a wide variety of disciplines contributing to chemoprevention, and it is envisioned that they will continue to work with NCI scientists and provide their expertise toward developing a strong and forward—looking chemoprevention research effort. The CIG roster is found in Appendix 1. Its functions include: 1) setting priorities for agents to be developed and evaluated in chemoprevention clinical trials; 2) advising on the best designs for chemoprevention clinical studies; 3) identifying research challenges and opportunities for chemoprevention; and 4) developing strategies for advancing chemoprevention research, including attracting new investigators to the field. Some of the CIG’s work will be carried out by subcommittees comprising CIG members, NCI staff, and ad hoc extramural members with relevant expertise. An example is the Basic Science Implementation Committee, which has already met to develop recommendations for expanding basic science research activities in chemoprevention (see Appendices 2 and 3). Also, the CIG has coordinated with the NCI Nutritional Science and Early Detection Implementation Groups. Report of the Chemoprevcntion Implementation Group 1 l ,, Sham“, amsm Emu». wmw acammwwm smWWJEMEW _ V wwnfi , V duasuwamamsi 19%. 9mg , , nae mmaanm a A m a swim. , e a?» , , , maamfiememns mar mfimsfii gm «WWW mm?» , ,, , , _ film » is a ; mmuarwa , , , flmumwmay ,Eu New, .Jm _ mwrflm ,Wma an a5 a, , figme Tbe DCP bas been reorganized into a matrix structure tbat reflects recommendations fiom tbe CI G to incorporate core researcb functions (agent development, biometry, large trials, basic science, biomarkers, early detection, and nutritional science) at a division-wide level along wit/7 specific target-organ-centered researcb groups to develop and follow clinical studies. Integration of functions among all groups and witb tbe CIG and its subcommittees is provided by a coordinating unit comprising tbe cbiefi of each researcb group and target—organ—centered group, and led by tbe DCP Director. Tbe coordinating unit evaluates and prioritizes projects requiring integration oftbe various groups, convening project teams to carry fortb tbe «ejfirts. A primary interest of the CIG has been more emphasis on the basic science aspects of chemoprevention (e.g., by establishing dedicated core groups). The CIG also recognized the importance of having other core resources—agent development, biometry, nutritional science, early detection, and large trials coordination (e. g., via the Oncology Groups and Community Clinical Oncology Program (CCOP)). There was also high interest in having target—organ-based functional groups to parallel the structure in the NCI—recognized cancer centers. These groups would include breast/ gynecological, prostate/urologic, gastrointestinal and other, and lung/ upper aerodigestive tract. Another important objective was to have functions that addressed two major focuses of prevention research, that is, prevention strategies being developed for medical settings (e. g., reversing carcinogenesis prior to cancer development, as in the tamoxifen and finasteride studies) and those directed toward public health (e. g., dietary and multiple endpoint studies, vaccines), To meet these objectives, the DCP Director reorganized the Division. The new DCP structure is a matrix organization based on seven foundation research groups and four target—organ—based research groups (Exhibit 1). Integration of filnctions among all groups and with the CIG and its subcommittees is provided by a coordinating unit comprising the chiefs of the foundation and target-organ-centered research groups, and overseen by the DCP Director. These research groups are interrelated by project teams made up of appropriate staff members from the foundation and target—organ—based research groups. The workings of the CIG will be coordinated with the DCP research groups and incorporated into the project teams. CIG members and other extramural scientists may participate in the project teams. Another important objective of the CIG was to increase the level of training available to potential chemoprevention scientists. The Office of Preventive Oncology will continue to oversee the Cancer Prevention Fellowship Program and address other opportunities related to training. All the research groups have responsibility for promoting collaboration and communication with other programs within NCI and National Institutes of Health, as well as with the extramural research community. The specific missions of the research groups and the Office of Preventive Oncology follow: Report of tbe Cbemoprevention Implementation Group 13 FOUNDATION RESEARCH GROUPS Chemopreventive Agent Development. Provides scientific and administrative oversight for preclinical agent development through early clinical studies, particularly Phase I safety, pharmacokinetics, and clinical chemopreventive agent research utilizing physiological endpoints in healthy volunteers. Research includes all classes of agents (e.g., pharmaceuticals, micronutrients), and includes synthesis/extraction and mechanistic studies (e. g., assays using high—throughput gene analysis technology, cell cultures from high—risk tissue, carcinogenesis—related biochemical activities, and technologies focusing on molecular targets and their modulation leading to the identification and optimization of promising chemo— preventive agents). Assists extramural investigators to bridge the gap between discovery and clinical testing through management of RAPID. Works with the DCP organ- system—based research groups in clinical trials development, agent acquisition, regulatory affairs, regulatory toxicology, and related research. Provides coordination, technical support, and research resources for chemopreventive agent devel— opment. Acts as DCP liaison with the Food and Drug Administration for chemopreventive agent development. Initiates and maintains collaborative efforts with industry for developing chemopreventive agents. Community Oncology and Prevention Trials. Develops programs to improve clinical oncology practice in community settings and provide broader access by the public to research advances supporting clinical trials and translational research in the full range of clinical cancer prevention and morbidity prevention. Coordinates community oncology activities through the CCOP with other research programs of the NCI and the National Cancer Program. Plans, promotes, and supports the design, development, implementation, and follow—through of cancer prevention clinical trials through the CCOP Research Bases and investigator—initiated grant funding mechanisms. Develops and maintains a national resource on methodology and procedures to conduct prevention clinical trials that includes such areas as recruitment, training, compliance, retention, audits, human subject protection issues (informed consent), and specimen banking/testing. Supports research on the roles of nurses and other health care providers in the full spectrum of prevention research, from the identification of high—risk populations and design and implementation of clinical trials to dissemination and application of research results, including research on recruitment, retention, and management of morbidity related to prevention trials participation. Develops and supports research on the management of symptoms related to cancer and its treatment, including supportive care during and after 14 National Cancer Institute 0 Division of Cancer Prevention treatment and palliation and end of life issues. Promotes and supports research on the psychosocial and symptom management aspects of prevention clinical trials in order to understand the impact of interventions and their application in appropriate target populations. Nutritional Science. Plans, develops, directs, and coordinates a research program in diet, nutrition, and cancer as it relates to cancer prevention. Develops, refines, and tests hypotheses of diet and the etiology and prevention of cancer. Works with the Chemopreventive Agent Development Research Group on preclinical development studies of diet—derived agents. Develops quantitative methods to monitor nutritional intake in large populations and to convert diet into nutrient content. Studies baseline dietary data on populations in chemoprevention trials and assesses strategies for altering diet in relation to cancer risks, weighing scientific knowledge and the impact of such strategies, and conducts applied research on diet and cancer. Works with the Organ Systems Research Groups to incorporate dietary modification strategies into clinical cancer prevention studies. Basic Prevention Science. Supports and facilitates a broad spectrum of research activities on molecular biology and genetics in cancer prevention. Develops research and, working closely with the Chemopreventive Agent Development Research Group, supports preclinical studies on interventions with potential to decrease incidence of cancers caused by infectious and environmental agents. Works closely with the Organ System Research Groups to support the design, development, and implementation of pilot vaccine or antimicrobial clinical studies in the extramural community. Cancer Biomnrkers. Supports research activities that address early development and initial validation stages of molecular biology and genetics, including biomarkers that can be applied in risk prediction and early detection and primary prevention of cancer. Facilitates and coordinates national and international research programs to develop clinically useful biomarkers in premalignant lesions that accurately predict the risk of subsequent invasive cancer or the presence of early cancer in asymptomatic individuals not previously diagnosed with the disease. Supports the development of databases on the utility of biomarkers and expression patterns that will serve as background information for larger validation and efficacy studies. Works closely with the Chemopreventive Agent Development Research Group and Organ Systems Research Groups to validate biomarkers for use as endpoints in cancer prevention trials. Early Detection. Develops scientific information and concepts and disseminates knowledge regarding early detection techniques, practices, and strategies to reduce mortality and morbidity from cancer. Manages and supports clinical trials of early detection and a biorepository related to prostate, lung, colon, and ovarian cancers, and analyzes research results on screening for breast and other cancers. Works with the Biometry Research Group and the Organ System Research Groups to support clinical trials and other appropriate research. Fosters technological development, and encourages the publication of scientific findings and adoption of early detection practices. Biometry. Using methods of mathematical and analytical statistics, plans and conducts independent and cooperative research studies on cancer prevention, clinical trials, epidemiology, screening, and diagnosis. Works with the Early Detection and Organ System Research Groups on these studies. Plans and conducts independent and collaborative studies in biostatistical and epidemiologic methodology and in mathematical modeling of processes relevant to cancer prevention activities. Provides consultation and advice on biostatistical methodology and study design. ORGAN SYSTEM RESEARCH GROUPS Breast and Gynecologic Cancer Prostate and Urologic Cancer Lung and Upper Aerodigestiue Cancer Gastrointestinal and Other Cancer The four Organ System Research Groups have common underlying missions, while each focuses on specific cancer targets. The Groups’ primary research efforts focus on the design, development, implementation, and monitoring of clinical prevention strategies. These strategies can include pharmacologic, nutritional, biologic, genetic, vaccine, or immunologic interventions, and focus largely on organ—specific Phase I and Phase II surrogate endpoint biomarker studies, some of which arise from the preclinical and Phase I clinical program of the Chemopreventive Agent Development Research Group. The goal is to move promising interventions into Phase III clinical testing—in many cases, collaborating with the Community Oncology and Prevention Trials Research Group. The testing and validation of new technologies for identifying and assessing the modulation of precancerous lesions is also important. The Groups interact closely with the Early Detection and Cancer Biomarkers Research Groups on these aims. The Organ System Research Groups also monitor clinical prevention trials to foster the faster development of agents by including research into modulation of surrogate endpoint biomarkers that could potentially supplant cancer incidence reduction as endpoints. The Office of Preventive Oncology is charged with 1) developing principles and practice of cancer prevention and control for oncologists, other practicing physicians, and public health professionals; 2) administering the Cancer Prevention Fellowship Program; 3) developing, coordinating, and administering divisional staff training programs in preventive aspects of medical oncology, other clinical specialties, and public health research and application; 4) planning, developing, and maintaining divisional staff career development programs; and 5) planning and developing curricula in cancer prevention and control, including the Summer Academic Course in Cancer Prevention and Control. An immediate goal is expansion of the Fellowship Program to 20 per year (60 total, from 30 previously). Report oft/7e Chemoprevention Implementation Group 15 mmfiwmmmas Maw” »: mwmmwmmm an. Ewwmam“ mammmmmm allenges The NCI cancer research review groups and the CIG have identified significant challenges and opportunities for advancing chemoprevention research. These impact all phases of chemoprevention research, from identifying agents and molecular targets through preclinical development to designing clinical trials. An overarching challenge is developing chemoprevention expertise in the research community by attracting new investigators and implementing chemoprevention programs at research institutions. The challenges and opportunities are listed below. Basic Science The Basic Science Implementation Subcommittee met at the National Academy of Sciences, January 21, 1999 (Appendix 2 is the summary of this meeting; Appendix 3 is the Subcommittee Roster). The recommendations of the Subcommittee are captured in the following, along with those of other NCI review groups. ' Develop meaningful models of human carcinogenesis— e.g., transgenic/gene—knockout models that mimic human carcinogenesis, cell culture models (particularly in non—neoplastic cells). Reliable models for several important cancers are also lacking—cg, squamous cell lung cancers and ovarian, estrogen receptor negative (ER‘) breast, and prostate cancers. Capitalize on the advances in cancer genetics to identify molecular targets for chemopreventive intervention and cohorts benefitting from chemoprevention. For example, results of the Cancer Gene Anatomy Project (CGAP) and the mouse CGAP that identify cancer—related genes, as well as information on genetic susceptibility gathered under the Cancer Genetics Network, could be the basis for identifying molecular targets and designing assays for early detection and efficacy evaluation. €MOPV62/enti0n ~~ 0 Increase understanding of carcinogenesis. Correlate the presence of gene mutations and gene expression to cellular, tissue, and clinical characteristics of precancer and its progression to invasive disease. Increase efforts to evaluate biological characteristics of carcinogenesis— e.g., nuclear receptors, cell—cell interactions (e.g., stromal—epithelial, endothelial, inflammatory), and metabolic enzymes. Results of such research would contribute to the development of molecular markers and other precancerous lesions as biomarkers for cancer—for cancer risk estimation and potentially as endpoints for chemoprevention studies. Both the Breast and Prostate Cancer Progress