Chemoprevention with mTOR & Farnesyltransferase Inhibitors

雷帕霉素在抑制小鼠和人肺癌细胞的生长方面是有效的。FTI 使用化学预防性和治疗性药物， 在A/J小鼠中的实验方案。最近的研究已经将雷帕霉素的哺乳动物靶标（mTOR）和Rheb (Ras在脑中富集的同源性，FTI的靶标）一起作为TSC-Rheb-mTOR的关键组分 通路我们假设雷帕霉素和FTI是突变肺的有效化学预防剂 在癌症模型中，雷帕霉素和FTI的组合将具有协同作用， 肺癌的化学预防具体目的包括：（1）评价雷帕霉素和FTI的作用 在转基因小鼠肺癌模型中对肺腺癌癌变的影响 （2）检测人肺癌中常见的化学预防效果 雷帕霉素和FTI对TSC基因敲除小鼠肿瘤发生的抑制作用;（3）探讨雷帕霉素和FTI对TSC基因敲除小鼠肿瘤发生的作用机制。 雷帕霉素和FTI对小鼠肺癌的化学预防功效。这一建议是及时的， 重要的原因如下。首先，mTOR抑制剂和FTI的临床化学预防试验 抗肺癌的药物将需要对其功效和机制进行有力的临床前表征。 特别地，临床相关化合物（用于雷帕霉素的CCI-779和用于FTI的R115777）将用于 这个提议。其次，我们将使用一种新开发的突变小鼠肺肿瘤模型， 组织病理学特征和遗传学改变（激活的癌基因和灭活的肿瘤 抑制因子）。第三，我们将全面 动物生物测定以测试雷帕霉素+ FTI的组合功效，以显著增加 这些药物在预防肺癌中的有效性和降低潜在毒性。结果是 该提案将提供有关mTOR抑制剂和FTI如何协同影响mTOR的重要见解 小鼠肺肿瘤发生过程中的信号通路。此外，该提案将提供一个坚实的 为mTOR抑制剂和FTI作为肺癌化学预防剂的临床试验奠定基础。

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 histopathologicalfeatures 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.