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（由申请人提供）：本申请将定义雷帕霉素介导的肿瘤发作延迟或预防的机制，并将剖析 mTOR 直接对肿瘤的影响与免疫细胞的影响。它解决了挑衅性问题 5：定义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 介导的免疫效应预防癌症的潜力。我们假设口服雷帕霉素抑制 mTOR 可以部分通过免疫机制延迟或预防癌症发作，并将在明确的致癌物诱发皮肤癌模型中测试概念，其中 T 细胞和 IFN-¿ 是重要的保护剂，而 mTOR 抑制可预防癌症。小鼠将用二甲基苯并(a)-蒽(DMBA)加上启动子12-O-十四烷酰佛波醇-13-乙酸酯(TPA)诱导肿瘤，并用口服雷帕霉素或对照进行治疗。将研究肿瘤发病时间、恶性变化、肿瘤大小以及对肿瘤免疫监视的影响，以及肿瘤与其他细胞中的 mTOR 信号传导。目标 1 检验 T 细胞有助于口服雷帕霉素介导的癌症预防这一假设。目标 2 检验 IFN-¿ 有助于口服雷帕霉素介导的癌症预防这一假设。目标 3 检验雷帕霉素通过直接作用于肿瘤细胞来预防癌症的假设。直接抑制肿瘤细胞中的 mTOR 与免疫机制并不相互排斥。 相关性：癌症是美国的第一大杀手。过去 50 年来，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且适用范围更广。因此，我们提出了一种新颖、安全、广谱的癌症预防方法，使用雷帕霉素作为潜在的一流药物。

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