Review Groups stressed the importance of appropriately collected and well—characterized tissue and plasma/ serum samples for this purpose. Develop new molecular markers for early detection of cancer and develop and improve new high— throughput technologies for implementation of promising molecular diagnostic approaches in clinical and population-based studies. Increase research to understand the biological mechanisms underlying putative associations between diet and cancer incidence, particularly concerning fruits and vegetables, fats, and total energy consumption, as well as the mechanisms whereby physical activity may reduce cancer risk. Increase research on the role of viruses and Helicobacter pylori as factors or cofactors in the etiology of certain cancers and initiate research to develop appropriate vaccines. Develop standardization criteria for biomarkers— e.g., definition of sampling techniques, fixation, where tissue sampled. A program analogous to, or in collaboration with, that of the National Institute of Standards and Technology (NIST) was recommended for biomarkers. Report oftke Chemaprcz/emian Implementation Group 17 Cbemopreventive Agent Development ° Research scientists in the academic community are capable of identifying chemopreventive agents with potential clinical uses; however, they may not have access to the resources required to develop these agents for clinical evaluation (eg, preclinical toxicity and efficacy testing, scale—up manufacturing, regulatory affairs, Phase I safety testing). An NCI funding mechanism to support research investigators in developing promising agents would benefit chemoprevention. Chemoprevention is a relatively new medical discipline with much research still required to establish endpoints and cost-effective clinical trial designs. The pharma- ceutical industry is actively engaged in the development of drugs or has drugs approved for other indications with high potential as chemopreventive agents, but may be hesitant to commit resources to chemo— prevention without clearer definition. Many promising chemopreventive agents are manufactured by non—pharmaceutical companies (e.g., dietary supplement manufacturers) with less experience in drug development. Continued collaboration of the NCI with industry to work out strategies for developing chemopreventive agents and with the FDA to establish criteria for chemoprevention marketing approval will also advance the field. Development and validation of more relevant and reliable in vitro and animal models for application in chemopreventive agent development are needed (see also under Basic Science). Such models may include high—volume gene chip screening for agent discovery, cell—based and short—term animal models for efficacy screening, as well as models for more in-depth efficacy evaluation (e.g., transgenic mice, systems for evaluating agent delivery systems). Grant—based funding is difficult to obtain for such translational research; therefore, NCI funding mechanisms for encouraging these efforts are needed. Similarly, translational research to validate biomarkers as surrogate endpoints for cancer is a high priority need. It is well—recognized that the “gold standard” for evaluating a chemopreventive agent is the Phase III randomized, controlled clinical trial demonstrating cancer incidence reduction. However, the time and resources will be available to evaluate only a very few high—priority agents in such settings. The use of 18 National Cancer Imtitute ' Division of Cancer Prevention validated surrogate endpoints in Phase II trials should allow more effective prioritization for cancer incidence reduction trials. Modulation of well—validated surrogate endpoints (see p. 22—23) is expected eventually to be sufficient for demonstrating chemopreventive efficacy. As stated, grant—based funding is difficult to obtain for such research, and special NCI funding mechanisms are needed to encourage this activity. Clinical Chemoprevention Trials ' Ensure the conduct of randomized trials in human populations as the gold standard for scientifically demonstrating ways to reduce cancer incidence. Ensure the existence of a well—defined process of decision-making about target organ sites, appropriate populations, credible endpoints, and candidate chemoprevention agents for human trials. Large—scale studies should be preceded by extensive preclinical studies, epidemiological analyses, and favorable clinical safety and efficacy (tag, from Phase I and II chemoprevention studies). Design recruitment strategies to attract healthy people as participants in cancer prevention trials. High-risk but otherwise healthy people are identified as the following: individuals with predisposing genetic traits or a positive family history of cancer, persons engaging in high—risk behaviors, individuals with high exposures to occupational and environmental carcinogens and cancer—associated infections, and the elderly. Phase II studies need to be assured of a non—toxic efficacious dose and have a well—characterized biomarker endpoint before proceeding. Each study should consider the best biomarkers to use—~those appropriate across tissues and classes of agents, or those that have specific relevance to agent/ tissue under study. Phase III trials should be done within the “window of opportunity,” before use of agent is widespread and when efficacy can still be demonstrated in a randomized clinical trial. Design should consider applicability of outcomes with study participants to overall target population. Developing Cbemoprevention Expertise in the Research Community ' New investigators are needed for chemoprevention research, but funding mechanisms that attract young investigators are minimal. Contracts and cooperative agreements work well for established investigators, but are not attractive to young investigators. Academic institutions do not consider these awards to be investigator-initiated; hence, they are not credits to the awardee in building resumes. There is a need to change the perception of contracts and cooperative agreements or find a mechanism that allows NCI to provide career development awards or research grants for ancillary studies to young investigators who participate in such studies. Expand the chemoprevention research community to incorporate medical specialties besides oncology. For example, gynecologists, gastroenterologists, urologists, dermatologists, and dentists evaluate and treat precancers. Strengthen the nutritional science component of prevention research. Approaches include establishing nutritional science programs in medical schools (they are now found primarily in agriculture schools) and integrating biomarker development with nutrition to attract basic scientists. NCI-recognized cancer centers may be underutilized as sites for developing chemoprevention expertise. Investigators at several cancer centers participate in specific grant— and contract-funded projects; however, the possibility remains of providing funding to establish more comprehensive chemoprevention research programs at these centers. ° Increase prevention training opportunities through grants, workshops, and publications. Report of the Chemoprevention Implementation Group 19 Trogress 4715113de to Address Challenges for Chemopreventz’on The CIG first met in July 1998 to identify the challenges facing chemoprevention and to develop initial plans for restructuring the NCI chemoprevention effort to address these challenges. NCI staff, with additional advice from CIG subcommittees and individual members, took on the task of developing the specific programs needed. In March 1999, the CIG met again to review progress and finalize plans for restructuring. The revitalized and reorganized DCP resulting from this effort was described above. The programs and plans addressing basic science, agent development, clinical trials, and expansion of the chemoprevention research community are presented here. Expansion of Basic Science Program In response to the challenges identified by the NCI review groups, staff, and CIG and recommendations of the CIG, the DCP has been restructured to expand and enhance its basic science research effort, and has developed a new initiative to foster collaborative basic science research in the academic and industrial communities: ' As described above, four foundation research groups have been created within the DCP that will champion the varied, complex, and exciting advances in the fundamental knowledge of carcinogenesis that impact on chemoprevention. These are the Basic Prevention Science, Cancer Biomarkers, Nutritional Science, and Early Detection Research Groups. Each Group has in its mission the functions required to explore and develop new technologies that will contribute to defining and modeling the molecular, cellular, and tissue events in carcinogenesis as they relate to chemoprevention—for example, by using the findings on cancer genetics and technology of the CGAP project to design gene chips for evaluating cancer progression. The potentially subtle changes in measurable parameters during carcinogenesis that are observed and should be captured in evaluation of cancer risk and chemopreventive efficacy are also a focus of these four research groups. The basic science research groups will foster development and validation of technologies for detecting and measuring carcinogenesis in chemoprevention settings (e. g, digital imaging, computer—assisted imaging analysis). The NCI has announced the formation of the EDRN to address the challenge of developing and validating biomarkers for early detection and risk assessment. The network was proposed by the Early Detection Implementation Group and incorporates recommendations of the other NCI groups with interests in chemoprevention. The goal of the EDRN is to establish a consortium of investigators, both academic and industrial, with resources for basic, translational, and clinical research. The Network has three subgroups: Biomarkers Developmental Laboratories, Biomarkers Validation Laboratories, and Clinical/ Epidemiology Centers. The Developmental Laboratories will develop and characterize new, or refine existing, biomarkers; the Validation Laboratories will provide the resources for laboratory and clinical validation, as well as technological development and refinement. The Clinical/ Epidemiology Centers will conduct clinical and epidemiological research on application of the biomarkers. NCI intramural projects may also be incorporated into the Network. A Steering Committee composed of the Principal Investigators in the Network and appropriate NCI staff will coordinate the work of the consortium, and logistics and informatics will be provided by a Data Management and Coordinating Center. Additional input to the Steering Committee will come from an overall advisory committee (which provides independent scientific advice). The Requests for Applications (RFA) for the components have been published. Awards (cooperative agreements) to establish the Biomarkers Developmental Laboratories are anticipated in Fall 1999. Awards for the Validation Laboratories, Clinical/Epidemiology Centers, and the Data Management and Coordinating Center are expected early in 2000. Report oftbe C/Jemoprer/emiorr Implementation Group 21 New Program for Chemopreventive Agent Development Besides planning for the continued collaboration of the NCI with industry and the FDA to work out strategies for developing chemopreventive agents, four major challenges and opportunities in chemopreventive agent development have been addressed by the DCP in response to the recommendations of the CIG: 1) providing research investigators access to resources for early agent development, 2) developing new models for evaluating chemopreventive efficacy, 3) incorporating new technology into the discovery and characterization of chemopreventive agents, and 4) validating surrogate endpoints for cancer incidence to use as endpoints in chemoprevention efficacy studies. ' The RAPID program is designed to make NCI expertise and resources available to the research community on a competitive basis for the preclinical and early Phase I clinical development of potential chemopreventive agents. RAPID is similar to the Rapid Access to Intervention Development (RAID) program sponsored by the NCI Division of Cancer Treatment and Diagnosis for cancer chemotherapeutics. The intent is to help researchers bridge the gap between agent discovery and clinical testing when they lack all or some of the facilities required (e.g., scale—up synthesis, formulation, preclinical toxicology, regulatory affairs, Phase I Clinical safety, and pharmacokinetics). The tasks required to complete the winning projects will be carried out under NCI chemopreventive agent development contracts. The first round of RAPID proposals is due in November 1999, with awards anticipated in early 2000. An RFA concept is planned for review by the NCI Executive Committee on new animal model development for chemoprevention. This RFA will be looking for systems relevant to human cancer (61g, development and progression of lesions similar to human precancers, high predictive value for human chemopreventive efficacy) that are useful in preclinical efficacy screening and evaluation. Examples of the types sought are those using viral vectors to introduce susceptibility genes, genetically altered mice exposed to carcinogens by inhalation, irradiation carcinogenesis, chronic inflammation, cytological smears, and novel drug delivery. The RFA will recognize the strong recommendations of the CIG and other NCI review groups for the development of new models for certain organ—specific cancers—squamous cell lung cancers, prostate cancer, ER“ breast cancer. Four to five awards are expected, each of two to three years’ duration (one— two years for development, with one year for testing with standard agents). 