Exercise and Lung Cancer

运动与肺癌

基本信息

批准号：
10560971
负责人：
Rachel Jamison Perry
金额：
$ 19.19万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-12-12 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10560971
关键词：
Acute Affect Antiinflammatory Effect Cancer cell line Cell Communication Cell division Cell physiology Cells Cellular Metabolic Process Characteristics Chronic Clinical Clinical Research Clinical Trials Design Complement Data Dose Down-Regulation Exercise Failure Genetic Glucose Glycolysis Growth Hour Human IL6 gene Immune Immune system Immunotherapy In Vitro Incidence Infiltration Inflammation Inflammatory Infusion procedures Insulin Interval training Knock-out Knockout Mice Link Malignant Neoplasms Malignant neoplasm of lung Mediating Metabolic Metabolism Methods Modeling Mus Muscle Muscle Cells Myelogenous Myeloid Cells Myomatous neoplasm Obesity Pathologic Patients Performance Population Production Prognosis Recurrent Malignant Neoplasm Regimen Resolution Risk Reduction Rodent Role Running SLC2A1 gene Strenuous Exercise T-Cell Activation T-Lymphocyte Testing Tissue Model Tissues Training Tumor Immunity Veins Work anti-cancer awake blood glucose regulation cancer recurrence cancer type cytokine driver mutation epidemiology study evidence base exercise intensity exercise prescription exercise regimen exercise rehabilitation exercise training exhaustion fatty acid metabolism glucose metabolism glucose uptake immune activation immune function immunogenic immunoregulation improved in vivo inhibitor insight lung cancer cell malignant breast neoplasm mode of exercise mouse model neoplastic cell new therapeutic target oxidation physiologic model precision medicine prevent process optimization response standard of care sugar treadmill tumor tumor growth tumor metabolism tumor progression

项目摘要

PROJECT SUMMARY Clinical and epidemiologic studies have demonstrated that exercise reduces the incidence and improves the prognosis of numerous types of cancer; however, the mechanisms by which exercise exerts its anti-cancer effects remain poorly understood. Most exercise studies have been performed in breast cancer; however, as breast cancer is obesity-associated, insulin-driven, and only weakly immunogenic, it is likely that exercise may work differently in cancer types that are strongly immunogenic and not associated with obesity. A mechanistic understanding of how exercise slows tumor growth is important because it will inform the design of clinical trials to determine which exercise regimens are most likely to benefit a particular tumor type based on a patient's clinical characteristics, allowing an exercise prescription to be made using precision medicine approaches. Arguably more importantly, studies in this vein may reveal new therapeutic targets for lung cancer by modulating metabolism in combination with standard-of-care treatments. In this proposal, we will examine how exercise slows lung cancer growth in mice, with the Overarching Hypothesis that the beneficial effects of exercise on lung cancer progression result from a combination of systemic metabolic interactions linking muscle to the immune system to the tumor. We anticipate that exercise both reduces tumor glucose uptake, and increases immune cell glucose and fatty acid metabolism, thereby enhancing T cell activation, and preventing exhaustion. These hypotheses will be tested using a complement of tissue-specific knockout mice, methods that we developed to model tissue-specific substrate metabolism, and multiple exercise modalities mimicking low- intensity exercise as well as high-intensity interval training. In so doing, we anticipate generating new insights into how muscle-tumor-T cell interactions mediate the beneficial effects of exercise in immunogenic tumors, and may identify new immunometabolic targets to enhance the efficacy of exercise, generating an evidence-based exercise prescription for lung cancer in mice.

项目摘要临床和流行病学研究表明，运动可以降低发生率并改善多种类型的癌症的预后；但是，运动施加反癌的机制效果仍然很了解。大多数运动研究都是在乳腺癌中进行的。但是，如乳腺癌是与肥胖相关，胰岛素驱动的，并且仅是弱免疫原性的，运动可能可能在强烈免疫原性并且与肥胖无关的癌症类型中的工作不同。机械了解运动如何减慢肿瘤的生长很重要，因为它将为临床试验的设计提供信息确定哪种运动方案最有可能使特定肿瘤类型受到患者的影响临床特征，允许使用精确医学方法进行运动处方。可以说，更重要的是，这种静脉的研究可能会通过调节来揭示肺癌的新治疗靶点代谢与护理标准治疗结合。在此提案中，我们将研究如何运动减慢小鼠的肺癌生长，总体假设是运动对肺癌的进展是由将肌肉与免疫系统对肿瘤。我们预计运动既可以减少肿瘤葡萄糖的摄取，并增加免疫细胞葡萄糖和脂肪酸代谢，从而增强T细胞活化并防止疲惫。这些假设将使用组织特异性敲除小鼠的补充进行检验，我们的方法是开发用于模拟组织特异性底物代谢，以及模仿低 - 的多种运动方式强度运动以及高强度间隔训练。这样做，我们预计会产生新的见解肌肉肿瘤-T细胞相互作用如何介导免疫原性肿瘤中运动的有益作用，以及可以识别新的免疫代谢靶标以增强运动的功效，从而产生循证小鼠肺癌的运动处方。