Chemoprevention with mTOR & Farnesyltransferase Inhibitors

描述(申请人提供)：雷帕霉素对抑制鼠和人肺癌细胞的生长都有效。FTI在A/J小鼠中使用化学预防和治疗方案显示出显著的抑制肺癌发生的效果。最近的研究将哺乳动物靶标雷帕霉素(MTOR)和Rheb(富含于脑中的Ras同源，FTI的靶标)联系在一起，作为TSC-Rheb-mTOR途径的关键组成部分。我们假设在突变肺癌模型中，雷帕霉素和FTI是有效的化学预防药物，而雷帕霉素和FTI的组合在肺癌的化学预防中将具有协同作用。具体目的包括：(1)在人肺癌基因突变的转基因小鼠肺癌模型上，评价雷帕霉素和FTI对肺腺癌发生的影响；(2)检测雷帕霉素和FTI对TSC基因敲除小鼠肺癌的化学预防作用；(3)研究雷帕霉素和FTI对小鼠肺癌的化学预防作用。由于以下原因，这项提议是及时和重要的。首先，针对肺癌的mTOR抑制剂和FTI的临床化学预防试验将需要对其有效性和机制进行积极的临床前表征(S)。特别是，临床相关化合物(雷帕霉素的CCI-779和FTI的R115777)将在该提案中使用。其次，我们将使用新开发的突变小鼠肺肿瘤模型，该模型既有组织病理学特征，也有人类肺腺癌发生过程中观察到的遗传变化(激活的癌基因和失活的肿瘤抑制基因)。第三，我们将进行全面的动物生物测试，以测试雷帕霉素FTI的联合疗效，以显著提高这些药物在预防肺癌方面的疗效并降低潜在的毒性。这项研究的结果将为mTOR抑制剂和FTI如何在小鼠肺肿瘤发生过程中协同影响mTOR信号通路提供重要的见解。此外，这一建议将为mTOR抑制剂和FTI作为肺癌化学预防药物的临床试验提供坚实的基础。

DESCRIPTION (provided by applicant): Rapamycin is effective in inhibiting the growth of both mouse and human lung cancer cells. FTI exhibited a significant efficacy against lung tumorigenesis using both chemopreventive and therapeutic protocols in A/J mice. Recent studies have linked the mammalian target of rapamycin (mTOR) and Rheb (Ras homology enriched in brain, a target of FTI) together as key components of the TSC-Rheb-mTOR pathway. We hypothesize that rapamycin and FTI are potent chemopreventive agents in a mutant lung cancer model and the combination of rapamycin and FTI will have a synergistic effect in chemoprevention of lung cancer. Specific aims include: (1) To evaluate the effect of rapamycin and FTI on lung adenocarcinoma carcinogenesis in a transgenic mouse lung carcinoma model with genetic changes commonly seen in human lung cancers; (2) To examine the chemopreventive efficacy of rapamycin and FTI against tumorigenesis in TSC knockout mice; (3) To investigate the mechanism of rapamycin and FTI's chemopreventive efficacy against lung cancer in mice. This proposal is timely and significant for the following reasons. Firstly, clinical chemoprevention trials of mTOR inhibitor and FTI against lung cancer will require vigorous preclinical characterizations of their efficacy and mechanism(s). In particular, clinical relevant compounds (CCI-779 for rapamycin and R115777 for FTI) will be used in this proposal. Secondly, we will use a newly developed mutant mouse lung tumor model, which shares both histopathological features and genetic alterations (activated oncogenes and inactivated tumor suppressors) observed in human lung adenocarcinogenesis. And thirdly, we will conduct comprehensive animal bioassays to test the combinatorial efficacy of rapamycin + FTI to significantly increase the efficacy and lowering potential toxicity of these agents in preventing lung cancer. The results from this proposal will provide significant insights on how mTOR inhibitor and FTI synergistically affect the mTOR signaling pathway during mouse lung tumorigenesis. In addition, this proposal will provide a solid foundation for clinical trials of mTOR inhibitor and FTI as lung cancer chemopreventive agents.