22 National Cancer Institute 0 Division of Cancer Prevention 0 A third RFA, still to be reviewed by the NCI Executive Committee, titled “Pilot Program Projects for the Discovery of Agents to Prevent Cancer” is planned, which will promote the use of the new knowledge and technologies arising from research in cancer genetics to identify cancer preventive agents. Three projects are envisioned for these programs, which will be funded as cooperative agreements. The first project will involve testing known effective chemopreventive agents from various classes (e.g., antiestrogens, nonsteroidal antiinflammatory drugs, COX—2 inhibitors, retinoids) in in vitro and in viva assays such as primary cell culture, human orthotopic transplants, and animal models of early dysplasia. The objective will be to identify a pattern of expressed genes (RNAs or proteins) that are differentially modulated by chemopreventive agents. The second objective of the project will be to standardize the assay(s) and recognition algorithm(s) to screen new chemical entities. The second project will involve identification of potential molecular targets associated with early dysplasia using the CGAP, Serial Analysis of Gene Expression (SAGE), or other databases or approaches (cDNA microarray analysis, subtractive cloning, differential display, or proteomics) and standardization of assays using these targets for screening candidate chemopreventive agents. In the third project, biophysical properties (tag, structure, partition coefficients, redox potential, absorption, cytotoxicity) and metabolites of candidate chemopreventive agents will be determined, and structure—activity analyses (using assays from the first two projects and possibly gene expression at toxicologically affected sites) will be done to characterize and provide criteria for optimizing candidate agents. Initial funding for the programs will be three years; additional competitive funding will be considered to allow development of informatics systems for data sharing and to support professional training with the intent to establish Centers of Excellence for chemopreventive agent discovery. The fourth agent development initiative planned, titled “Validation of Surrogate Endpoints in Preclinical Models for Chemoprevention Drug Development,” addresses the need expressed by members of the CIG and the other NCI review groups for reliable biomarker efficacy endpoints and the difficulty validating these endpoints in clinical studies. This initiative will seek projects that apply recognized chemopreventive agents to modulate molecular biomarkers and precancerous lesions in animal models useful in surrogate endpoint validation. The lesions in these models should reconstruct human disease. The models should provide the ability to measure high—priority biomarkers, precancer incidence, cancer incidence, and survival. They should be amenable to sequential sampling so that strategies can be designed to compare the effects of the agents on biomarkers, precancers, and cancers, thereby providing evidence for validating the biomarkers and early lesions as surrogate endpoints for cancer incidence. The DCP will also collaborate with the Division of Cancer Treatment and Diagnosis (DCTD) in two vanguard RFAs fostering research in agent development, which will be issued in Fall 1999. The first, titled “Molecular Target Drug Discovery Grants,” provides opportunities for characterizing new molecular targets for cancer treatment and preventive agents and discovery of new drugs that act at these targets. By providing awardees access to NCI’s resources in chemistry, structure determination, screening, and pharmacology, the RFA is designed to attract researchers with state-of—the—art capability in defining molecular targets to agent development. The purpose of the second RFA, titled “Centers of Excellence in Interventions Directed Molecular Targets,” is to stimulate the formation of multidisciplinary (and possibly, multi— institutional) teams to carry out translational research needed to support agent development. These Centers of Excellence will be charged with developing and validating methods (e. g., imaging, biochemical, pathology) for assessing effects of potential cancer treatment and preventive agents on high— priority targets in viva, first in preclinical models, then in early “proof-of-principle” clinical trials. An important aspect of the early development of chemo— preventive agents will continue to be systematic evaluation and prioritization of candidates, along with periodic review and analysis of testing progress and planning for clinical testing. The CIG recognizes the DCP contract research program as a necessary and valuable resource to ensure that potential chemopreventive agents can be evaluated and developed efficiently according to priorities set and testing needs identified. Continued Growth of DCP Clinical Chemoprevention Research Program The DCP structure provides many resources to address the opportunities and recommendations of the CIG and the NCI review groups for refining and expanding chemo— prevention clinical research. For example, the creation of organ-based research groups within the DCP addresses the recommendation of the CIG to provide focus for in—depth consideration of disease—specific issues by specialists that parallels the research activities at the academic cancer centers. As another example, the Community Oncology and Prevention Trials Research Group has been maintaining a comprehensive resource on methodology and procedures for conducting prevention clinical trials that includes recruitment, compliance, retention, and specimen banking/testing, which provide references for the careful design of large prevention trials as advocated by the CIG. Two other recommendations of the CIG are establishing selection criteria and an advisory committee for new clinical studies and integrating ancillary studies into larger clinical studies. Also, the CIG strongly endorses Program Project grants as a funding mechanism for academic sites looking to develop or expand a clinical chemoprevention program. Perspectivesfiom Current Large Clinical Cbemoprevention Trials The NCI and the academic research community have been engaged in cancer treatment trials for several decades, but cancer prevention trials present new challenges to community—based investigators. This was the case in the early 1990s, when the Breast Cancer Prevention Trial (BCPT) and Prostate Cancer Prevention Trial (PCPT) began recruitment. The BCPT was a double-blind randomized trial of >13,000 women 35 years of age and older at high risk of breast cancer. Participants were randomized to tamoxifen or placebo for five years. The study ended in April 1998 with the demonstration of a nearly 50% invasive breast cancer incidence reduction in the tamoxifen arm.1 The PCPT, a double—blind randomized trial of 18,000 men 55 years of age and older, is a two—arm study of finasteride versus placebo for seven years, ending with a prostate biopsy on all participants. These two studies have successfully demonstrated the ability to enroll healthy, cancer—free participants at increased risk of cancer into chemoprevention research studies. The process of recruiting healthy, high-risk participants to the BCPT and PCPT studies was a significant learning experience for NCI, the Oncology Group trial organizers, and the community investigators who participated. For example, the majority of potential participants were not identified through oncology practices, but through events such as educational presentations at churches and schools and by distribution of informational flyers and public service announcements. Also, it was found that enrollment of minority populations requires community—specific strategies and up—front planning. Involving minority community representation in the early stages of trial development and discussions on including minority populations with the Oncology Groups and community investigators, as well as identifying representatives from the targeted community to work on recruitment and compliance efforts, have been most useful. Recruitment is only half the challenge of chemoprevention studies. Participants often need to stay in a study for seven or more years. This may be particularly difficult if they experience Report oft/1e Chemoprez/entian Implementation Gran}; 23 bothersome symptoms, possibly related to the study drug. An effort has been made to develop strategies for retaining participants. For example, study coordinators are taught to be especially skilled in listening and motivation. Because of the vast experience gained from these first large studies, the DCP is launching two more studies that build on the knowledge and network already established. In May 1999, the Study of Tamoxifen and Raloxifene (STAR) began. This study is a double—blind, randomized, two—arm trial of 22,000 postmenopausal women at high risk for breast cancer to either tamoxifen or raloxifene for five years. Early in 2000, the DCP plans to begin a study of vitamin E and selenium in prostate cancer prevention. This study will be a four—arm, double-blind trial of 32,000 men age 55 and older. The CIG realizes that large chemoprevention studies may be once-in—a—lifetime opportunities to evaluate a particular agent or cohort, but also recognizes that simpler protocols with one or few endpoints are more likely to be successful (e.g., because of less difficulty with accrual). To realize the full potential of such studies, the CIG has recommended that preparations be made for long—term follow-up of study participants after treatment is completed and that ancillary studies be incor— porated into study planning. For example, it is envisioned that guidelines for investigator—initiated clinical studies will include, where appropriate, provisions for carrying out such ancillary studies. Investigators may be asked to include tissue and blood/serum collection as well as specifications for the ancillary studies with their applications. For some very large studies, the development of tissue and serum banks will be included in the design with the intent of requesting applications from the research community at large to use these resources for ancillary studies (tag, as has been done in the finasteride trial). The NCI needs to develop a policy for handling and long—term storage of specimens collected in these trials (particularly, once funding for a trial has ended). The CIG also views these smaller studies as opportunities to involve younger investigators in chemoprevention. Clinical Trials Decision Process The CIG recognizes the need for selection criteria for agents considered and trial design guidelines for Phase I/ II as well as Phase III chemoprevention clinical trials. This guidance will be beneficial in ensuring the most appropriate use of resources and the highest likelihood of successful clinical studies, as well as helping train new scientists to accomplish this research. Specific criteria and guidelines will be developed by project teams comprising Research Group staff, CIG 24 National Cancer Institute 0 Division of Cancer Prevention members, and other extramural experts. The prioritization of agents and studies and design of clinical studies will also be the focus of chemoprevention workshops. Such workshops have been a forum for bringing together expert scientists to develop consensus on these issues, as well as to encourage participation of scientists new to the field. For both Phase I/ II and III studies, guidelines that evolve will address factors such as the sufficiency of preclinical or epidemiological efficacy and safety data, clinical safety data, mechanistic rationale and results of previous clinical studies, endpoints, standards of trial design, risk/benefit of the intervention in the target population, and the likelihood of the study being accomplished. Responding to the recommendations of the CIG, the DCP has proposed a decision process for developing and prioritizing clinical trials. Exhibit 2 is a schemata of the process, showing the stages at which decisions are made that move agents and clinical study concepts along the path from early development to Phase III trials. At each decision stage, the DCP research groups, other NCI divisions, and extramural scientists that contribute expertise and information to the process are identified. An agent or clinical study concept may enter the process at any stage. For example, epidemiology data and/or secondary endpoints from other clinical intervention studies may be sufficient for the Cancer Prevention Trials Phase III Decision Committee to evaluate the agent and suggested clinical trial without further preclinical or early clinical research. Briefly, the process is as follows: Stage 1: Discovery. New agents/ agent combinations are identified and selected for early development (preclinical screening, efficacy, preclinical toxicology, formulation). Some leads for agents and targets come from the research funded under the Chemopreventive Agent Development Research Group (and RAPID) or carried out by other NCI divisions and results from previous DCP studies—for example, epidemiology studies now sponsored by the Division of Cancer Control and Population Sciences (DCCPS) or Division of Cancer Epidemiology and Genetics (DCEG). Basic research done intramurally or that funded by the Division of Cancer Biology (DCB) provides new agents and early efficacy characterization. Secondary endpoints in clinical studies carried out within the DCP may provide leads to cancer targets (e.g., the evidence for vitamin E efficacy in prostate from the Alpha—Tocopherol Beta—Carotene (ATBC) Trial). Evidence of Chemopreventive activity may also come from preclinical data generated in the DCTD screening program or in mechanism—based secondary endpoints from chemotherapy studies of non—cytotoxic agents. Additionally, leads may come from studies funded by other NIH institutes (e.g., National Heart, Lung and Blood Institute) that are focused primarily on non-cancer endpoints. Project teams comprising scientists from the Chemopreventive Agent Development Research Group, the Basic Science Research Group, the Organ Systems Research Groups, and other intramural and extramural scientists will meet periodically to review agent leads to select those for development, and to identify the testing needed to qualify the agents for clinical studies. In some cases (e.g., drugs already marketed for other indications), limited preclinical efficacy testing or no additional testing at all may be required. These agents with recommendations for their clinical development would be forwarded directly to the Phase I/II Clinical Trials Decision Committee for further consideration. Stage 2: Early Development (Efficacy and Preclinical Toxicology/Pharmacokinetics). As required, agents are evaluated in preclinical efficacy and toxicology studies, primarily under NCI contracts under the Chemopreventive Agent Development Research Group. Agents that show promise in in vitro and animal efficacy screening assays may be characterized more fully in animal efficacy models (e.g., to assess dose—response, activity in combination with other agents, and effect on intermediate biomarkers). Preclinical toxicology studies will be conducted as needed for the most promising agents. Agents/agent combinations that emerge from this stage with potent efficacy and low toxicity are then considered for clinical development. Stage 3: Cancer Prevention Phase I/II Clinical Trials Decision Committee. At least semi-annually, a Phase l/II Clinical Trials Decision Committee will be convened to select agents for clinical development, to consider appropriate surrogate endpoint biomarkers for these studies, and to review clinical development plans for agents in Phase I and II chemoprevention studies. The Phase I/II Committee will consider agents that have been evaluated in the DCP agent development program, those forwarded by agent selection Project Teams, and other agents recommended by intramural and extramural scientists, provided that sufficient preclinical data are available to meet DCP criteria for entering clinical studies. The Phase I/II Clinical Trials Decision Committee will comprise representatives from the Chemopreventive Agent Development, each of the Organ System, the Early Detection, and the Community Oncology and Prevention Trials Research Groups, as well as representatives from the CIG, and, as appropriate (on an ad boc basis), other NCI and extramural scientists. The Phase I/II Committee decides which of the agents it reviews should move into clinical trials, and which should be deferred. For those deferred, the Committee may recommend additional preclinical testing and reconsideration. Clinical development plans will be prepared for each agent selected for further development. Stage 4: Phase I/II Clinical Trials. Clinical safety, pharmacokinetics, and pharmacodynamics studies are conducted as appropriate for the promising agents and formulations that reach this stage. Single-dose studies may be carried out in healthy volunteers, while multiple dose studies (three to six months’ duration) may be carried out in cancer patients or subjects at high risk for cancer at a target suitable for the agent. Agents with acceptable safety and desirable pharmacodynamics according to the guidelines established by the DCP will then be considered for Phase II studies to evaluate early efficacy. These studies will explore dosing strategies and endpoints in cohorts of interest. Many of the Phase I and II studies initiated as part of the decision will be carried out under investigator—initiated grants, research contracts, and in intramural studies (Phase I studies under the Chemopreventive Agent Development Research Group; Phase II studies under the Organ System Research Groups or jointly with the Community Oncology and Prevention Trials Research Group). The DCP may also use Program Announcements or RFAs to solicit the research community’s interest in carrying out these studies. Stage 5: Cancer Prevention Trials Phase III Decision Committee. Agents that reach this point in the decision process, whether they have been developed sequentially through investigator—initiated research, within DCP programs, or other sources will have met the criteria established by the Committee for receipt and consideration for large Phase 111 Report of the Chemoprevention Implementation Group 25 chemoprevention studies in the cohorts of interest. A large Phase III trial usually evaluates at least several hundreds of subjects (and currently may be defined operationally as requiring NCI to expend 2532.5 million/year in direct costs). 