The main objective of this application is to seek full support for me to become an independent investigator in the field of cancer prevention. Two primary goals are: (1) to establish my career as an independent researcher in the field of cancer prevention, and (2) to make a research contribution in developing useful new agents for chemoprevention, based on understanding their mechanisms of action. My short-term goals involve the design of new agents, studying mechanisms of action of these new agents, and investigating new agents in preclinical studies. Collaborators from Dartmouth Medical School, Dartmouth College, and Norris Cotton Cancer Center, as well as a distinguished group of consultants, will help me to widen the breadth and increase the depth of my knowledge in the field of cancer prevention areas as diverse as organic chemistry, advanced molecular biology, pathology, and clinical study design. The immediate research plan proposed here has three Specific Aims: 1) to elucidate structure-activity relationships of new synthetic triterpenoids in my molecular biology laboratory; 2) to study molecular and cellular mechanisms of action of new chemopreventive agents. Based on preliminary studies with triterpenoids, specific molecular targets will be investigated as follows: inflammatory genes such as iNOS and COX-2, specific nuclear receptors, such as PPAR-gamma and its associated co-activators and co-repressors, and the TGF-beta receptor and Smad signaling system; and 3) to evaluate new chemopreventive agents in animal models relevant to human disease. Such studies will lead to the most effective clinical translation of my work. New chemopreventive agents will be tested in two models of breast cancer, namely ER positive (NMU-induced breast cancer model in rats) and ER negative (a transgenic mouse model), as well as the azoxymethane-induced colon cancer model in rats. Thus, the short-term goal of my research is to develop new chemopreventive agents whose use can be clinically validated. My long-term goal is to become an independent investigator who can contribute to the entire process of making basic scientific knowledge effective in preventing cancer in men and women.
