Targeting Senescence to Improve Frailty in Older Cancer Survivors

瞄准衰老以改善老年癌症幸存者的虚弱状况

基本信息

批准号：
10866293
负责人：
Mina S Sedrak
金额：
$ 24.3万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10866293
关键词：
Ablation Acceleration Adverse event Age Age Years Aging Automobile Driving Award Biological Biological Markers Blood CDKN2A gene Cancer Patient Cancer Survivor Cell Aging Cells Cessation of life Chemotherapy and/or radiation Clinical Data Diet Double-Blind Method Eating Elderly Exposure to Flavonoids Food Frail Elderly Fruit Funding Gait speed Generations Geroscience Goals Growth Half-Life Hand Strength Health Inflammation Inflammatory Infrastructure Interleukin-6 Intervention Intervention Studies Link Malignant Neoplasms Measures Multi-Institutional Clinical Trial Natural Products Normal tissue morphology Oral Outcome Patient Outcomes Assessments Persons Pharmaceutical Preparations Phenotype Physical Function Placebos Pre-Clinical Model Process Proteins Publishing Radiation Randomized Research Risk Safety Strawberries Survivors T-Lymphocyte Testing Tissues Training age related anticancer treatment cancer clinical trial cancer therapy career chemotherapy childhood cancer survivor dietary supplements efficacy trial experience falls fisetin frailty human tissue improved indexing mouse model multimodality pharmacologic primary endpoint programs randomized placebo controlled trial safety assessment safety testing secondary endpoint senescence side effect skills systemic inflammatory response treatment adherence tumor young adult

项目摘要

PROJECT SUMMARY/ABSTRACT Cancer treatment accelerates aging. In people over 65, accelerated aging may have far greater consequences than in younger adults. One of the most important consequences of accelerated aging is frailty. Frailty is linked to loss of independence, falls, and death. Older cancer survivors develop frailty 2- to 4-fold more frequently and at an earlier age than age-matched controls. Mechanisms underlying frailty are just starting to be understood. One key aging mechanism driving frailty is cellular senescence – a state of terminal growth arrest. Senescence is the result of both natural aging and cancer treatment; radiation and chemotherapy both generate senescent cells (Sncs). In pilot biomarker studies, I observed that older survivors treated with chemotherapy (vs. no chemotherapy) have increased T-cell expression of P16INK4a (p16). p16 is an established marker of Sncs. I also observed that the percentage of T-cells expressing p16 correlates with clinical frailty. My findings are consistent with published studies linking p16 and frailty in childhood cancer survivors. Together, these data provide the premise for testing clinical interventions to target and eliminate Sncs in older survivors. Recently, drugs have been discovered that selectively eliminate Sncs – senolytics. One such senolytic is fisetin, a natural product flavonoid found in strawberries and other fruits. Because the amount of fisetin varies considerably in food, it is not possible to achieve sufficient levels for eliminating Sncs in a natural diet; however, fisetin is available as a dietary supplement. In preclinical models, fisetin reduces Sncs, inflammation, and frailty. As such, fisetin is now in >10 efficacy trials to alleviate age-related conditions in frail older adults and, so far, has had a favorable safety profile. No trial to date has tested fisetin in frail older cancer survivors. Here, I propose a randomized placebo- controlled trial with multi-modality biomarkers to test the preliminary efficacy, safety, and tolerability of fisetin to improve frailty and reduce Snc burden in frail older cancer survivors. Guided by a firm mechanistic rationale and preliminary data, my overall hypothesis is that fisetin is efficacious (improves frailty), safe, and tolerable in frail older survivors. To test my hypothesis, I will randomize cancer survivors age >65 with diminished gait speed (<0.8 m/s) to a 60-day course of fisetin vs. placebo. The primary endpoint is change in gait speed from day 1 to day 60. Secondary endpoints include changes in p16, inflammatory biomarkers, and frailty measures (Fried’s criteria, frailty index, grip strength). I also will assess safety and tolerability of fisetin and explore longer- term sustainability of efficacy, as measured by gait speed at 150 days. Promising results from this study will provide preliminary evidence for a large multi-center clinical trial (R01) to establish the efficacy of fisetin in older survivors. Additionally, by completing this study, I will fill a gap in my prior training in cancer clinical trials with training in geroscience research. This study will form the basis of my independent research program to develop geroprotective interventions to ensure that older cancer survivors live healthy lives well after cancer treatment.

项目概要/摘要癌症治疗会加速衰老，对于 65 岁以上的人来说，加速衰老可能会产生更大的后果。与年轻人相比，加速衰老最重要的后果之一就是虚弱。老年癌症幸存者出现虚弱的频率是原来的 2 至 4 倍，并且更容易丧失独立性、跌倒和死亡。比年龄匹配的对照更早的年龄导致虚弱的机制才刚刚开始被了解。导致衰弱的一个关键衰老机制是细胞衰老——一种最终生长停滞的状态。是自然衰老和癌症治疗的结果；放疗和化疗都会导致衰老；在试点生物标志物研究中，我观察到接受化疗的老年幸存者（与未接受化疗的患者相比）。化疗）增加了 P16INK4a (p16) 的 T 细胞表达，p16 也是 Sncs I 的既定标志物。观察到表达 p16 的 T 细胞百分比与临床虚弱程度相关，我的研究结果是一致的。已发表的研究将 p16 与儿童癌症幸存者的虚弱联系在一起，这些数据提供了以下结果。测试临床干预措施以针对和消除老年幸存者中的 SNCs 的前提最近，药物已经出现。已发现选择性消除 Sncs（senolytics）的一种天然产物非瑟酮（fisetin）。草莓和其他水果中含有类黄酮，因为食物中非瑟酮的含量差异很大。不可能达到足够的水平来消除天然饮食中的 SNC；但是，非瑟酮可作为一种药物使用。在临床前模型中，非瑟酮可减少 SNC、炎症和虚弱。在超过 10 项缓解体弱老年人年龄相关疾病的功效试验中，迄今为止，安全性良好迄今为止，还没有试验在体弱的老年癌症幸存者中测试过非瑟酮。在这里，我提出了一种随机安慰剂。使用多模态生物标志物进行对照试验，测试非瑟酮的初步功效、安全性和耐受性以坚定的机制原理为指导，改善体弱的老年癌症幸存者的体质并减轻 SNC 负担。初步数据，我的总体假设是非瑟酮有效（改善虚弱）、安全且可耐受为了检验我的假设，我将步态减弱的年龄 > 65 岁的癌症幸存者随机分组。非瑟汀与安慰剂 60 天疗程的速度（<0.8 m/s）主要终点是步态速度的变化。第 1 天至第 60 天。次要终点包括 p16 的变化、炎症生物标志物和虚弱指标（弗里德的标准、虚弱指数、握力）我还将评估非瑟酮的安全性和耐受性，并探索更长期的- 通过 150 天的步态速度来衡量，这项研究的结果令人鼓舞。为大型多中心临床试验（R01）提供初步证据，以确定非瑟酮对老年患者的疗效此外，通过这项研究，我将填补我之前在癌症临床试验方面培训的空白。这项研究将构成我要开发的独立研究计划的基础。老年保护干预措施，确保老年癌症幸存者在癌症治疗后过上健康的生活。