1 A Phase III Decision Committee, comprised of representatives from the CIG, other extramural scientists with specialized expertise, DCP management, and scientists from the Community Oncology and Prevention Trials Research Group and each of the Organ Systems Research Groups will evaluate Phase II trial results and other supporting data, clinical trial design, and potential impact of the studies on cancer prevention. The Committee will set priorities for conducting proposed studies and will provide expert advice on trial design and implementation. This Committee will meet annually Proposed functions for the Committee are outlined in Exhibit 3, and factors to be considered in prioritization are listed in Exhibit 4. Cancer Prevention Studies Workshop. The DCP will convene semiannual workshops of the CIG, DCP scientists, other extramural and intramural scientists serving on DCP advisory committees (particularly, the Phase 1/11 and Phase III Cancer Prevention Studies Decision Committees), and interested members of the research community to review the progress in and develop strategies for future clinical cancer prevention studies. The workshop will include presentations . on promising new agents by the DCP Project Teams for agent discovery and early development. Scientists from each of the ‘ Organ System Research Groups will describe progress in developing cancer prevention strategies at the cancer sites targeted by their research (including Phase I—IH clinical studies), and will review the clinical development plans, recent results, and on-going testing for agents in the DCP Phase I/II program. A goal of the workshop will be to revise the clinical development plans based on new results and the consensus advice of the workshop participants; the clinical development plans will be published. With results of the workshop in mind, the Phase III Cancer Prevention Studies Decision Committee will meet the following day to consider investigator—initiated ideas and concepts for Phase III cancer prevention studies submitted in response to previous Program Announcements and RFAs or from other sources (e.g., unsolicited proposals from the Oncology Groups). The Committee may also draft Program Announcements for future studies. mi: L/{ppma’z'ces CHEMOPREVENTIUN IMPLEMENTATION GROUP Roster David S. Alberts, MD (Chair) Associate Dean for Research Arizona Cancer Center, College of Medicine University of Arizona Peter Greenwald, MD, Dr PH (Co-Chair) Director Division of Cancer Prevention National Cancer Institute Steven E. Benner, MD, MHS Group Director, Clinical Oncology Bristol-Myers Squibb Pharmaceutical Research Institute G. Tim Bowden, PhD Professor of Radiation Oncology Department of Radiation Oncology University of Arizona Health Science Center Otis W Brawley, MD Director Office of Special Populations Research National Cancer Institute Julie E. Buring, ScD Associate Epidemiologist Preventive Medicine Brigham and Women’s Hospital Robert T. Dorr, PhD, RPh Professor Department of Pharmacology and Medicine Arizona Cancer Center University of Arizona Raymond N. DuBois, MD, PhD Professor of Medicine and Cell Biology Mina C. Wallace Professor of Gastroenterology and Cancer Prevention Director of Gastroenterology and Cancer Prevention Department of Medicine Vanderbilt University Medical Center Carol J Fabian, MD Professor of Medicine Breast Program Director Kansas Cancer Institute Director Breast Cancer Prevention Center University of Kansas Medical Center Patrick J. Flynn, MD Principal Investigator Metro—Minnesota CCOP Institute for Research and Education Health System Minnesota Leslie G. Ford, MD Associate Director for Clinical Research Division of Cancer Prevention National Cancer Institute Patricia A. Ganz, MD Director Cancer Prevention and Control Research School of Public Health University of California, Los Angeles Gary B. Gordon, MD, PhD Director Clinical Research/ Oncology GD Searle Michael N. Gould, PhD Professor Human Oncology University of Wisconsin, Madison Report of the Chemoprevention Implementation Group 29 Sylvan B. Green, MD Professor Department of Epidemiology and Biostatistics School of Medicine Case Western Reserve University Waun Ki Hong, MD Professor and Chairman Department of Thoracic/ Head and Neck Medical Oncology University of Texas, M.D. Anderson Cancer Center Richard J. Howe, PhD National Prostate Cancer Coalition Robert L. Justice, MD Acting Director Division of Oncology Drug Products Food and Drug Administration Barnett S. Kramer, MD, MPH Deputy Director Division of Cancer Prevention National Cancer Institute Stephen C. Lam, MD Professor of Medicine University of British Columbia Consultant and Head, Bronchoscopy Program British Columbia Cancer Agency Scott M. Lippman, MD Chairman Department of Clinical Cancer Prevention University of Texas, M.D. Anderson Cancer Center David G. Longfellow, PhD Chief Chemical and Physical Carcinogenesis Branch Division of Cancer Biology National Cancer Institute Frank L. Meyskens Jr., MD Director Chao Family Comprehensive Cancer Center University of California, Irvine Gilbert S. Omenn, MD, PhD Executive Vice President for Medical Affairs University of Michigan 30 National Canter Institute 9 Division of Cancer Prevention Wael Sakr, MD Associate Professor Department of Pathology Detroit Medical Center ~ Wayne State University Michael B. Sporn, MD Professor of Pharmacology and Medicine Department of Pharmacology and Toxicology Dartmouth Medical School Lee W Wattenberg, MD Professor of Pathology Department of Laboratory Medicine and Pathology University of Minnesota Medical School D. Lawrence Wickerham, MD Associate Chair Person NSABP Biostatistics Center Ming You, MD, PhD Professor Department of Pathology Medical College of Ohio NCI, DCP STAFF PARTICIPANTS Christine Berg, MD Acting Chief Lung and Upper Aerodigestive Cancer Research Group James A. Crowell, PhD Program Director Chemopreventive Agent Development Research Group Ernest T. Hawk, MD, MPH Acting Chief Gastrointestinal and Other Cancers Research Group Karen Johnson, MD, PhD, MPH Acting Chief Breast and Gynecologic Cancer Research Group Gary J. Kelloff, MD Acting Chief Chemopreventive Agent Development Research Group Levy Kopelovich, PhD Program Director Chemopreventive Agent Development Research Group Julia Lawrence, DO Medical Officer Breast and Gynecologic Cancer Research Group Ronald Lieberman, MD Acting Chief Prostate and Urologic Cancer Research Group Ronald A. Lubet, PhD Program Director Chemopreventive Agent Development Research Group Winfred Malone, PhD, MPH Program Director Chemopreventive Agent Development Research Group Howard Parnes, MD Program Director Community Oncology and Prevention Trials Research Group Barry Portnoy, PhD Planning Officer Office of the Deputy Director Kara Smigel Senior Writer Mass Media Branch Office of Cancer Communications Vernon E. Steele, PhD, MPH Program Director Chemopreventive Agent Development Research Group Jaye L. Viner, MD Program Director Gastrointestinal and Other Cancer Research Group SCIENCE WRITER Caroline C. Sigman, PhD President CCS Associates FACILITATORS Shannon Brandon Secretary to the Director Division of Cancer Prevention National Cancer Institute Sharon Don Program Coordinator Arizona Cancer Center Sally Marshall Conference Coordinator Scientific Consulting Group Cindy Rooney Office of the Deputy Director Division of Cancer Prevention National Cancer Institute Report oft/9e Chemoprevention Implementation Group 31 BASIC SCIENCE IMPLEMENTATION SUBCOMMITTEE National Academy of Sciences BSIS Members Washington, DC 20418 Non—NCI ' Summary of Meeting Dr. David S. Alberts (Chairperson) January 21, 1999 Dr. Bruce Alberts Dr. Susan Fischer The Basic Science Implementation Subcommittee (BSIS) Dr. Vay Liang W Go convened for its meeting at 9:30 a.m., January 21, 1999, Dr. Bernard Levin in Conference Room 250, National Academy of Sciences. Dr. Gilbert 5. Omenn Dr. Jill Pelling Dr. David Sidransky Dr. Vernon R. Young NCI Staff Dr. Peter Greenwald (Co—Chairperson) Dr. Iqbal Ali Dr. Carolyn K. Clifford Dr. Barbara Dunn Dr. Levy Kopelovich Dr. Douglas Lowy Dr. Ronald Lubet Dr. Sudhir Srivastava TABLE OF CONTENTS—APPENDIX 2 II. III. IV. VII. VIII. IX. Welcome and Charge to Subcommittee—Dr. David S. Alberts ........................................................................................ 33 DCP Mission and Proposed New Organization—Dr. Peter Greenwald ........................................................................... 33 Discussion ........................................................................................................................................................................ 33 Recommendations of Implementation Groups—Group Chairs ........................................................................................ 36 Discussion ........................................................................................................................................................................ 37 Discussion/ Suggestions for Building Genetics and Molecular Biology into DCP—Dr. Jill Pelling ................................... 38 Discussion/ Suggestions for Strengthening Basic Nutritional Science and Cancer Prevention Research in DCP—Dr. Vay Liang W Go .................................................................................... 40 Discussion ........................................................................................................................................................................ 40 How Can Cancer Prevention Research Best Be Accomplished in a Primarily Investigator—Initiated Environment?—Dr. Gilbert S. Omenn .................................................................... 40 Discussion ........................................................................................................................................................................ 4 1 Discussion/ Suggestions for Building Infectious Agent Cancer Prevention into DCP—Dr. Douglas Lowy. ...................... 42 Discussion ........................................................................................................................................................................ 42 Discussion/ Suggestions for Strengthening Basic Chemoprevention and Biomarker Research in DCP—Dr. David Sidransky. ................................................................................................. 43 Discussion ........................................................................................................................................................................ 43 Discussion/ Suggestions for Strengthening Cancer Prevention Science at Cancer Centers—Dr. David S. Alberts ............. 43 Discussion ........................................................................................................................................................................ 43 Discussion/ Suggestions for Strengthening Training and Career Development in Cancer Prevention Research—Dr. Bernard Levin ....................................................................... 44 Discussion ........................................................................................................................................................................ 44 Adjournment—Dr. David S. Alberts ................................................................................................................................ 44 32 National Cancer Imtitute 0 Division of Cancer Prevention I. WELCOME AND CHARGE TO SUBCOMMITTEE ——DR. DAVID S. ALBERTS Dr. David S. Alberts, University of Arizona, called to order the meeting of the Basic Science Implementation Subcommittee (BSIS). He thanked the committee members for their attendance and Dr. Bruce Alberts, National Academy of Sciences (NAS), for providing the forum for the day’s meeting. Dr. D. Alberts noted that efforts to enhance the basic science component of cancer prevention within the Division of Cancer Prevention (DCP) have been discussed for at least a decade. Dr. D. Alberts stated that the meeting was the first attempt at advising Dr. Peter Greenwald, Director, Division of Cancer Prevention, National Cancer Institute (DCP, NCI) in the establishment of basic science as a major component of the DCP—in particular, the melding of basic science with epidemiology and nutrition science. One difficulty, noted by Dr. D. Alberts, in this effort is the fact that the DCP—being a wholly extramural program—does not lend itself to the sort of rapid transition possible in an intramural program. Following introductions by each of the committee members, Dr. D. Alberts noted that the union of basic science and nutrition represented a great opportunity for both the field overall as well as the scientists engaged in its exploration and encouraged the committee members to speak their minds in an effort to stimulate the maximum amount of discussion. ||. DCP MISSION AND PROPOSED NEW ORGANIZATION —Dr. PETER GREENWALD Dr. Greenwald began by noting that the DCP was interested in receiving from the Basic Science Implementation Sub— committee (BSIS) feedback on the DCP’s future goals and the best course to take in achieving those goals. Dr. Greenwald next provided the BSIS with the Division’s view of prevention—incorporating two areas, public health and medicine. The former area includes smoking prevention, changing eating behavior, screening, exposure to sunlight, and eventually vaccines. The medical side somewhat mirrors the history of developments in cardiovascular disease (i.e., identification of biomarkers of risk) with the objective of developing interventions to lower risk. In the case of cancer, there is a need to better identify and validate biomarkers; interventions would include chemoprevention (e. g, tamoxifen and breast cancer). Dr. Greenwald next identified a number of areas considered major opportunities for cancer prevention: tobacco control—although primary responsibility for this area lies with the Division of Cancer Control and Population Sciences (DCCPS); diet and nutrition; hormone modulation; chemoprevention; infectious agents; and environmental factors and gene interaction. Dr. Greenwald noted themes common to the various Implementation Committees: enhancement of the prevention infrastructure—particularly at cancer centers and major research universities; strengthening of the science base and links with basic science—the reason for the existence of the Basic Science subcommittee; and an emphasis on training. In addition, retreats involving (primarily) NCI staff have focused on changes in organizational structure within the DCP and integration of DCP prevention activities with other agencies, including improvement in communication within the prevention community. Proposed Organizational Structure. Dr. Greenwald presented a chart depicting the proposed new organizational structure of the DCP—a matrix with one axis consisting of “Prevention Research Groups” (linked primarily to the basic sciences—e.g., chemoprevention, nutritional science, biomarkers) and another axis “Organ System Research Groups” associated with medical science areas (e. g, breast, gynecologic, prostate). At the intersection of each organ system and prevention research group was a “project team” or “research group” designed to deal with the specific cancer prevention research issue resulting from its origin on the Prevention and Organ System Research axes. Project teams may be formed and disbanded quickly, thus permitting greater responsiveness to research needs. Discussion