Preclinical chemopreventive agent development.

PL04-01

The Chemopreventive Agent Development Program of the Division of Cancer Prevention, NCI has established a systematic research and development program to identify, develop, and qualify potential cancer preventive agents for clinical trials. The preclinical stages of the program encompass processes to identify potential agents and molecular targets, in vitro screening and in vivo efficacy and intermediate endpoint testing, pharmacology/toxicology assessments, and agent chemistry/formulation. The methods of agent identification have been similar to those used by industry, as noted by Lipinski et al. (1) when he introduced the "rule of 5" characterizing bioavailable drugs. Increasing knowledge of the molecular biology of cancer and developments in cheminformatic databases now provide large numbers of potential agents, molecular targets, and their combinations for possible testing. The Initiative for Chemical Genetics, sponsored by the NCI (2) and the Molecular Libraries Screening Centers Network, part of the NIH Roadmap for Medical Research (3) are evaluating and making large chemical libraries and molecular target screening technologies available to investigators, in addition to libraries that are commercially available (e.g., ChemDiv Inc.). The extent to which the genome/proteome is "druggable" is a subject of discussion in medicinal chemistry literature (4,5). These advances provide opportunities and challenges for current preclinical approaches to optimize agent identification and screening and to accelerate traditional development safely and efficiently. One pragmatic approach, emerging as a niche in the pharmaceutical sector (6), is "repurposing" approved agents or agents with substantial prior development. The evaluation of statins for cancer prevention, at lower doses and in combinations with other agents (NSAIDs), is an example. Another approach involves using quantitative structure activity relationships (QSAR) and predictive toxicology modeling of potential agents as early filters for agent selection (7). Both the evaluation of approved agents, especially in combinations, and the use of screening algorithms for chemical and biological space are being incorporated into the program. The developing field of systems biology modeling, applied to pharmacology (8), is also beginning to provide computational approaches, particularly to address developing combinations of agents (9). In addition, new in vitro phenotypic and mechanism based models using human cells are being evaluated and molecular endpoints are being incorporated into established, validated, phenotypic screens. New techniques and models for efficacy and safety testing may also increase preclinical agent development efficiency. The role of the exploratory IND in prevention research will likely be addressed on a case by case basis. Whether implemented as medical interventions in high risk subjects; dietary, lifestyle, and supplement recommendations to population subsets; or changes in screening algorithms, the continued government commitment to cancer prevention promises to reduce significantly the economic, social, and medical burden of cancer. References 1. Lipinsky, C. et al. Advanced Drug Delivery Rev. 23: 3-25, 1997. 2. Tolliday, N. et al. Cancer Res. 66: 8935-8942, 2006. 3. Inglese, J. et al. PNAS 103: 11473-11478, 2006. 4. Keller T.H. et al. Current Opin. Chem. Biol. 10: 357-61, 2006. 5. Kubinyi, H. Nature Drug Discovery 2: 665-8, 2006. 6. O'Connor, K.A. and Roth, B.L. Nature Drug Discovery 4: 1005-1014, 2005. 7. Contrera, J.F. et al. Current Drug Discovery Technol. 2: 55-67, 2005. 8. Fitzgerald, J. et al. Nature Chem. Biol. 2: 458-66, 2006. 9. Keith, C.T. et al. Nature Drug Discovery 4: 1-8, 2005.