Recent advances in elucidating the molecular defects underlying prostate carcinogenesis provide a foundation for the molecular targeting of defective cellular pathways with novel agents that will prevent or delay progression of this disease. Our laboratory has developed small-molecule, orally bioavailable inhibitors of two clinically relevant targets of prostate cancer initiation and progression: Akt signaling and Bcl-xL/Bcl-2. Our mechanistic studies of the anticancer effects of celecoxib and troglitazone revealed that their apoptosis-inducing actions are independent of their well-known pharmacological activities (COX-2 inhibition and PPAR? activation). Subsequent structural optimization of celecoxib and troglitazone generated novel analogues devoid of COX-2 inhibitory and PPAR? activating effects, but possessing potent inhibitory effects on Akt signaling and Bcl-2/Bcl-xL functions, respectively. We hypothesize that Akt signaling and Bcl-2/Bcl-xL functions represent clinically relevant targets for prostate cancer prevention. Moreover, we postulate that the relationship between Akt and Bcl-2/Bcl-xL in modulating apoptosis can be exploited with the combination of Akt- and Bcl-2/Bcl-xL-targeted agents to induce mechanistic synergy in the prevention of prostate carcinogenesis. The proposed studies will address these hypotheses through the use of an established model of prostate carcinogenesis to achieve the following Specific Aims. 1) To demonstrate that the novel Akt signaling inhibitor OSU-03012 inhibits prostate carcinogenesis in the NMU and TRAMP models. 2) To perform structural optimization of troglitazone-derived Bcl-2/Bcl-xL binding inhibitors through contemporary medicinal chemistry techniques and to further characterize mechanisms. 3) To demonstrate the in vivo chemopreventive efficacy of troglitazone-derived Bcl-2/Bcl-xL inhibitors and to exploit the mechanistic synergy between Akt inhibition and Bcl-2/Bcl-xL inhibition in prostate carcinogenesis. These studies represent the first translation of our in vitro observations to an in vivo model of prostate cancer prevention. Endpoints of tumor incidence will be complemented by examination of biomarkers that will provide in vivo correlations for the activities and mechanisms established in our in vitro studies. We expect the proposed studies to yield data in support of our hypothesis and to serve as a critical step in developing new approaches to prostate cancer prevention. ? ?
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