Funding. Dr. B. Alberts asked the total budget amount for the DCP. Dr. Greenwald replied that last year the Division spent about $160 million; a little over $100 million being for pro- grammatic entities (e. g., clinical trials) with the remainder consisting of investigator—initiated grants. Dr. Greenwald added that the growth rate of the DCP budget was slightly less than that of the total NCI budget. Dr. Greenwald expanded on the role of the Division and the research groups—its sponsorship of extramural research through cooperative arrangements and partnerships—and cited new drug develop— ment as an example. Dr. B. Alberts then asked for the number of DCP staff. Dr. Greenwald stated there were 100 full—time equivalents (FTEs). Dr. Jill Pelling, University of Kansas, asked for a breakdown of the budget based on contracts relative to investigator—initiated funding. Dr. Greenwald, using chemo- prevention as an example, stated that $2 million (out of $14 million) had been allocated for competitive investigator— initiated use. He added that the single largest component of the DCP budget was for the Community Clinical Oncology Program (CCOP)—approximately $40 million—and noted that another significant portion of the budget was devoted to the Early Detection Program. Dr. Ronald Lubet, Program Director, DCP, NCI, clarified the process by which an investigator—initiated chemoprevention R01 would be reviewed Report oftIJe Chemaprevention Implementation Group 33 and noted that one with an emphasis on basic science would be seen by an NCI Division other than the DCP—even if a significant portion of the work does, in fact, involve prevention or translational (prevention—oriented) research. Dr. D. Alberts observed that it is often difficult for outstanding basic science research projects to obtain funding if they contain a novel prevention component and are reviewed by a basic science funding panel. Dr. Greenwald concurred with this observation, noting that review groups are sometimes not well represented by experts in prevention— thus such proposals do not always receive an adequate review. Dr. Greenwald added that this problem was circular—not enough prevention-oriented applications are received, thus it is difficult to justify adding reviewers expert in prevention, yet such reviewers are needed in order for prevention proposals to receive a proper review. Dr. Gilbert Omenn, University of Michigan, noted that the amount of the NCI budget spent on prevention was a matter of definition—in FY 96, the total NCI prevention budget was about $400 million, of which $188 million was appropriated to the (then) Division of Cancer Prevention and Control. Of that $188 million, $154 million was associated with diet and nutrition and chemoprevention. If one included physical, clinical, and biological carcinogenesis, other nutrition, observational epidemiology, and cancer control programs under the prevention umbrella, added Dr. Omenn, then the figure would be about $740 million. Dr. Omenn asked Dr. Douglas Lowy, Deputy Director, Division of Basic Sciences, National Cancer Institute (DBS, NCI), if he could comment on the methods that determine why a particular research program—with a prevention component—is (or is not) funded by the Division of Cancer Biology (DCB). Dr. Lowy stated that he was not involved in such matters. Dr. Greenwald commented that such decisions were not NCI-driven—the peer review structure is the critical factor. Dr. Levy Kopelovich, Program Director, DCP, NCI, com— mented that one recommendation of the B515 might be the creation of a study section dedicated to cancer prevention. Dr. Pelling agreed, noting that the establishment of such a section would send a positive message to scientists doing prevention research and would encourage additional prevention—related applications. Dr. Greenwald, while acknowledging that this idea had some merit, sounded a cautionary note, pointing out that, for example, money already exists for prevention training but few applications for nutrition or chemoprevention training are received—largely because of inadequate training at the university level in these areas. Dr. Greenwald concluded by stressing that a sufficient number of prevention—related applications would have to be received in order to justify the existence of a study section devoted to this area. 34 National Cancer Imtitute 0 Division of Cancer Prevention Dr. Greenwald noted that infrastructure development through program project—type grants at cancer centers and universities with a strong interest in prevention stimulates future R015 for training. Dr. D. Alberts agreed, adding that few such program r project grant opportunities exist and that strong leaders, interested in the advancement of prevention, within cancer centers and universities are necessary to advance the field. Dr. B. Alberts noted the lack of emphasis on prevention in medical and graduate school curricula. Dr. Greenwald and Dr. D. Alberts agreed, stating the need for training programs in preventive oncology. Dr. Greenwald then commented on the historical perception of nutrition, the need to emphasize its basic science aspects, and its critical relationship to cancer prevention. Dr. Omenn, while acknowledging the importance of infrastructure development, cited the importance of the BSIS in generating interest in the stimce of prevention— so as to attract researchers and funding. Regarding nutrition, Dr. Omenn stressed the need to remake the field, linking it with genetics, metabolism, epidemiology, and environmental health. Dr. Omenn also emphasized the importance of development of good animal models of the carcinogenic process. Dr. Pelling asked what effect the 1997 Cancer Prevention Program Review Group report, which advocated an increase in Requests for Applications (RFAs) involving animal models, had been. Dr. Greenwald answered that $14 million had been devoted to agent development, plus a $2 million for new developments and testing methods and biomarkers—the goal, stated Dr. Omenn, being to increase the number of investigator-initiated proposals and stimulate new research contributions. Dr. Lubet related his experience in using new (transgenic) animal models and certain patent- related difficulties he had encountered. Discussion centered on the patent issues surrounding development of new animal models. Basic Science in Nutrition. Dr. Vernon Young, Massachusetts Institute of Technology, inquired whether appropriate animal models existed that would stimulate collaboration between basic and nutritional scientists. Dr. Omenn agreed that this was an important consideration. Both Dr. Young and Dr. Omenn commented on the complexity of diet and the fact that fundamental investigation of dietary prevention of cancer requires sophisticated knowledge of biochemistry, metabolism, and other areas. Dr. D. Alberts stated that changing the misperception in the basic science community that nutrition is not “cutting—edge” science is key to the advancement of dietary prevention of cancer. Dr. D. Alberts added that, at all levels of training, there is a need to make basic scientists aware of their importance to cancer prevention and suggested further discussion of how the basic science curriculum could be modified to incorporate opportunities for prevention-related research. Conversely, noted Dr. D. Alberts, it is important to blend basic science into prevention—related curricula (e. g., What are the mechanisms of physical exercise that may reduce the incidence of certain cancers?) Training. Dr. Lowy asked what the relationship was between the DCP and schools of public health. Dr. Greenwald replied that the relationship varies with the particular school—some have a strong science base, others do not. Dr. Omenn added that the same was true for medical schools. Dr. Greenwald commented that the training opportunities in prevention at schools of public health and health departments require strengthening. Dr. Vay Liang W Go, University of California at Los Angeles (UCLA), emphasized that, in order to provide the science base for cancer prevention/nutrition, there was a need for more faculty to teach basic science to medical, public health, and other students. Dr. Go added that leadership at the university level is necessary to develop such a curriculum. Dr. Go cited UCLA as being an institution that has developed an innovative curriculum and infrastructure for the teaching of modern nutrition science and prevention. Such integrated training must begin at the BA/BS stage and be carried on through the MS/PhD levels, noted Dr. Go, in order to be effective. Dr. B. Alberts inquired into efforts to involve young researchers in prevention. Dr. Greenwald described training opportunities in prevention, including the use of RFAs— noting that there is an effort to reduce the number of such RFAs and that additional funding is needed. The advice of the B815, added Dr. Greenwald, represents critical input into the priority given this issue. Dr. Bernard Levin, University of Texas, commented that prevention was insufficiently represented in most medical school faculties and suggested that (pre— and postdoctoral) training programs in prevention be enhanced (e.g., rechannel medical oncology—or other—fellows into prevention). Dr. D. Alberts noted that the issue of training grants for basic science—prevention had been raised with Dr. Richard Klausner, Director, NCI. Dr. B. Alberts mentioned that development of a textbook, similar to a landmark 19705 text on structural biology, outlining the linkages between basic science and prevention might be useful in stimulating interest in the field. Dr. Greenwald asked if such a text could be written under contract with the NAS. Dr. B. Alberts replied that it would need to have more than a single author—similar to Diet and Health. Dr. Young commented that a format different from Diet anal Health was needed; Dr. B. Alberts agreed. Dr. Go stated that such a text could serve as the framework for what defined cancer prevention (i. e., What are the scientific principles of cancer prevention?) and stressed the need for curriculum development in prevention. Other points made by Dr. Go included the need to 1) discuss the best methods to disseminate such curricula; 2) inform and educate scientists that the work they are currently doing is, in fact, “cancer prevention”—or at least bears a meaningful relation— ship to cancer prevention; and 3) encourage such scientists to integrate their work into cancer prevention. Discussion turned to funding (R25 grants) available for curriculum development. Dr. B. Alberts commented that curricula developed with federal funds should be made available to everyone via the Internet; Dr. Go agreed. Dr. Young noted that one method of increasing the visibility of the prevention field, and particularly the role of basic science, was the development of high—level, state-of—the—art, interdisciplinary workshops (e.g., on nutrition and signal transduction); a series of publications might result from such a workshop, serving a purpose similar to that noted by Dr. B. Alberts in his comments regarding production of a textbook. Dr. B. Alberts stated that presentations at major professional meetings (e. g., the American Society of Cell Biology) might also be useful in stimulating interest among both established researchers and those in training. Dr. Pelling thought the “Histopathology of Neoplasia” symposia at Keystone, Colorado, and Lake Placid, New York, would be good forums for presenting prevention research to a young and diverse basic science audience. Dr. Pelling suggested “Molecular Basis of Cancer Prevention” as a possible title for such a presentation. Dr. Pelling also stressed that it was critical for young researchers to be aware that funding existed for such prevention research, lest they be discouraged from entering the field. Dr. B. Alberts suggested such a symposium be conducted at the NCI. Dr. Go agreed, adding that partnership with the American Association for Cancer Research (AACR) or some other organization might also be useful. The Perception of Prevention. Dr. Susan Fischer, University of Texas, commented on the need to change the perception that prevention is a soft science—an emphasis on molecular approaches might be beneficial in this regard. Drs. D. Alberts, Pelling, and Lowy all echoed the sentiment that prevention, as it is currently thought of in the scientific community, may suffer from an image problem and this issue should be addressed—perhaps through expansion of the roles of molecular and cell biology. Dr. Levin cited the growth of molecular and genetic epidemiology as examples of the incorporation of elements of basic science into a prevention— related field (epidemiology). Dr. Omenn added that the molecular epidemiology group within the AACR has grown Report of the Chemoprevention Implementation Group 35 from the original 20 to over 500. There was discussion of whether the term “prevention” was helpful in advancing the field and whether a new term was necessary; Dr. Iqbal Ali, Chemist, DCP, NCI, suggested “molecular Chemoprevention” as being more attractive. Dr. Barbara Dunn, Program Director, DCP, NCI, thought it important to retain the term prevention in order to maintain the link with clinical prevention trials and suggested “molecular prevention” as an alternative. Dr. Greenwald commented that examples from other disciplines that were previously not considered in the scientific mainstream (e. g., structural biology, photobiology) but subsequently proven important might serve as “arguments by example” for the development of prevention science. Dr. Omenn suggested that a third axis be added to the DCP’s proposed organizational structure (within the Organ System Research Groups) that explores the specific factors/ agents that are targets for intervention (e. g., tobacco—dopamine receptors, nicotine receptors) thereby further focusing the interest of the scientific community. Dr. Omenn noted a number of addi— tional areas that might be added to such a third axis, including infectious agents, environmental factors, and hormones. Inclusion of these factors as a third axis, stated Dr. Omenn, would facilitate the development of an action plan and stimulate the interest of scientists interested in organ biology and pathology. Dr. Lubet cited two areas that might stimulate interest in prevention in the basic science community: 1) development of transgenic models and 2) production of a series of slides highlighting some key aspects of cutting-edge prevention science (e. g., results of the tamoxifen trial—particularly emphasizing molecular and genetic mechanisms) that would be made available widely. Dr. Dunn suggested a meeting to discuss the development of prevention—oriented medical school curricula with that body responsible for medical school training. Dr. Go commented on the difficulty of incorporating prevention—related issues in the typical medical school curri— culum. Dr. G0 cited the American Institute for Cancer Research (AICR) publication, Food, Nutrition, and Cancer Prevention: A Global Perspective, as being a good example of a text that integrates current knowledge of basic mechanisms of carcinogenesis with recommendations to prevent various cancers (e. g, the linkage of folic acid and smoking). Information summarizing the relationships noted by Dr. Go is found in Fig. 2.7 of Food, Nutrition, and Cancer Prevention (p. 71). Dr. Go reported that a survey he conducted of recent medical school graduates found the majority did not believe they received adequate instruction in nutrition and public health—fundamental areas of prevention science. Thus it is critical, stated Dr. Go, to enhance training at all levels 36 National Cancer Institute 9 Division of Cancer Prevention (undergraduate and graduate) in these areas to develop the leadership capable of advancing the field. Dr. Go related his experience at UCLA in analyzing the typical one—day patient load and relating the characteristics of the patients (e. g., obese, : diabetic, hypertensive, etc.) to changes in the medical school curriculum (i.e., a greater emphasis on nutrition and nutrition— related disease). Dr. Levin stated that such an approach must extend to residency and specialty board training. Summary Dr. D. Alberts summarized the discussion to this point, noting that 1) there is a need for training grants that target basic science; 2) existing curricula are deficient regarding cancer prevention and nutrition; 3) a text integrating basic science with nutrition and cancer prevention may stimulate interest in the field; 4) the Internet should be used to make information available to all parties and stimulate additional interest—perhaps the NCI, as part of its training program, could establish a training module in this area and place it on its Website; and S) the forums of professional workshops, symposia, and meetings would be useful in stimulating interest in innovative prevention research to a wider (basic science) audience. III. RECOMMENDATIONS OF IMPLEMENTATION GROUPS —GROUP CHAIRS T/Je Chemoprevention Implementation Group. Dr. D. Alberts, chairman of the Chemoprevention Implementation Group (CIG), reviewed the issues developed within his group: 1) the need to continue development of new in vitro and in vivo models for the identification and assessment of efficacy of chemopreventive agents that integrate knowledge of genetics and molecular alterations involved in human carcinogenesis; 2) patent issues, as discussed earlier, surrounding the development of such models remain a concern; 3) develop intermediate biomarkers for assessment of exposure and biological effects applicable in prevention studies—and validate their use in parallel studies in animals and humans; 4) increase research concerning the biological mechanisms underling putative associations between diet and cancer incidence—especially fruits and vegetables, fats and total energy consumption, and mechanisms whereby physical activity may reduce cancer risk; 5) involve basic scientists, especially predoctoral candidates looking for thesis projects, in prevention research and carry this interest and support through postdoctoral training; 6) emphasize basic and applied studies on the role of viruses and Helicobacter pylori as risk factors or cofactors in the etiology of certain cancers and initiate development of appropriate vaccines; 7) develop new molecular markers for early detection; 8) develop and improve new high-throughput technologies for implementation of promising molecular diagnostic approaches in clinical and population—based trials—emphasizing the validity of these techniques; 9) form an advisory subcommittee of the NCI Board of Scientific Advisors (BSA) supplemented with other outstanding extramural scientists to advise on increasing the amount of basic science in cancer prevention; and 10) request that the BSA subcommittee define the drug discovery program, stimulate creative approaches in the development and use of new animal model systems, and evaluate candidate chemopreventive agents for cellular and animal screening tests. T he Early Detection Implementation Group. Dr. Levin, chairman of the Early Detection Implementation Group (EDIG), presented a series of recommendations regarding the formation of a new vertical structure within the NCI for biomarker evaluation. The first issue addressed was whether surrogate endpoints can replace cause—specific mortality in definitive screening trials and how such endpoints could be validated. Validation criteria developed by the EDIG included differential expression of the surrogate biomarkers; stage of carcinogenesis; specificity, sensitivity, and predictive values; ease of measurement; modulation by chemoprevention; and the degree to which modulation correlates with a decrease in cancer rate. The EDIG recommended a vertical approach to biomarker research involving the Early Detection Research Network (EDRN). This infrastructure would support collaborative research on molecular, genetic, and other bio— markers in both detection and risk assessment and is similar to the proposals made by the Cancer Prevention Program Review Group, the CIG, the Breast Cancer Program Review Group, and the Prostate Cancer Review Group. The goals of this proposed infrastructure are: establishment of a stable connection between basic laboratory research and rapid clinical applications, provision of multidisciplinary expertise and multiinstitutional resources, and provision of access to industry, academia, and clinical investigators. Quality assurance is critical to development of biomarkers as indicators of early cancer, surrogate endpoints, and prognostic or risk factors. Emphasis should be placed on the interaction of academic, clinical, and pharmaceutical industry leaders for the development of high—throughput sensitive assays for biomarkers. Dr. Levin outlined the organizational structure for early detection efforts: 1) high technology and biotech companies 2) instrument and reagent development and 3) biomarker development and validation laboratories— including interaction with clinical epidemiology chairs. The infrastructure is supported by an independent scientific advisory committee providing oversight review, a steering committee of investigators constituting the main governing body, and a single data management coordinating center. This structure is flexible, flowing from biomarker discovery to clinical validation, using a consortium mechanism. Specifically: 1) it allows easy access to outside investigators; 2) unpromising projects can be replaced; 3) there is opportunity to set priorities and provide funds for meritorious projects from investigators both within and outside the network; 4) it is interdisciplinary—allowing scientific expertise beyond the scope of network centers; 5) it is translational— stimulating innovative scientific approaches, focusing translational research goals, and bringing basic science to all levels; 6) it can foster translational research using available biomarkers as well as new ones—the advent of chip technology will allow for the creation of comprehensive marker databases; 7) it will attempt to maximize collaborations within the scientific community (tag, the Cancer Genome Anatomy Project (CGAP), and the Cancer Genetics Network); and 8) it will foster non—NCI funded opportunities (mg, other NIH initiatives, DoD, VA, biotechnology, international and intergroup collaborations). The program requires evaluation by an advisory committee. Workshops should involve basic scientists and consultation should occur with members of the BSA and National Cancer Advisory Board (NCAB), along with periodic progress reports to the BSA. Funding in the first year (1999) would be $3 million, and $10 million and $12 million in succeeding years. Discussion Dr. Sudhir Srivastava, Program Director, DCP, NCI, elaborated on the current status of biomarker development efforts, noting that the components mentioned by Dr. Levin will be funded through separate RFAs. The biomarker development RFA was released January 20, 1999, and virus and epidemiologic biomarker RFAs will be released in late summer. The goal is that by FY 00 all components will be funded and that a steering committee will be established by February 2000. Dr. Srivastava provided the URL to access the biomarker RFAs. Dr. Pelling asked where the biomarker development effort fit within the proposed DCP organizational chart—Biomarkers or Early Detection? Dr. Greenwald replied that it fell under the Biomarkers heading (funding will be managed through the Biomarkers Research Group) although it was related to Early Detection as well. Dr. Greenwald added that the Early Detection Research Group is focused primarily on a large clinical trial (Prostate, Lung, Colon, and Ovary) and the associated repository. Dr. Srivastava added that the steering group for this particular cooperative group has extra funds to bring in individuals who did not receive initial funding— it is a more inclusive approach than is normally the case. Report oft/ye Chemoprevention Implementation Group 37 T he Nutrition Implementation Group. Dr. Young, chairman of the Nutrition Implementation Group (NutrIG), provided an overview of the activities of his group. The NutrIG held its first meeting on August 26, 1998, and a second meeting is planned. The goal of the NutrIG is to develop recom— mendations concerning the enhancement of nutrition sciences across the United States, primarily involving a greater emphasis on the basic sciences, so as to advance cancer prevention. There has been significant discussion of the issues, striking themes similar to those already discussed at this BSIS meeting (e.g., training and career development initiatives). There is a View within the NutrIG that nutrition science should be represented more strongly within the NCI— possibly as an intramural activity—thus serving as a model for nutrition cancer research. Also discussed within the NutrIG was the need to improve the peer review system. The Final Report of the NutrIG will outline leading—edge diet, nutrition, and cancer research, pointing out the importance of this area for the advancement of cancer prevention. IV. DISCUSSION/SUGGESTIONS FOR BUILDING GENETICS AND MOLECULAR BIOLOGY INTO DCP— DR. JILL PELLING Dr. Pelling began by noting the favorable public perception of chemoprevention and asked the BSIS members to con- tribute their suggestions regarding other strengths of the field. Dr. Greenwald stated that there was promising preclinical and clinical evidence for some drug and non-nutritive agents. Dr. Kopelovich commented that progress was being made in developing bona fide chemopreventive agents for certain cancers. Dr. Omenn asked whether a matrix of specific cancers and their promising chemopreventive agents might be constructed. Dr. Greenwald and Dr. Kopelovich thought this was possible. Dr. Greenwald noted that there is increasing industry interest in cancer prevention. Dr. D. Alberts pointed out that an encouraging sign was the growing interest in the identification of specific molecular and biochemical targets for drug development and cancer prevention strategies and provided an example of such an effort. Dr. Pelling stated that such interest should be expanded. Dr. D. Alberts agreed, commenting that the historic lack of targets has been a liability to the field, as has the lack of trained basic scientists. Dr. Fischer cited a related problem: the view of basic scientists that they should avoid prevention (or prevention-related) research because of: 1) insufficient funding for such work and 2) the perception that prevention is a “soft science.” Dr. D. Alberts agreed with these comments and suggested that one remedy might be the use of a program project or large R01 opportunities to slowly integrate basic scientists into translational research. 38 National Cancer Institute ’ Division of Cancer Prevention Identification of targets. Dr. Ali commented that one promising research area was the molecular profiling of preneoplastic lesions and their correlation with histopathology, using a target—organ—oriented approach. Such an approach, ! added Dr. Ali, would provide relevant biomarkers, help i develop relevant animal model systems, and form a basis for molecular targeting of drugs. Dr. Pelling continued her presentation, noting the need not only for new animal models but for animal models that more closely mirror the genetics , of human carcinogenesis. Dr. Lubet questioned whether the latter goal was feasible and provided the rationale for his argument. There was additional discussion of animal models of carcinogenesis. Dr. Pelling noted that the problem would come when one tries to translate the results of animal studies to human prevention/therapy. Dr. Lowy generally agreed with Dr. Pelling’s earlier comment—stating that it should be possible to develop models that have multiple changes. Dr. D. Alberts commented that whatever success chemo— therapy has had is partially attributable to the fact that it identified specific molecular and biochemical targets. Similarly, Dr. D. Alberts noted that there should be an effort to target chemoprevention agents. Animal models. Dr. D. Alberts also mentioned that transgenic models should not become too complex—lest they lose their ability to be extrapolated to human carcinogenesis. Dr. Pelling stated that, in certain situations, complex animal models did serve a useful purpose and deserved additional - financial support. Dr. D. Alberts agreed and added that there was a need for a more global view of animal model develop— ment-—the NCI should enunciate its point of view regarding animal model development in order to organize the field. Dr. Srivastava pointed out that the NCI recently initiated a mouse model consortium. Dr. Lubet added that the consortium will soon begin making recommendations. Dr. Pelling cited as an additional need the dearth of molecular genetics studies in the rat relative to the number of such studies done in the mouse—the rat genome project is deserving of more attention. More broadly, Dr. Pelling commented on the need for modeling in multiple species to avoid a single animal model (La, the mouse). Dr. David Sidransky, Johns Hopkins University, agreed with the need for a broader array of animal models but cautioned that too many animal models would distract attention from the primary goal—prevention of human cancer. Dr. Sidransky stressed the need for an equilibrium to the various aspects of cancer research (sag, advances in the development of intermediate biomarkers might be more expeditious than spending longer periods of time developing animal models). Dr. Sidransky suggested that, within the Organ System Research Groups of the proposed DCP reorganization, attention be focused on the “best” models for that particular organ type rather than an across-the-board attempt to develop numerous models and strategies. Dr. D. Alberts added that another possibility might be the examination of specific pathways. Dr. Pelling inquired into the feasibility of developing resistant/sensitive strains to certain chemo— preventive agents. Dr. Pelling presented a number of additional questions to the B815: 1) Are the number of delivery systems sufficient? 2) To what degree is resistance to chemoprevention genetically conferred? 3) Is there a need for the development of new endpoints and assays in biomarker research? 