Immune aspects of mTOR inhibition for cancer prevention (PQ5)

mTOR 抑制的免疫方面预防癌症 (PQ5)

• 批准号: 8538910
• 负责人: Tyler J. Curiel
• 金额: $ 15.28万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8538910
• 关键词: Address; Advanced Malignant Neoplasm; Anthracenes; Cancer Model; Carcinogens; Cells; Drug usage; Growth; Human; Immune; Immunologic Surveillance; Interferons; Malignant - descriptor; Malignant Neoplasms; Mediating; Mediator of activation protein; Metabolic; Modeling; Mus; Oral; Pathway interactions; Prevention; Property; Protective Agents; Signal Transduction; Sirolimus; Skin Cancer; T-Lymphocyte; Testing; Tetradecanoylphorbol Acetate; Time; cancer prevention; carcinogenesis; cost effective; dimethylbenzanthracene; human FRAP1 protein; mTOR Inhibitor; mTOR inhibition; mouse model; neoplastic cell; novel; prevent; promoter; tumor

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.

描述（由应用程序提供）：此应用将定义雷帕霉素介导的肿瘤发作延迟或预防的机制，并将直接剖析对肿瘤与免疫细胞效应的MTOR效应。它解决了挑衅性问题5：定义用于其他目的的药物作用机理。我们挑战MTOR抑制作用通过MTOR生长和代谢作用直接影响肿瘤的范围来降低或防止癌症，并探索MTOR抑制剂通过MTOR介导的免疫作用预防癌症的潜力。我们假设口服雷帕霉素延迟或通过免疫机制抑制MTOR抑制作用，或者通过免疫机制进行了预防，并且将在定义明确的致癌性皮肤癌模型中测试概念，其中T细胞和IFN-®是重要的受保护剂，并且MTOR抑制作用可预防癌症。小鼠将用二甲基苯子（A） - 蒽（DMBA）诱导肿瘤，再加上启动子12-甲基苯基苯乙烯-13-乙酸酯（TPA），并将用口服雷帕霉素或对照处理。肿瘤发作，恶性变化和肿瘤大小以及对肿瘤免疫监测的影响将进行研究，肿瘤与其他细胞中的MTOR信号传导也将被研究。 AIM 1检验了T细胞有助于口服雷帕霉素介导的预防癌症的假设。 AIM 2检验了IFN-有助于口服雷帕霉素介导的癌症预防的假设。 AIM 3检验了雷帕霉素通过直接影响肿瘤细胞阻止癌症的假设。直接在肿瘤细胞中的MTOR抑制作用并非与免疫力学相互排斥。 相关性：癌症是美国排名第一的杀手。在过去的50年中，晚期癌症的治愈率变化不大。预防比治疗更具成本效益，并且广泛适用。因此，我们提出了一种使用雷帕霉素作为潜在的一流药物的新型，安全，广泛的方法来预防癌症。

项目成果

Chronic mechanistic target of rapamycin inhibition: preventing cancer to delay aging, or vice versa?.

雷帕霉素抑制的慢性机制目标：预防癌症延缓衰老，反之亦然？

• DOI: 10.1159/000343625
• 发表时间: 2013
• 期刊: Interdisciplinary topics in gerontology
• 作者: Sharp,ZeltonDave;Curiel,TylerJay;Livi,CarolinaBecker
• 通讯作者: Livi,CarolinaBecker