Immune aspects of mTOR inhibition for cancer prevention (PQ5)

描述（由申请人提供）：本申请将定义雷帕霉素介导的肿瘤发病延迟或预防机制，并将剖析mTOR对肿瘤和免疫细胞的直接影响。它解决了具有争议的问题5：确定用于其他目的的药物的作用机制。我们挑战mTOR抑制通过mTOR生长和代谢作用直接作用于肿瘤来减少或预防癌症的范式，并探索mTOR抑制剂通过mTOR介导的免疫作用来预防癌症的潜力。我们假设口服雷帕霉素抑制mTOR在一定程度上通过免疫机制延迟或预防癌症的发生，并将在一个明确的致癌物质诱导的皮肤癌模型中测试概念，其中T细胞和IFN-¿是重要的保护剂，mTOR抑制可以预防癌症。小鼠用二甲基苯(a)-蒽（DMBA）加启动子12-O-十四烷基酚-13-乙酸酯（TPA）诱导肿瘤，口服雷帕霉素或对照。将研究肿瘤发病时间、恶性变化和肿瘤大小以及对肿瘤免疫监测的影响，以及mTOR信号在肿瘤与其他细胞中的作用。目的1验证T细胞参与口服雷帕霉素介导的癌症预防的假设。目的2验证IFN-¿有助于口服雷帕霉素介导的癌症预防的假设。目的3验证雷帕霉素通过直接作用于肿瘤细胞来预防癌症的假说。直接在肿瘤细胞中抑制mTOR与免疫机制并不相互排斥。

DESCRIPTION (provided by applicant): This application will define mechanisms of rapamycin-mediated tumor onset delay or prevention and will dissect mTOR effects directly on the tumor versus immune cell effects. It addresses Provocative Question 5: defining mechanisms of action of drugs used for other purposes. We challenge the paradigm that mTOR inhibition reduces or prevents cancer by direct effects on tumors through mTOR growth and metabolic effects, and explore the potential for mTOR inhibitors to prevent cancer through mTOR-mediated immune effects. We hypothesize that mTOR inhibition with oral rapamycin delays or prevents cancer onset in part through immune mechanisms, and will test concepts in a well-defined carcinogen-induced skin cancer model in which T cells and IFN-¿ are important protective agents and in which mTOR inhibition prevents cancer. Mice will have tumor induced with dimethylbenz(a)-anthracene (DMBA) plus the promoter 12-O- tetradecanoylphorbol-13-acetate (TPA) and will be treated with oral rapamycin or control. Time to tumor onset, malignant change and tumor size and effects on tumor immune surveillance will be studied as will mTOR signaling in tumor versus other cells. Aim 1 Test the hypothesis that T cells contribute to oral rapamycin- mediated cancer prevention. Aim 2 Test the hypothesis that IFN-¿ contributes to oral rapamycin- mediated cancer prevention. Aim 3 Test the hypothesis that rapamycin prevents cancer by direct effects on tumor cells. mTOR inhibition directly in tumors cell is not mutually exclusive with immune mechanisms. Relevance: Cancer is the number one killer in the US. Cure rates for advanced cancers have changed little in the past 50 years. Prevention is more cost effective and broadly applicable than treatments. We thus propose a novel, safe, broad spectrum approach to cancer prevention using rapamycin as a potential first-in-class agent. PUBLIC HEALTH RELEVANCE: This application will use a well-characterized carcinogen-induced mouse model for skin cancer to test whether immune effects of rapamycin contribute to its cancer prevention properties. This model mirrors important tumor signaling and host immune defense pathways involved in major human cancers.