4) How can molecular geneticists be encouraged to examine chemopreventive strategies? and 5) Can microarrays and microchips be applied to chemoprevention at the molecular level? Dr. Kopelovich noted that considerable prevention research was now being conducted, beginning at the in oitro level and continuing on to animal systems. Dr. D. Alberts noted a parallel with chemotherapy: the determination of resistance mechanisms is critical to the improvement of cancer chemotherapy agents, perhaps through the use of microchips. Dr. D. Alberts then suggested that the term “therapy” be abandoned and a term such as “molecular pharmacy/ molecular drug” or “genetic drug” be substituted. Dr. Ali suggested the term “molecular genomics.” Dr. Lubet noted some differences between the development of chemotherapeutic and chemo— preventive agents. Dr. D. Alberts asked about the relationship between DCP and the Genome Project and/ or the DNA microarray efforts at the NCI. Dr. Greenwald responded that most of the tie-in was within Working Groups and dealt with gene discovery and making such discoveries relevant to clinical treatment and prevention. Dr. Greenwald added that, currently, the prevention aspect of such activities was not a major focus. Dr. Ali added that there is discussion in the Working Groups of normal, premalignant, and invasive cancer, with the interest of the DCP being on precancerous, well- defined lesions. Dr. Ali stated that once the information is made available widely (e. g., on the Web), individuals interested in chemoprevention could seek R01 funding. Dr. Levin commented that there was a need to communicate to basic scientists the fact that a continuum exists from early to late molecular intervention (i.e., basic scientists should be made more aware of the range of resources available to them (e. g, CGAP) and how those resources are linked to cancer prevention research). Dr. Pelling reiterated the importance of workshops/symposia/ training opportunities as a means of educating scientists as to available opportunities. Dr. Greenwald commented that one constraint on the NCI’s activities in any particular area is depth of staff and suggested that such activities as sabbaticals and two—way exchanges might be beneficial in facilitating the transfer of expertise. Dr. D. Alberts suggested that the DCP be represented on the DNA microarray project. Dr. Dunn agreed that the DCP should play a more active role in this area. Dr. Srivastava made a number of comments regarding the CGAP: 1) it is currently an internal project (with two external components dealing with the CDNA library); 2) discussions with CGAP personnel are held regularly; 3) the purpose of the CGAP is gene discovery; 4) microarray technology is available to any internal scientist; and 5) Dr. Greenwald will discuss with Dr. Klausner the possibility of establishing a Pathology Task Force that will advise the CGAP regarding histopathology. Dr. Fischer stated that there was a need for greater information exchange— many scientists in academia are unaware of certain internal NCI programs such as the CGAP. Dr. Greenwald agreed, and Dr. Ali noted that information on most programs is available on the Web. Additional discussion centered on the need to make information on the NCI Website more accessible. Dr. Lowy commented that a real opportunity existed for work on potential molecular targets for premalignant lesions. Dr. D. Alberts agreed, commenting that current (particularly in oitro) models do not relate to clinical applications. Research on premalignant lesions. Dr. Lowy commented that research on premalignant lesions would advance secondary prevention. Following up, Dr. Omenn cited the importance of stimulating the interest of basic scientists in working on such lesions, and Dr. Young added that nutritional science could potentially contribute to this area. Dr. Kopelovich provided an illustration of current work within the DCP regarding premalignant lesions. Dr. D. Alberts asked whether, rather than bring researchers to NCI to inform them of research developments, NCI—sponsored videoconferences might be used to communicate results to the extramural community. Dr. Fischer agreed that videoconferences would be beneficial. Dr. D. Alberts reiterated the need to stimulate basic scientists’ interest in developing 1) new models through the use of premalignant lesions and 2) animal models that parallel the human situation. Dr. Lowy stated that one poten— tial method of evaluating agents in premalignant situations was examination of the degree to which they induced apoptosis—through examination of the genes that were pro— or antiapoptotic. Dr. D. Alberts agreed and mentioned a project along these lines at the University of Arizona. Report oft/9e Chemopreoemion Implementation Group 39 V. DISCUSSION/SUGGESTIONS FOR STRENGTHENING BASIC NUTRITIONAL SCIENCE AND CANCER PREVENTION RESEARCH IN DCP—DR. VAY LIANG W. Go Dr. Go began by noting that nutritional science has tended to emphasize a holistic, rather than molecular, approach to its activities. He added that there is a need to better understand the multistep nature of carcinogenesis—from the cellular level up to the human level—as illustrated in Figure 2.7 of Food, Nutrition, and the Prevention of Cancer: A Global Perspective. Once the basic nature of the continuum of carcinogenesis is understood, the mechanisms determining the elements of the continuum can be addressed. Identification of elements within the continuum also facilitate communication with researchers in other areas (e. g., smoking, nutrient-drug interaction, energy expenditure and obesity, receptors, intracellular processing, transcription/translation, etc.). Nutrition science, said Dr. Go, suffers from its inability to explicitly state what it does not know. Dr. Go made the following points: 1) understanding of the mechanistic action of nutrients is critical—therefore, nutritional science must be made relevant to basic scientists; 2) nutritional scientists must make clear the rationale for doing a particular interventional trial; 3) gene expression is nutrient- dependent; 4) the link between nutritional science and cancer prevention must be made clear—a good curriculum explaining nutritional science in relation to carcinogenesis and cancer prevention is necessary; and 5) the information regarding the nutritional prevention of disease is conflicting and requires clarification. Also, enhancement of nutritional science in cancer prevention requires 1) an improved curriculum 2) support (including financial) of young people to enter the field and 3) linkage with the basic sciences. In terms of NIH infrastructure, Dr. Go cited the need for modification of the Clinical Nutrition Research Unit (CNRU) concept, perhaps emphasizing the genetic and molecular biology aspects of its work. More broadly, it is important for nutrition to establish itself as a highly visible science so as to attract the interest of other basic scientists and form research linkages (e. g., smoking and folic acid). Dr. Go identified the following major needs for the development of nutritional science: 1) training of young scientists, 2) better communication of nutrition research activities to the academic community, 3) improvement of the peer review process, and 4) leadership at the NIH level to facilitate development of the nutritional sciences (e. g., a vibrant Nutrition Coordinating Committee), with the goal of stimulating nutritional sciences across the country. 40 National Cancer Imtitute 0 Division of Cancer Prevention Discussion Dr. Carolyn Clifford, Chief, Diet and Cancer Branch, DCP, NCI, remarked on the misperception of the field of nutrition: the general belief is that nutrition is about health promotion, nutrition education, dietetics, and dietitians, whereas schools of public health tend to emphasize nutritional epidemiology. Dr. Clifford stated that the field of nutrition is fragmented, with little communication among the various camps. In addition, most of the basic science in nutrition is conducted in schools of agriculture and involves animal—~rather than human/clinical—studies. Dr. Clifford agreed with Dr. Go’s comment that the NIH Nutrition Coordinating Committee would benefit from revitalization. Dr. Young echoed the previous recommendations for strengthening nutritional science and identified the following as additional needs: 1) strengthening of nutrition research within the NIH and the NCI, 2) enhancement of intramural nutrition research within the NIH, and 3) integration of biomarker development with nutrition as a means of attracting basic scientists into the program. Dr. Young concluded by noting that nutrition is an integrative, rather than a basic, science—hence the need to achieve the correct mixture of components to advance the field. Discussion centered on the activities of the biotechnology industry regarding genetic and molecular research in nutrition and the need for NCI to monitor such work. Dr. Clifford commented that the science of prevention lags behind the technology, and Dr. D. Alberts agreed. There was discussion of dietary supplements and alternative medicine and their relationship with nutrition. VI. HOW CAN CANCER PREVENTION RESEARCH BEST BE ACCOMPLISHED IN A PRIMARILY INVESTIGATOR-INITIATED ENVIRONMENT? —DR. GILBERT S. OMENN Dr. Omenn interpreted the title of this presentation in two ways: 1) How to interest R01 investigators in cancer prevention research? and 2) How can scientists do cancer prevention research through the R01 mechanism? Dr. Omenn outlined the context and challenges in this area: 1) not enough is known about the carcinogenic process in various cancer organ sites—research on biomarkers (including intermediate biomarkers), premalignant states, histopathology, and molecular studies is needed; 2) there is a need for greater clarification, coherency, and validation of chemopreventive agents—a stronger emphasis should be placed on hypothesis— driven research as opposed to the current cataloging of effects, perhaps through the establishment of expert groups; 3) certain pathway (e. g., lipid peroxidation, prostaglandin, and leukotriene) and organ system (e. g., lung, pancreas) targets require additional investigation; 4) more work is needed to identify candidate agents; and 5) a greater effort must be made to attract investigators to clinical studies—particularly public health studies. Dr. Omenn acknowledged that chemo— prevention studies have the attention of Dr. Varmus as well as outside constituency groups supportive of translational research. Regarding the DCP in particular, Dr. Omenn noted that there is currently a non-traditional mechanism for basic science R01s—the Chemoprevention Branch Agent Development Program—but that this approach was underutilized; greater emphasis on focus and depth, as opposed to breadth, is needed in agent development; and obtaining agents because of legal constraints is sometimes a problem. In terms of investments, Dr. Omenn suggested: 1) leaders in the field must be mobilized to characterize the nature of the field for others (i.e., What is cancer prevention and what are its boundaries?); 2) evidence of success in the field must be shown (i.e., What are examples (such as tamoxifen) of good prevention science? Where has prevention made a difference?); 3) strengthening of core facilities and service laboratories (i. e., genotyping, DNA sequencing, proteomics, instrumen- tation, and services are all expected by basic scientists); 4) valid and reproducible test systems need to be developed; 5) the NCI needs to coordinate extramural and contract activities to ensure that the entire system is functioning in the most effective manner (e. g., to minimize duplication of effort and other inefficiencies); 6) greater access to specimens and cells is needed; 7) priority for giving a specimen bank to others requires clarification, as do issues concerning quality and legal possession of the specimen bank; 8) there is a need for well-defined populations (e. g., patient registries); and 9) critical areas of basic science vital to prevention research include genetics, nutrition and metabolism, and pharmacology/ toxicology. Discussion Funding and study review. Regarding problems associated with agent development, Dr. D. Alberts noted that the contract mechanism is more cumbersome than the grant mechanism in terms of speed of protocol development and ability to begin research. Dr. Greenwald commented that both contract and grant mechanisms had issues associated with them (e. g, the number of Phase II trials brought to a sound conclusion is very small). Dr. Greenwald added that the restructuring of DCP was an effort to improve this situation, particularly regarding improved lines of communication. Dr. Omenn remarked that the review process for Phase II and III trials was tortuous and conflict exists because the review process discourages biomarker or other ancillary studies regarding important underlying biological events. Also, Dr. Omenn stated the need for an expert group that would guide the work and budget of Phase Hb and III trials, especially decisions concerning which trials would advance to Phase III, as well as determining what types of ancillary studies, biomarkers, hypotheses, and biological studies should be linked to the trials. Dr. D. Alberts remarked that one approach to increasing the prevention budget would be to stimulate R01 research in drug development, pharmacology, biomarker development, basic mechanisms, etc. through the use of workshops and other educational opportunities at cancer centers and universities. Dr. B. Alberts commented that he does not think the R01 mechanism was adequate for what was needed and suggested a DARPA-type mechanism as being a better approach. Dr. D. Alberts expressed some skepticism at inducing well—established basic scientists to enter prevention, but was more optimistic that postdoctoral basic scientists might do so. Dr. Omenn and Dr. Levin agreed that the postdoctoral scientists represented the more likely candidates. Ancillary studies/study design. Another point made by Dr. Omenn was that subjects recruited but who did not actually participate in a trial can and should be used as a pool for ancillary studies. Experienced investigators, commented Dr. Omenn, should be encouraged to educate other researchers regarding methods to construct clinical trials that would allow a greater amount of fundamental biological knowledge to be obtained from them. Dr. Greenwald stated that the emphasis on the cost of clinical trials, particularly large trials, often results in the abandonment of potentially important ancillary studies. One solution to this problem, proposed by Dr. Greenwald, was that of a large or large/ moderate trials budget as well as a trials—oriented review group that would, on a regular basis, examine the results of the past year’s trials and make decisions regarding future funding opportunities. Dr. Dunn stated the need for two parallel tracks for trial activities—the first involving trial design, the agent, and ancillary studies, and the second involving development of priorities for the next trial. Dr. Dunn also emphasized the importance of research involving potential biomarkers at an early stage in study development. Dr. Greenwald noted that potential trans—Institute research opportunities existed (e.g., with the National Heart, Lung, and Blood Institute (NHLBI) regarding folic acid) but there are sometimes impediments to such activities. Report of five Chemoprevention Implementation Group 41 VII. DISCUSSION/SUGGESTIONS FOR BUILDING INFECTIOUS AGENT CANCER PREVENTION INTO DCP—DR. DOUGLAS Lowv Dr. Lowy stated that the theme of molecular carcinogenesis has been the derangement of cellular genes and that the advantage when talking about infectious agents as etiological agents of cancer is that (these agents) are environmentally transmitted—therefore it is possible to eliminate them and thereby remove the risk of developing cancer. Moreover, in those instances where an infectious agent has been associated with cancer, the infection is normally benign and self—limited (z'.e., only a small subset of infected individuals eventually develop cancer). Further, identification of individuals at risk for the particular cancer provides pathogenetic knowledge regarding that particular cancer. Dr. Lowy identified two major classes of agents related to cancer development— direct (e.g., human papilloma virus (HPV)) and indirect (e.g., Helicobacterpylarz). The classification of other agents (e.g., hepatitis B (HBV)) remains uncertain. The inability of host defense mechanisms to remove the infectious agent is responsible for the cancer. Thus there are two methods, both involving vaccines, to combat infection: displace the existing infection or prevent the infection from occurring. Cellular (ag, the Pap smear) as well as infectious agent biomarkers may be used for purposes of diagnosis. Discussion Dr. Omenn remarked that immunization constituted the classic public health intervention and cited HBV immu— nization as having a dramatic impact against primary liver cancer in the world today. Using the work of Jenner on cowpox as an example, Dr. Omenn suggested that for cancer sites where infectious agents are thought to be involved, a strong program in vaccine development might be very beneficial. Dr. Dunn clarified that the DCP is in an extra— mural program whereas Dr. Lowy is in an intramural program—therefore funding for any suggested vaccine program would come from the former source. In fact, noted Dr. Dunn, Dr. Greenwald has formed a working group to develop plans for development of HPV vaccines. Dr. Lowy commented on the two broad classes of vaccines—preventive and therapeutic—and that gynecologic groups have been more oriented toward the latter. 