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

• 批准号: 10514069
• 负责人: Mina S Sedrak
• 金额: $ 24.3万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10514069
• 关键词: 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; Ensure; 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 Childhood Neoplasm; Malignant Neoplasms; Measures; Multi-Institutional Clinical Trial; Natural Products; Normal tissue morphology; Older Population; Oral; Outcome; Patient Outcomes Assessments; Persons; Pharmaceutical Preparations; Pharmacology; 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; primary endpoint; programs; randomized placebo controlled trial; safety testing; secondary endpoint; senescence; side effect; skills; systemic inflammatory response; treatment adherence; tumor; young adult

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.

项目摘要/摘要 癌症治疗加速衰老。在65岁以上的人中，加速衰老可能会带来更大的后果 比在年轻人中。加速衰老的最重要后果之一是脆弱。脆弱的链接 失去独立，跌倒和死亡。较旧的癌症存活频率更高2至4倍，并且 在年龄较早的年龄匹配对照中。脆弱的机制刚刚开始被理解。 驱动脆弱的一种关键衰老机制是细胞感应 - 一种末端生长停滞状态。衰老 是自然衰老和癌症治疗的结果；放射和化学疗法都会产生感觉 细胞（SNC）。在Pilot BioMarker研究中，我观察到接受化学疗法治疗的较旧生存（vs. no 化学疗法的T细胞表达增加了P16INK4A（p16）。 P16是SNC的既定标记。我也是 观察到表达P16的T细胞百分比与临床脆弱相关。我的发现是一致的 通过发表的研究，将P16和脆弱的儿童癌症存活联系起来。这些数据一起提供了 测试临床干预措施以靶向和消除较旧生存的SNC的前提。最近，药物有 被发现有选择地消除SNCS - 塞溶剂。一种这样的鼻溶剂是菲塞汀，一种天然产品 在草莓和其他水果中发现的类黄酮。因为食物中小心的渔蛋白品种数量，所以 无法获得足够的水平来消除自然饮食中的SNC；但是，fisetin可作为 饮食补充。在临床前模型中，Fisetin减少了SNC，注射和脆弱。因此，Fisetin现在是 在> 10个有效的试验中，以减轻脆弱的老年人与年龄相关的状况，到目前为止， 轮廓。迄今为止，尚无试用试验在脆弱的老癌症存活中测试了菲塞汀。在这里，我提出了一个随机的安慰剂 - 具有多模式生物标志物的对照试验，以测试FITHETIN的初步效率，安全性和耐受性 改善脆弱的癌症生存中的脆弱并减少SNC燃烧。在坚定的机械原理和 初步数据，我的总体假设是，渔民是有效的（改善脆弱），安全且可容忍的 在脆弱的旧生存中。为了检验我的假设，我将随着步态降低的年龄> 65岁的癌症存活率随机 速度（<0.8 m/s）至60天的Fisetin vs.安慰剂。主要终点是从 第1天到第60天。次要终点包括P16的变化，炎症生物标志物和脆弱的措施 （弗里德的标准，脆弱的指数，握力强度）。我还将评估鱼类素的安全性和耐受性，并探索更长的 效率的期限可持续性，通过步态速度在150天内衡量。这项研究的有希望的结果将 提供大型多中心临床试验（R01）的初步证据，以确定渔蛋白在较老的效率 幸存者。此外，通过完成这项研究，我将填补我先前在癌症临床试验中的培训的空白 GEROSCIENCE研究培训。这项研究将构成我独立研究计划的基础 癌症治疗后，老年保护干预措施以确保较老的癌症生存健康。