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 乳腺癌治疗的进展导致了显着的生存率。但是，治愈或控制 乳腺癌不一定伴随着完全恢复健康。我们已经表明，作为乳腺癌 幸存者的年龄，与年龄匹配相比，他们经历了化学疗法引起的功能下降的加速 未接受化学疗法治疗的幸存者和没有癌症的女性。化学疗法诱导的功能下降 导致生活质量差，独立丧失和过早死亡。拟议的研究建立在我们的基础上 临床工作表明细胞衰老是与化学疗法诱导的功能有关的中心过程 衰退。细胞衰老是一个以细胞周期停滞为特征的基本衰老过程。衰老细胞 积聚在衰老组织中，并分泌促进与年龄相关的功能下降的促炎因子。我们 已经观察到，在乳腺癌幸存者中，化学疗法诱发了高水平的持续存在 循环衰老细胞，并且衰老细胞负担高的幸存者更有可能体验 化学疗法引起的疲劳，神经病和功能下降。这些数据为定位提供了理由 并减少衰老细胞以减轻化学疗法诱导的功能下降。在非癌症中， 可以通过使用运动或鼻溶液（散热衰老细胞的药物）来减少衰老细胞。最近的 临床前研究还表明，塞溶剂剂与运动相结合的衰老减少了。 与单独干预相比，细胞相比。但是，锻炼和鼻孔能力减少衰老的能力 细胞，最终尚未测试乳腺癌幸存者的身体机能。我们假设 通过运动和乳腺癌幸存者中的鼻溶剂靶向衰老细胞的靶向细胞将独立产生和 加性效应以改善身体功能并减少生物衰老的标记。为了检验这一假设，我们 提出一项多中心随机安慰剂对照试验，以测试运动和鼻溶疗法的功效 （单独或合并）生物衰老的身体功能和标记。我们将随机化疗 - 经过6分钟步行评估的绝经后乳腺癌幸存者的功能降低 距离[6MWD]，到4个武器中的1个：运动 +鼻孔；独自运动；单独鼻塞；或控制。主要 终点将是从基线到治疗结束的6MWD的变化（AIM 1）。次要终点包括 临床和生物老化标记（AIM 2）。我们还将评估两种干预措施的安全性和遵守性。 总而言之，随着乳腺癌幸存者的数量急剧上升（估计到2040年> 600万）， 减轻化学疗法引起的功能下降是紧急的公共卫生问题，也是NIH的优先事项。 该试验的成功完成将确定两种有针对性治疗以减轻化学疗法的功效 - 诱导功能下降。鉴于衰老是许多中期和晚期慢性疾病的基础，这是一个安全的 改善身体机能的治疗将产生重大的积极影响，远远超出了肿瘤学。