Chemoprevention with mTOR & Farnesyltransferase Inhibitors

mTOR 化学预防

• 批准号: 7048765
• 负责人: MING YOU
• 金额: $ 28.4万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-08 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7048765
• 关键词: alkyltransferase; chemoprevention; lung; neoplasm /cancer

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.

描述（申请人提供）：雷帕霉素可有效抑制小鼠和人类肺癌细胞的生长。在 A/J 小鼠中使用化学预防和治疗方案时，FTI 对肺部肿瘤发生表现出显着的功效。最近的研究将哺乳动物雷帕霉素靶点 (mTOR) 和 Rheb（大脑中富集的 Ras 同源性，FTI 的靶点）联系在一起，作为 TSC-Rheb-mTOR 通路的关键组成部分。我们假设雷帕霉素和FTI是突变型肺癌模型中有效的化学预防剂，并且雷帕霉素和FTI的组合将在肺癌的化学预防中产生协同作用。具体目标包括：（1）在具有人类肺癌常见基因改变的转基因小鼠肺癌模型中评估雷帕霉素和FTI对肺腺癌癌变的影响； (2) 考察雷帕霉素和FTI对TSC敲除小鼠肿瘤发生的化学预防作用； (3)探讨雷帕霉素和FTI对小鼠肺癌化学预防作用的机制。由于以下原因，该建议是及时且重要的。首先，mTOR 抑制剂和 FTI 对抗肺癌的临床化学预防试验需要对其功效和机制进行强有力的临床前表征。特别是，本提案将使用临床相关化合物（雷帕霉素的 CCI-779 和 FTI 的 R115777）。其次，我们将使用新开发的突变小鼠肺肿瘤模型，该模型具有在人类肺腺癌发生过程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测定，以测试雷帕霉素+FTI的组合功效，以显着提高这些药物预防肺癌的功效并降低潜在毒性。该提案的结果将为 mTOR 抑制剂和 FTI 如何协同影响小鼠肺部肿瘤发生过程中的 mTOR 信号通路提供重要见解。此外，该提案将为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。