eRapa-Mediated T Cell Effects in Intestinal Neoplasia

eRapa 介导的 T 细胞对肠肿瘤的影响

基本信息

批准号：
8649868
负责人：
Vinh Anh Dao
金额：
$ 3.06万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-01 至 2019-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8649868
关键词：
Address Adenomatous Polyposis Coli Adverse effects Age-Years American Benign CD4 Positive T Lymphocytes CD8B1 gene Cancer Burden Cancer Death Rates Cause of Death Clinical Trials Colitis Colon Colon Carcinoma Cytotoxic T-Lymphocytes Data Development Diagnostic Neoplasm Staging Drug Formulations Economics Ensure Enteral Functional disorder Growth Human Immune Immunity Immunologic Surveillance In Vitro Individual Inflammation Inflammatory Inflammatory disease of the intestine Interferons Interleukin-17 Intestinal Cancer Intestinal Neoplasms Knock-out Longevity Malignant Neoplasms Mediating Modeling Mus Mutation Myeloid Cells Pathway interactions Physicians Prevention Prevention strategy Production Property Public Health Regulatory T-Lymphocyte Research Training Role Scientist Signaling Molecule Sirolimus Sodium Dextran Sulfate System T cell differentiation T-Lymphocyte Testing Therapeutic Agents Time United States Work analog anticancer research cancer care cancer prevention cancer therapy carcinogenesis career cell growth clinical effect combat cost effective cytokine economic cost follow-up immune function improved in vivo inhibitor/antagonist innovation interleukin-22 killings mTOR protein mouse model novel oncology prevent public health relevance statistics treatment strategy tumor tumor growth

Address Adenomatous Polyposis Coli Adverse effects Age-Years American Benign CD4 Positive T Lymphocytes CD8B1 gene Cancer Burden Cancer Death Rates Cause of Death Clinical Trials Colitis Colon Colon Carcinoma Cytotoxic T-Lymphocytes Data Development Diagnostic Neoplasm Staging Drug Formulations Economics Ensure Enteral Functional disorder Growth Human Immune Immunity Immunologic Surveillance In Vitro Individual Inflammation Inflammatory Inflammatory disease of the intestine Interferons Interleukin-17 Intestinal Cancer Intestinal Neoplasms Knock-out Longevity Malignant Neoplasms Mediating Modeling Mus Mutation Myeloid Cells Pathway interactions Physicians Prevention Prevention strategy Production Property Public Health Regulatory T-Lymphocyte Research Training Role Scientist Signaling Molecule Sirolimus Sodium Dextran Sulfate System T cell differentiation T-Lymphocyte Testing Therapeutic Agents Time United States Work analog anticancer research cancer care cancer prevention cancer therapy carcinogenesis career cell growth clinical effect combat cost effective cytokine economic cost follow-up immune function improved in vivo inhibitor/antagonist innovation interleukin-22 killings mTOR protein mouse model novel oncology prevent public health relevance statistics treatment strategy tumor tumor growth

