Chemoprevention with mTOR & Farnesyltransferase Inhibitors

雷帕霉素对小鼠和人肺癌细胞的生长均有抑制作用。FTI 使用化学预防和治疗方法对肺癌的发生有显著的效果 A/J小鼠的实验方案。最近的研究将雷帕霉素(MTOR)和Rheb的哺乳动物靶标联系在一起 (富含大脑的RAS同源物，FTI的靶点)一起作为TSC-Rheb-mTOR的关键组件 路径。我们假设雷帕霉素和FTI是突变肺中有效的化学预防药物。 肿瘤模型及雷帕霉素和FTI的联合应用将在 肺癌的化学预防。具体目标包括：(1)评价雷帕霉素和FTI的疗效 转基因小鼠肺癌模型中肺腺癌发生的研究 人类肺癌常见的变化；(2)检查化学预防效果 雷帕霉素和FTI对TSC基因敲除小鼠肿瘤的抑制作用；(3)探讨雷帕霉素的作用机制 雷帕霉素和FTI对小鼠肺癌的化学预防作用。这项建议是及时和 重要的原因有以下几点。首先，mTOR抑制剂和FTI的临床化学预防试验 抗肺癌将需要对其疗效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)将用于 这项提议。其次，我们将使用一种新开发的突变小鼠肺肿瘤模型，该模型共享 组织病理学特征和遗传改变(激活的癌基因和失活的肿瘤 抑制物)在人类肺腺癌发生过程中观察到。第三，我们将全面开展 动物生物试验，以测试雷帕霉素+FTI的组合有效性，以显著增加 这些药物在预防肺癌方面的有效性和降低潜在毒性。由此产生的结果是 提案将提供关于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，这项提议将提供一个坚实的 MTOR抑制剂和FTI作为肺癌化学预防药物的临床试验基础。

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.