Targeting Senescence to Mitigate Chemotherapy-induced Functional Decline

靶向衰老以减轻化疗引起的功能衰退

• 批准号: 10638071
• 负责人: Mina S Sedrak
• 金额: $ 70.06万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10638071
• 关键词: Ablation; Acceleration; Address; Adherence; Age; Aging; Biological Aging; Biological Markers; Breast Cancer Treatment; Breast Cancer survivor; CD3 Antigens; CDKN2A gene; Cancer Patient; Cell Aging; Cell Cycle Arrest; Cells; Cessation of life; Chemotherapy-Oncologic Procedure; Chronic Disease; Clinical; Clinical Markers; Data; Diabetes Mellitus; Elderly; Exercise; Fatigue; Functional disorder; Geriatric Assessment; Growth; Health; Inflammation; Inflammatory; Intervention; Link; Malignant Neoplasms; Measures; Neuropathy; Oncology; Oral; Patients; Pharmaceutical Preparations; Phase; Phenotype; Physical Function; Population; Postmenopause; Process; Public Health; Pulmonary Fibrosis; Quality of life; Randomized; Risk; Survivors; T-Lymphocyte; Testing; Tissues; Toxicity due to chemotherapy; Treatment-related toxicity; United States National Institutes of Health; Walking; Woman; Work; age related; arm; cancer therapy; chemotherapy; clinical practice; comparative efficacy; design; dietary supplements; disability; efficacy evaluation; efficacy testing; exercise program; exercise training; experience; falls; fisetin; frailty; functional decline; improved; malignant breast neoplasm; middle age; muscle form; older patient; preclinical study; premature; prevent; primary endpoint; randomized placebo controlled trial; restoration; safety assessment; secondary endpoint; senescence; tele-exercise; therapy design; treatment arm; young adult

PROJECT SUMMARY/ABSTRACT Advances in breast cancer treatment have resulted in significant survival gains. However, cure or control of breast cancer is not necessarily accompanied by full restoration of health. We have shown that as breast cancer survivors age, they experience accelerated chemotherapy-induced functional decline compared to age-matched survivors not treated with chemotherapy and women without cancer. Chemotherapy-induced functional decline results in poor quality of life, loss of independence, and premature death. The proposed study builds on our clinical work showing that cellular senescence is a central process linked to chemotherapy-induced functional decline. Cellular senescence is a fundamental aging process characterized by cell cycle arrest. Senescent cells accumulate in aging tissues and secrete proinflammatory factors that drive age-related functional decline. We have observed that, in breast cancer survivors, chemotherapy induces the persistent presence of high levels of circulating senescent cells, and that survivors with high senescent cell burden are more likely to experience chemotherapy-induced fatigue, neuropathy, and functional decline. These data provide rationale for targeting and reducing senescent cells to alleviate chemotherapy-induced functional decline. In non-cancer populations, senescent cells can be reduced through use of exercise or senolytics (drugs that ablate senescent cells). Recent preclinical studies also showed that senolytics combined with exercise yielded a greater reduction in senescent cells compared to either intervention alone. However, the ability of exercise and senolytics to reduce senescent cells and, ultimately, improve physical function in breast cancer survivors has not been tested. We hypothesize that targeting senescent cells via exercise and senolytics in breast cancer survivors will yield independent and additive effects to improve physical function and reduce markers of biological aging. To test this hypothesis, we propose a multicenter randomized placebo-controlled trial to test the efficacy of exercise and senolytic therapy (alone or combined) on physical function and markers of biological aging. We will randomize chemotherapy- treated postmenopausal breast cancer survivors with diminished function, assessed using the 6-minute walk distance [6MWD], to 1 of 4 arms: exercise + senolytic; exercise alone; senolytic alone; or control. The primary endpoint will be the change in 6MWD from baseline to end of treatment (Aim 1). Secondary endpoints include clinical and biological aging markers (Aim 2). We also will assess the safety and adherence of both interventions. In summary, as the number of breast cancer survivors rises dramatically (estimated to be >6 million by 2040), mitigating chemotherapy-induced functional decline is an urgent public health issue and a priority of the NIH. Successful completion of this trial will establish the efficacy of two targeted treatments to mitigate chemotherapy- induced functional decline. Given that senescence underlies many mid- and late-life chronic diseases, a safe treatment that improves physical function would have a major positive impact that extends far beyond oncology.

项目摘要/摘要 乳腺癌治疗的进步使患者的存活率显著提高。然而，治愈或控制 乳腺癌并不一定伴随着健康的完全恢复。我们已经证明，作为乳腺癌， 幸存者年事已高，与年龄匹配的人相比，他们经历了化疗导致的功能衰退加速 未接受化疗的幸存者和未患癌症的妇女。化疗所致功能减退 导致生活质量不佳、丧失独立性和过早死亡。拟议的研究是建立在我们的 临床研究表明，细胞衰老是与化疗诱导的功能有关的中心过程 拒绝。细胞衰老是以细胞周期停滞为特征的基本衰老过程。衰老细胞 在老化的组织中积聚，并分泌促炎因子，导致与年龄相关的功能下降。我们 已经观察到，在乳腺癌幸存者中，化疗导致持续存在高水平的 循环衰老细胞，衰老细胞负荷高的幸存者更有可能经历 化疗引起的疲劳、神经病变和功能衰退。这些数据为确定目标提供了依据 减少衰老细胞以减轻化疗引起的功能衰退。在非癌症人群中， 衰老细胞可以通过使用运动或衰老药物(去除衰老细胞的药物)来减少。近期 临床前研究也表明，结合运动可以更有效地减少衰老。 与任何一种单独干预相比。然而，运动和抗衰老药物延缓衰老的能力 细胞，并最终改善乳腺癌幸存者的身体功能还没有经过测试。我们假设 通过运动和老年药物靶向乳腺癌幸存者的衰老细胞将产生独立和 改善身体机能和减少生物衰老的标志的相加效应。为了检验这一假设，我们 建议进行一项多中心随机安慰剂对照试验，以测试运动和感觉神经溶解疗法的疗效。 (单独或联合)身体机能和生物衰老的标志。我们会随机化化疗- 使用6分钟步行对绝经后功能减退的乳腺癌幸存者进行治疗 距离[6 MWD]，至4个手臂中的1个：运动+感觉神经分解；单独运动；单独感觉神经分解；或对照。初级阶段 终点将是6MWD从基线到治疗结束(目标1)的变化。次要终端包括 临床和生物衰老标志物(目标2)。我们还将评估这两种干预措施的安全性和依从性。 总而言之，随着乳腺癌幸存者的数量急剧上升(预计到2040年将达到600万英镑)， 缓解化疗引起的功能衰退是一个紧迫的公共卫生问题，也是美国国立卫生研究院的优先事项。 这项试验的成功完成将确立两种靶向治疗的疗效，以缓解化疗- 诱发的功能衰退。鉴于衰老是许多中老年慢性病的基础，一个安全的 改善身体功能的治疗将产生重大的积极影响，远远超出肿瘤学的范畴。