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项目摘要

DESCRIPTION (provided by applicant): Cancer is the leading cause of death worldwide. In the US, it claims more lives in Americans younger than 85 years of age compared to any other cause. As a nation, hundreds of billions of dollars are spent annually on cancer research and care, but cancer death rates have not changed significantly for most advanced-stage cancers. These grim statistics point to a need for novel and effective cancer prevention strategies, as prevention can be more clinically effective and is clearly more cost effective than most cancer treatment strategies. A landmark study from our collaborators in 2009 found that a novel enteric formulation of rapamycin (eRapa) prolonged survival in normal mice and follow-up studies suggested cancer delay or prevention as a mechanism for eRapa's longevity extension properties. In the ApcMin/+ mouse model of intestinal neoplasia, our preliminary data established that eRapa extends lifespan of ApcMin/+ mice by reducing their intestinal tumors, consistent with the role of eRapa in delaying or preventing cancer. Rapamycin and its analogs are currently being studied as possible cancer therapeutic agents, including in human clinical trials, but there has been relatively little focus on its use as a cancer prevention agent. Also litle studied are rapamycin's significant immune modulating effects in cancer treatment or prevention. Cancer immune surveillance is a normal endogenous mechanism that helps to prevent cancer from becoming clinically apparent. T cells are critical modulators of this surveillance mechanism. Our preliminary data in normal mice show that eRapa boosts T cell effects generally favorable to cancer immune surveillance while diminishing unfavorable suppressive T cell effects, but these findings have yet to be proven mechanistically in a tumor setting. Thus ApcMin/+ mice will be used to test our main hypothesis that eRapa-mediated T cell effects in intestinal neoplasia contribute to cancer prevention through enhanced cancer immune surveillance. This main hypothesis will be addressed through the following specific aims: (1) test the hypothesis that eRapa reduces spontaneous intestinal neoplasia by boosting T cell immunity and/or (2) by mitigating tumor-associated T cell dysfunction, and (3) test the hypothesis that eRapa reduces inflammation-driven intestinal neoplasia through immune effects. To address specific aims 1-2, parental ApcMin/+ mice and various cytokine and T cell knockout ApcMin/+ mice will be given eRapa for a defined amount of time and sacrificed to study intestinal tumor formation and effects on specific T cell properties (e.g., cytokine production, Th differentiation, expression of immune suppressive factors). Additionally, in vitro systems will be utilized to generate specific myeloid cell subsets to study eRapa's effects on T cell differentiation pathways as a way to confirm in vivo results. To address specific aim 3, ApcMin/+ mice will be challenged with the inflammatory agent, dextran sodium sulfate, to induce malignant tumor degeneration. Then survival and similar T cell properties as in aims 1-2 will be assessed to elucidate mechanisms of eRapa-mediated clinical effects. These proposed studies are significant because they will support the use of rapamycin and its analogs as potential first-in-class cancer prevention agents.

描述（由申请人提供）：癌症是全球死亡的主要原因。在美国，与其他任何原因相比，它在85岁以下的美国人中拥有更多的生活。作为一个国家，每年在癌症研究和护理上花费了数百十亿美元，但是大多数高级癌症的癌症死亡率并未发生显着变化。这些严峻的统计数据表明，需要新颖有效的预防癌症预防策略，因为预防可能在临床上更有效，并且显然比大多数癌症治疗策略更具成本效益。我们合作者在2009年的一项具有里程碑意义的研究发现，一种新型的雷帕霉素（ERAPA）的肠道肠道延长了正常小鼠的生存率，随访研究表明，癌症延迟或预防是ERAPA寿命延伸特性的一种机制。在肠道肿瘤的APCMIN/+小鼠模型中，我们的初步数据确定ERAPA通过减少其肠道肿瘤来延长APCMIN/+小鼠的寿命，这与ERAPA在延迟或预防癌症中的作用一致。雷帕霉素及其类似物目前正在作为可能的癌症治疗剂，包括在人类临床试验中，但对其作为癌症预防剂的使用相对较少。所研究的雷帕霉素还对癌症治疗或预防的显着免疫调节作用。癌症免疫监测是一种正常的内源性机制，有助于防止癌症在临床上变得明显。 T细胞是该监视机制的关键调节剂。我们在正常小鼠中的初步数据表明，ERAPA增强了T细胞的影响，通常有利于癌症的免疫监测，同时减少了不利的抑制性T细胞效应，但是在肿瘤环境中，这些发现尚未得到证明。因此，APCMIN/+小鼠将用于测试我们的主要假设，即ERAPA介导的T细胞在肠道肿瘤中的T细胞效应通过增强的癌症免疫监测有助于预防癌症。这一主要假设将通过以下特定目的解决：（1）测试通过提高T细胞免疫和/或（2）来减轻肿瘤相关的T细胞功能障碍和（3）测试ERAPA炎症性肠内肠内促进症的假设，该假设通过提高T细胞免疫和/或（2）来降低自发性肠道肿瘤的假设。为了解决特定目的1-2，将给予父母APCMIN/+小鼠以及各种细胞因子和T细胞基因敲除APCMIN/+小鼠的eRAPA，以定义的时间量，并牺牲以研究肠道肿瘤的形成以及对特定T细胞特性的影响（例如，细胞因子产生，分化，免疫抑制因素的表达）。此外，体外系统将用于生成特定的髓样细胞亚群，以研究ERAPA对T细胞分化途径的影响，以确认体内结果。为了解决特定的目标3，APCMIN/+小鼠将受到炎症剂葡聚糖硫酸钠的挑战，以诱导恶性肿瘤变性。然后，将评估与AIMS 1-2中的生存和类似的T细胞特性，以阐明ERAPA介导的临床效应的机制。这些提出的研究很重要，因为它们将支持使用雷帕霉素及其类似物作为潜在的一流癌症预防剂。