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.

项目概要临床和流行病学研究表明，运动可以降低发病率并改善病情多种癌症的预后；然而，运动发挥抗癌作用的机制其影响仍知之甚少。大多数运动研究都是针对乳腺癌进行的。然而，作为乳腺癌与肥胖相关，由胰岛素驱动，且免疫原性较弱，因此运动可能可能对于具有强免疫原性且与肥胖无关的癌症类型，其作用不同。机械论了解运动如何减缓肿瘤生长很重要，因为它将为临床试验的设计提供信息根据患者的情况确定哪些运动方案最有可能对特定肿瘤类型有益临床特征，允许使用精准医学方法制定运动处方。可以说更重要的是，这方面的研究可能会通过调节来揭示肺癌的新治疗靶点新陈代谢与标准护理治疗相结合。在本提案中，我们将研究如何锻炼减缓小鼠肺癌的生长，总体假设是运动对肺癌的有益影响肺癌的进展是由将肌肉与肌肉联系起来的全身代谢相互作用共同导致的。免疫系统对肿瘤的作用。我们预计运动既可以减少肿瘤葡萄糖的摄取，又可以增加免疫细胞葡萄糖和脂肪酸代谢，从而增强T细胞活化，防止疲劳。这些假设将使用一系列组织特异性基因敲除小鼠进行测试，这些方法是我们所采用的方法。开发用于模拟组织特异性底物代谢，以及模仿低浓度的多种运动方式强度运动以及高强度间歇训练。通过这样做，我们预计会产生新的见解研究肌肉-肿瘤-T 细胞相互作用如何介导运动对免疫原性肿瘤的有益影响，以及可能会识别新的免疫代谢目标来增强运动的功效，从而产生基于证据的小鼠肺癌的运动处方。