Targeting Akt and Bcl-2 in Prostate Cancer Prevention

描述(由申请人提供)：在阐明前列腺癌发生的分子缺陷方面的最新进展，为用新型药物以缺陷细胞通路为分子靶点提供了基础，这些药物将防止或延缓前列腺癌的进展。我们的实验室已经针对前列腺癌发生和发展的两个临床相关靶点：AKT信号转导和Bclxl/Bcl2，开发了小分子口服生物利用型抑制剂。我们对塞来昔布和曲格列酮抗肿瘤作用的机制研究表明，它们诱导细胞凋亡的作用不依赖于它们众所周知的药理活性(COX-2抑制和PPAR？激活)。塞来昔布和曲格列酮随后的结构优化产生了新的类似物，没有COX-2抑制和PPAR？对Akt信号转导和Bcl2/Bclxl功能有较强的抑制作用。我们假设Akt信号和Bcl2/Bclxl功能代表了前列腺癌预防的临床相关靶点。此外，我们推测Akt和Bcl2/Bclxl靶向药物联合应用可在前列腺癌的发生中发挥机制协同作用，从而发挥Akt与Bcl2/Bclxl调控细胞凋亡的关系。拟议的研究将通过使用已建立的前列腺癌发生模型来解决这些假设，以实现以下特定目标。1)研究AKT信号转导抑制剂OSU-03012对NMU和TRAMP模型前列腺癌的抑制作用。2)利用现代药物化学技术对曲格列酮衍生的Bcl2/Bclxl结合抑制剂进行结构优化，并进一步研究其作用机制。3)验证曲格列酮衍生的Bcl2/Bclxl抑制剂的体内化学预防效果，探讨Akt抑制与Bcl2/Bclxl抑制在前列腺癌发生中的机制协同作用。这些研究首次将我们的体外观察转化为前列腺癌预防的体内模型。肿瘤发病率的终点将通过检测生物标志物来补充，这些生物标志物将为我们的体外研究中建立的活动和机制提供体内相关性。我们期望拟议的研究将产生支持我们的假设的数据，并作为开发前列腺癌预防新方法的关键一步。

DESCRIPTION (provided by applicant): 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.