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的机制，并将剖析mTOR对肿瘤与免疫细胞的直接影响。它处理了具有挑衅性的问题5：界定用于其他目的的药物的作用机制。我们挑战了mTOR抑制通过mTOR生长和代谢效应对肿瘤产生直接影响从而减少或预防癌症的范式，并探索了mTOR抑制剂通过mTOR介导的免疫效应预防癌症的可能性。我们假设，口服雷帕霉素抑制mTOR可部分通过免疫机制延迟或预防癌症的发生，并将在定义明确的致癌物诱导皮肤癌模型中测试概念，在该模型中，T细胞和干扰素是重要的保护剂，在该模型中，mTOR抑制可预防癌症。用二甲基苯并(A)菲(DMBA)加促进剂12-O-十四酰佛波醇-13-乙酸酯(TPA)诱发小鼠肿瘤，口服雷帕霉素或空白对照。将研究肿瘤发病时间、恶变和肿瘤大小以及对肿瘤免疫监测的影响，以及肿瘤中mTOR信号相对于其他细胞的影响。目的1验证T细胞参与口服雷帕霉素抗癌作用的假设。目的2验证干扰素对口服雷帕霉素抗癌作用的假设。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。 相关信息：癌症是美国的头号杀手。在过去的50年里，晚期癌症的治愈率几乎没有变化。预防比治疗更具成本效益和更广泛的适用性。因此，我们提出了一种新的、安全的、广谱的癌症预防方法，使用雷帕霉素作为潜在的一流药物。 公共卫生相关性：这项应用将使用一个具有良好特征的致癌物诱导的皮肤癌小鼠模型来测试雷帕霉素的免疫作用是否有助于其癌症预防特性。这个模型反映了与人类主要癌症有关的重要肿瘤信号和宿主免疫防御途径。

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.