This project is aimed at conducting seminal translational research to develop a new class of molecularly targeted agents for prostate cancer prevention. These agents were developed in the Pl's laboratory by using celecoxib as a molecular starting point via computer modeling-based structural analysis, of which the rationale is multifold. First, the ability of celecoxib and its novel derivatives to arrest cell cycle, activate apoptosis, and inhibit angiogenesis is independent of COX-2 inhibition, and is primarily attributable to the inhibition of phosphoinositide-dependent kinase-1 (PDK-1)/Akt signaling. The apoptosis induction in prostate cancer cells is irrespective of androgen dependency, p53 functional status, and Bcl-2 expression levels. Second, PDK-1/Akt signaling is constitutively activated in prostate tumors, and its dysregulation furnishes a mechanism whereby prostate tumor cells withstand the withdrawal of survival factors, and develop an androgen-independent phenotype. The biological importance of this signaling pathway in carcinogenesis provides a molecular rationale to justify its inhibition as a viable approach to prostate cancer prevention. Third, these agents can be orally dosed, and have manageable toxicological profiles compatible with chronic treatment. We hypothesize that the PDK-1/Akt signaling inhibitor administered at doses providing serum concentrations of 5-10 microM will result in preventing the onset of prostate cancer or delaying the progression of carcinogenesis. This proposal consists of two specific aims, of which the results will provide a strong rationale for our long-term goal to develop novel molecularly targeted chemopreventive agents. The first specific aim is to assess the chemopreventive efficacy of OSU-02067, a structurally optimized derivative in inhibiting PDK-1/Akt signaling with no COX-2 activity, in the N-methyI-N-nitrosourea androgen induced model of prostate carcinogenesis in Wistar-Unilever rats. The second specific aim is to assess the chemopreventive effect of OSU-01010 to addrerss the issue of whether concurrent inhibition of COX-2 and PDK-1/Akt signaling will provide a synergistic effect on chemoprevention. OSU-01010 is a dual function derivative that displays enahnced inhibitory activities against both COX-2 and PDK-1/Akt signaling as compared to celecoxib. In parallel, we will examine the safety of chronic oral treatment with these compounds in non-carcinogen-treated tumor-free animals.
| Sargeant, Aaron M; Klein, Russell D; Rengel, Robert C et al. (2007) Chemopreventive and bioenergetic signaling effects of PDK1/Akt pathway inhibition in a transgenic mouse model of prostate cancer. Toxicol Pathol 35:549-61 |