42 National Cancer Institute 9 Division of Cancer Prevention Dr. Greenwald asked whether it would be logical to extend the CGAP to screen every tumor, tumor type, and precancer for viral and retroviral sequences. Dr. Sidranksy thought this an interesting question given the sporadic reports of virus particles identified in different tumor types not normally associated with viruses (e.g., colon tumors). A problematic issue in such an endeavor, noted by Dr. Sidransky, was whether the tumor was actively expressing its genes. Dr. Lowy thought that, to a large degree, that experiment has already been done (i.e., the observation of a particular type of cancer among immunologically suppressed persons would lead one to suspect the presence of an infectious agent). Dr. D. Alberts asked why an effort could not be made to identify a young person infected with HPV, with other risk factors for cervical cancer, and target such an individual for vaccine intervention. Dr. Omenn asked Dr. Lowy to define the epidemiologic and virologic criteria for preventive intervention. Dr. Lowy replied that, in the case of HPV, the majority of researchers consider genital HPV infection to behave as a sexually transmitted disease and, therefore, immunization prior to sexual exposure will prevent infection. Dr. Omenn commented that collaboration with Dr. Lowy’s laboratory was critical to the basic science activities of the DCP. More broadly, said Dr. Omenn, the DCP would benefit from formal collaboration and research workshops, and joint sponsorship of intra— and extramural activities with other basic and clinical science areas within the NCI. Dr. Levin suggested that inter—Institute collaborations would also be beneficial as well and cited an example of a recent workshop on premalignant lesions of the gastrointestinal tract given at the National Institute of Diabetes, Digestive, and Kidney Diseases (NIDDK). Dr. D. Alberts echoed the statements of Dr. Levin and Dr. Omenn and suggested that the development of an NIH—wide prevention consortium, involving basic science, might be an important objective. Dr. Greenwald commented that such a center might not receive adequate funding. Dr. D. Alberts remarked that there was an opportunity for DCP to take the lead in defining the role of prevention within the NIH—particularly regarding the interaction of prevention with basic science. Dr. Go inquired whether the Office of Disease Prevention was still functioning. Dr. Greenwald replied that it was but that it deals primarily with data compilation. Dr. Go stated that there was both an intra— and an extramural constituency for DCP to better define the role of prevention. Dr. Greenwald added that one method of testing interest in the area might involve the use of - teleconferences. Dr. Greenwald also noted that NCI staff are encouraged to work in laboratories or in clinics part—time in order to remain knowledgeable regarding different areas. Dr. Omenn suggested that the DCP be selective regarding its R01 funding initiatives for basic science so as to maximize the allocation of resources. ' VIII. DISCUSSION/SUGGESTIONS FOR STRENGTHENING BASIC CHEMDPREVENTION AND BIOMARKER RESEARCH IN DCP—— DR. DAVID SIDRANSKY Dr. Sidransky began by noting that there have been major advances in chemoprevention and biomarker research in the last few years. Dr. Sidransky commented that knowledge of basic mechanisms, including molecular pathogenesis studies, was critical to marker development. Molecular progression models—which some people consider too broad—are also critical to biomarker research, but Dr. Sidransky did not think that the CGAP was adequately addressing those issues (1'. a, most progression models have not been determined). Another area requiring additional work, cited by Dr. Sidransky, was that of universal markers. It is also necessary to be mindful of the limitations of markers (i.e., issues of sensitivity, specificity, and range of applicability). Dr. Sidransky identified three major areas for chemoprevention and biomarker research: 1) primary prevention/chemoprevention, 2) early detection, and 3) staging/ recurrence. And although certain biomarkers may be useful in more than one of the areas, the manner in which research is addressed within each of the areas can be quite different. Dr. Sidransky added that regular cellular mechanisms should not be neglected. Enthusiasm exists in this research area—this summer a conference will be held in Geneva, Switzerland—but there is a need for increased funding as well as a mechanism to ensure that the best research receives funds. Dr. Sidransky cited the EDRN as a good model for vertical integration but stated that the program project was also a good mechanism because of its multidisciplinary approach. Discussion Dr. Fischer commented that she agreed with Dr. Sidransky’s remarks and added that funding was one of the major problems for this area: the R01 process often is not an effective review mechanism, funding difficulties are particularly discouraging to young investigators, and innovative funding opportunities for this area of research may be warranted. Dr. D. Alberts agreed with Dr. Sidransky’s comments regarding the importance of studies involving universal markers. Dr. Kopelovich commented that when speaking of biomarkers, it is important to distinguish between the contexts of prevention or diagnosis—biomarkers for at—risk populations are critical to prevention efforts. Dr. D. Alberts noted that more research is needed in the examination of biomarkers that may exist in the carcinogenic pathway and agreed that the program project was a desirable funding mechanism for such work. Dr. Srivastava commented that the NIH will host a conference on April 14—15, 1999, on biomarkers—about 600 participants are expected, it is not cancer-specific, and more information is available on the Web. Dr. D. Alberts also commented that research in this area is exciting because it can lead into many potential areas: it can remain very basic (e. g, defining the biomarker and its role in the pathway), the biomarker can be examined as a diagnostic and modulatable tool, etc. IX. DISCUSSION/SUGGESTIONS FOR STRENGTHENING CANCER PREVENTION SCIENCE AT CANCER CENTERS—DR. DAVID ALBERTS Dr. D. Alberts began by noting the difficulties of basic scientists housed in cancer centers in doing prevention or translational research: 1) peer review is by basic science faculty and translational research and requires a more specialized review process; 2) emphasis is placed on publishing in basic science journals; and 3) physical research space is often limited. As solutions to these and related issues, Dr. D. Alberts offered the following: 1) training grants for basic scientists (postdoctoral and other) allowing them to become familiar with epidemiology, nutritional science, clinical pharmacology, and other prevention—related sciences; 2) RFAs for basic scientists interested in clinical research (e. g., researchers interested in endpoint biomarkers, chemoprevention agent development) including stimulation of collaborative research in cancer centers and medical schools through basic science— driven program project grant RFAs; 3) intellectual (e.g., retreats, seminars, courses; NIH/NCI—sponsored videoconferences) and financial incentives to participate in translational research; 4) development of basic science infrastructure through P30 cancer center core grant supplements; and 5) development of RFAs for analytical chemistry and molecular biology core service laboratories— particularly for the purpose of enhancement of quality control. Discussion Dr. Fischer remarked that a video conference series on DNA repair occurs monthly, and a similar event could deal with prevention. Dr. D. Alberts noted that this would be an efficient mechanism for involving young people in the field. Dr. Sidransky added that the AACR sponsors a molecular biology conference in Aspen, Colorado, for young researchers—a similar effort (perhaps cosponsored with the AACR) in molecular epidemiology or biomarkers should be considered. Comments were made that the time to develop and fund program projects was too long. Dr. Greenwald asked to what degree the EDM met the need for quality control. Dr. Levin replied that, as conceived, biomarker validation involves rigorous quality assurance methodology and standards. Further, the National Institute of Standards and Technology (NIST) may play a helpful role, but the NCI will be the (ultimate) judge of the quality of applicants. Report oft/7e C/Jemoprevemion Implementation Group 43 Dr. Greenwald further inquired whether a sufficient priority has been given to quality control issues. Drs. Levin, Srivastava, and Sidransky all agreed that the EDRN effort needed additional funding and that more expertise may be needed at individual laboratories. Dr. Greenwald asked whether there is a need for a collaborative effort with NIST to strengthen standardization and quality control activities. Dr. Lowy reiterated the need for quality control of biomarkers, citing the lack of quality control in the detection of HPV infection during the 19805 as an example of what may occur when such standards are lacking. Dr. Go and Dr. Srivastava supported this idea, and Dr. Sidransky thought it worthy of future consideration. Dr. Levin expressed the need for horizontal working groups at cancer centers where basic scientists collaborate with clinical scientists. Dr. Levin reported that in his capacity as chairman of the ad 1706 committee of the Directors of Prevention of the American Society for Preventive Oncology (ASPO), he will survey comprehensive cancer centers regarding the support available to core laboratories collaborating with prevention activities. This survey, said Dr. Levin, will provide the NCI with feedback regarding field activities since core laboratory support is important for basic science issues and cancer center development. Dr. Go commented that his experience is that core laboratories are underfunded. X. DISCUSSION/SUGGESTIONS FOR STRENGTHENING TRAINING AND CAREER DEVELOPMENT IN CANCER PREVENTION RESEARCH—DR. BERNARD LEVIN Dr. Levin began by focusing attention on the problems associated with the recruitment of postdoctoral researchers into prevention (e.g., low salaries, little encouragement regarding career development, lack of the multidisciplinary knowledge needed to conduct prevention research). Possible solutions to these problems, noted by Dr Levin, included: 1) encouragement of grant applicants to include pre— and postdoctoral fellow positions within the list of funded personnel, 2) encouragement of travel opportunities to prevention meetings, and 3) support of P13 with prevention— related grants to send their postdoctoral students and fellows to special research design workshops (tag, those sponsored by AACR, ASPO, and the American Association for Cancer Education). Dr. Levin also discussed the need to educate current Principal Investigators and basic science department chairs through NCI training grants, career development awards, and K07, K22, K23, and K24 awards, and the establishment of two— to four—week mini—sabbaticals at NCI for young scientists. 44 National Cancer Institute 9 Division of Cancer Prevention Discussion Dr. Go and Dr. Levin commented on the difficulty of recruiting faculty into prevention research, both to do research and to teach the field. Dr. Levin added that top— down leadership is required to foster development of such individuals. Dr. G0 stated another problem: there are not enough available positions for individuals once they have completed their postdoctoral training (116., there are an insufficient number of prevention research opportunities available to postdoctoral students completing their training). As a corollary, Dr. Fischer noted that it is often difficult to get people to train in prevention because they realize there are few opportunities available to them once they complete their training. Dr. Levin suggested a possible solution to this problem: enhancement of prevention programs within cancer centers, resulting in the establishment of permanent faculty positions. Dr. D. Alberts remarked that he sees the long—term penetration of basic science into prevention as being the greatest challenge to advancement of the field. This effort, stated Dr. D. Alberts, requires a bottom—up approach. Dr. D. Alberts recommended that the BSIS reconvene at a future date to further discuss and analyze issues. Dr. Greenwald asked if most of the members could participate in a future meeting via videoconference. The majority said they could. Dr. Kopelovich suggested that future meetings of the implementation committees would permit greater cross-representation of members in an effort to maximize the exchange of ideas (ag, NCI personnel in chemoprevention should attend the next meeting of the CIG). Dr. Co also commented that greater cross—communication among the various implementation groups would be beneficial to all. Dr. D. Alberts remarked that videoconferences might be a useful forum for such an effort. Dr. Omenn stated that he saw the role of the DCP as serving as a link between cancer biology and clinical research. Dr. B. Alberts suggested that the Markey board model, which provides senior postdoctoral students with two years of support plus three years of faculty support, might be helpful in resolving some of the training and support issues noted throughout the discussion. Dr. Levin asked whether the Institute of Medicine (IOM) has an interest in prevention research. Dr. B. Alberts answered that he could not speak for the IOM. Dr. Greenwald suggested that the NCAB might be interested in this issue, and Dr. Levin agreed. XI. ADJOURNMENT—DR. DAVID S. ALBERTS Dr. D. Alberts thanked Dr. B. Alberts for allowing the BSIS meeting to take place at the NAS. There being no further business, the meeting of the B515 was adjourned at 4:22 pm. on Thursday, January 21, 1999. Dr. David S. Alberts, Chairperson Dr. Peter Greenwald, Co—Chairperson National Cancer Institute Division of Cancer Prevention Chemoprevention Implementation Group SUBCOMMITTEE FOR BASIC SCIENCE Roster David S. Alberts, MD (Chair) Associate Dean for Research Arizona Cancer Center, College of Medicine University of Arizona Peter Greenwald, MD, DrPH (Co—Chair) Director, Division of Cancer Prevention National Cancer Institute Bruce Alberts, PhD President National Academy of Sciences Susan M. Fischer, PhD Professor of Carcinogenesis (Biochemistry) University of Texas, M.D. Anderson Cancer Center— Science Park Vay Liang W Go, MD Associate Director UCLA Center for Human Nutrition Bernard Levin, MD Vice President for Cancer Prevention University of Texas, M.D. Anderson Cancer Center Gilbert S. Omenn, MD, PhD Executive Vice President for Medical Affairs University of Michigan Jill Pelling, PhD Professor Department of Pathology University of Kansas Medical Center David Sidransky, MD Otolaryngology/ Head and Neck Cancer Res. Johns Hopkins University Vernon R. Young, PhD, DSc. Professor Nutritional Biochemistry NCI Program Staff Participants Iqbal Ali, PhD Program Director Basic Science Research Group Division of Cancer Prevention Carolyn K. Clifford, PhD Acting Chief Nutritional Science Research Group Division of Cancer Prevention Barbara Dunn, MD, PhD Program Director Basic Science Research Group Division of Cancer Prevention Levy Kopelovich, PhD Program Director Chemopreventive Agent Development Research Group Division of Cancer Prevention Douglas Lowy, MD Deputy Director Division of Basic Science Ron Lubet, PhD Program Director Chemopreventive Agent Development Research Group Division of Cancer Prevention Sudhir Srivastava, PhD Acting Chief Cancer Biomarkers Research Group Division of Cancer Prevention Report oft/7e Chemoprevention Implementation Group 45 “$39 33? W M ,mmmwggmm swung" 3mm fi 9mm: “fl IONAL mm 1 TITUTE — October 1999 T419 U. C. BERKELEY UBRANEi‘ rcnvnvuuavm