Chemoprevention with mTOR & Farnesyltransferase Inhibitors

描述（由申请人提供）：雷帕霉素对小鼠和人肺癌细胞的生长均有抑制作用。在a /J小鼠中，FTI在化学预防和治疗两种方案下均对肺肿瘤发生有显著的抑制作用。最近的研究将哺乳动物雷帕霉素靶点（mTOR）和Rheb（在大脑中富集的Ras同源物，FTI的靶点）联系在一起，作为TSC-Rheb-mTOR途径的关键成分。我们假设雷帕霉素和FTI在突变型肺癌模型中是有效的化学预防药物，雷帕霉素和FTI联合使用将在肺癌的化学预防中产生协同作用。具体目的包括：(1)评价雷帕霉素和FTI对具有人类肺癌常见基因改变的转基因小鼠肺癌模型中肺腺癌发生的影响；(2)探讨雷帕霉素和FTI对TSC基因敲除小鼠肿瘤发生的化学预防作用；(3)探讨雷帕霉素和FTI对小鼠肺癌的化学预防作用机制。这一建议是及时和重要的，原因如下。首先，mTOR抑制剂和FTI对肺癌的临床化学预防试验将需要对其疗效和机制进行强有力的临床前表征。特别是临床相关的化合物（CCI-779用于雷帕霉素和R115777用于FTI）将在本提案中使用。其次，我们将使用新开发的突变小鼠肺肿瘤模型，该模型具有人类肺腺癌发生中观察到的组织病理学特征和遗传改变（激活的癌基因和灭活的肿瘤抑制基因）。第三，我们将进行全面的动物生物试验，检测雷帕霉素+ FTI的联合疗效，显著提高这些药物预防肺癌的疗效，降低潜在毒性。该提案的结果将为mTOR抑制剂和FTI如何协同影响小鼠肺肿瘤发生过程中的mTOR信号通路提供重要见解。为mTOR抑制剂和FTI作为肺癌化学预防药物的临床试验提供了坚实的基础。

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.