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，为用新型药物靶向缺陷细胞通路提供了基础，这些药物将预防或延缓这种疾病的进展。我们的实验室已经开发了小分子，口服生物可利用的抑制剂，用于前列腺癌发生和进展的两个临床相关靶点：Akt信号传导和Bcl-xL/Bcl-2。我们对塞来昔布和曲格列酮抗癌作用的机制研究表明，它们的细胞凋亡诱导作用独立于它们众所周知的药理活性(COX-2抑制和PPAR？激活)。随后，塞来昔布和曲格列酮的结构优化产生了新的类似物，不具有COX-2抑制和PPAR？激活作用，但对Akt信号和Bcl-2/Bcl-xL功能分别具有强抑制作用。我们假设Akt信号和Bcl-2/Bcl-xL功能是前列腺癌预防的临床相关靶点。此外，我们推测Akt和Bcl-2/Bcl-xL在调节细胞凋亡中的关系可以通过Akt-和Bcl-2/Bcl-xL靶向药物联合使用来诱导机制协同作用，从而预防前列腺癌的发生。本研究将通过使用已建立的前列腺癌模型来解决这些假设，以实现以下具体目标：1)证明新型Akt信号抑制剂OSU-03012在NMU和TRAMP模型中抑制前列腺癌的发生。2)利用现代药物化学技术对曲格列酮衍生的Bcl-2/Bcl-xL结合抑制剂进行结构优化，并进一步表征作用机制。3)验证曲格列酮类Bcl-2/Bcl-xL抑制剂的体内化学预防作用，探索Akt抑制与Bcl-2/Bcl-xL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查生物标志物来补充，这些生物标志物将为我们在体外研究中建立的活性和机制提供体内相关性。我们期望所提出的研究能够产生支持我们假设的数据，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.