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NATIONAL INSTITUTES OF HEALTH
National Cancer Institute, Division of Cancer Prevention

New Directions for Chemoprevention Research at the National Cancer Institute
Report of the Chemoprevention Implementation Group September 1999: Executive Summary

ExecutiveSummary
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.¹ 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 selenium 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 Programs.
Provide focus and support for basic science research in chemoprevention-e.g., 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 Effort.
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 Infrastructure 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.

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.

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.
• 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 Chemoprevention 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

• 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.
• 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

Fisher, B., Costantino, J.P., Wickerham, D.L., Redmond, C.K., Kavanah,M., Cronin, WM., Vogel, V., Robidoux, A., Dimstrov, N., Atkins, J., Daly, M., Wieand, S., 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-1 Study.J Natl.Cancer Inst. 90: 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. Congr. Ser. 1120: 249-254, 1996.

Heinonen, OP., Albanes, D., Virtamo, J., Taylor, P.R., Huttunen, J.K.,Hartman, A.M., Haapakoski, J., Malila, N., Rautalahti, M., Ripatti, S., Maenpaa, H., Teerenhovi, L., Koss, L., Virolainen, M., and Edwards, B.K. Prostate cancer and supplementation with 4-tocopherol and ß-carotene: Incidence and mortality in a controlled trial. J. Natl. Cancer Inst. 90: 440-446, 1998.

Clark, L.C., Dalkin, B., Krongrad, A., Combs, G.E Jr., Turnbull, B.W., Slate, E.H., Witherington, R., Herlong, J.H., Janosko, E., Carpenter, D., Borosso, C., Falk, S., and Rounder J. Decreased incidence of prostate cancer with selenium supplementation: Results of a double-blind cancer prevention trial. Br. J. Urol. 81: 730-734, 1998.

For the complete implementation report, see
http://dcp.nci.nih.gov

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