Sen-Survivors: An open-label intervention trial for frailty and senescence

Sen-Survivors：针对虚弱和衰老的开放标签干预试验

• 批准号: 9890475
• 负责人: Gregory Armstrong
• 金额: $ 227.77万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9890475
• 关键词: Address; Adult; Age; Age-Years; Aging; Apoptosis; Biological Aging; Biological Markers; Blood; Bone Marrow Transplantation; Bone Resorption; CDKN2A gene; Cell Aging; Cells; Chemotherapy and/or radiation; Child; Chronic; Chronic Disease; Clinical; Cohort Studies; Common Terminology Criteria for Adverse Events; Communities; DNA Damage; Dasatinib; Data; Diagnosis; Elderly; Energy Metabolism; Exposure to; Fatigue; Flavonoids; Functional disorder; Future; General Population; Genetic Transcription; Glucose Intolerance; Health; Individual; Inflammatory; Institution; Insulin Resistance; Intervention Trial; Knowledge; Life; Longevity; Malignant Childhood Neoplasm; Malignant Neoplasms; Measures; Mediating; Outcome; Pathway interactions; Persons; Phenotype; Physiological; Pilot Projects; Population; Premature aging syndrome; Process; Quercetin; RNA Interference; Radiation therapy; Randomized; Regimen; Research; Resistance; Retinoblastoma Protein; Risk; Safety; Saint Jude Children' s Research Hospital; Supportive care; Survivors; T-Lymphocyte; Thinness; Transplant Recipients; Work; arm; base; bone mass; cancer therapy; cellular targeting; chemokine; chemotherapy; childhood cancer survivor; cognitive function; cohort; cytokine; dietary supplements; early onset; efficacy clinical trial; efficacy testing; experience; fisetin; frailty; healthspan; idiopathic pulmonary fibrosis; improved; improved functioning; inflammatory marker; mRNA Expression; mortality; mouse model; muscle form; open label; peer; peripheral blood; premature; primary endpoint; safety testing; secondary endpoint; senescence; spreading factor; therapy development; walking speed

ABSTRACT Over 80% of children diagnosed with cancer will survive at least ten years after diagnosis. However, by age 50 years each survivor, on average experiences >4 severe or life-threatening (CTCAE grades 3-4) health chronic conditions (rates typically seen in persons decades older) raising concern for early onset of physiologic frailty. Frailty is a loss of physiologic capacity that interferes with normal function, most commonly described in older adults and characterized (Fried Criteria) by three or more of: 1) low lean muscle mass, 2) reduced strength, 3) slow walking speed, 4) low energy expenditure, and 5) fatigue. In the general population frailty is seen in the elderly. However, at a median age of only 33 years (range 18-50), 8% of survivors are frail, an additional 22.2% meet the definition of pre-frail (two of five criteria), rates similar to adults >65 years of age. Cellular senescence, a quiescent state representing the loss of a cell's ability to replicate or grow, is an important and established mechanism in the aging process. Senescence is strongly associated with frailty and aging biomarkers in the elderly population. There is now evidence that p16INK4A is elevated in survivors treated with chemotherapy and radiotherapy, and the magnitude of elevation is associated with measures of frailty. Thus, cellular senescence may provide a targetable pathway to improve measures of aging. Agents such as Dasatinib and flavonoids (Quercetin; Fisetin, available as nutritional supplements) interfere with this pathway and thus are “senolytic”. Six clinical trials of efficacy are now underway in chronic disease states associated with senescence (e.g. idiopathic pulmonary fibrosis) and frail populations, including adult bone marrow transplant recipients demonstrating initial evidence for safety and tolerability and that senolytics alleviate physical dysfunction. However, to date, no trial has evaluated senolytic agents in adult survivors of childhood cancer. In order to address this gap in knowledge, we utilize the well-phenotyped population of the St. Jude Life Cohort Study to propose a two arm, randomized, open-label pilot intervention trial in frail survivors (Fried Criteria) of childhood cancer who have diminished walking speed and increased cellular senescence (increased p16INK4a mRNA expression level in peripheral blood T lymphocytes). We aim to test the efficacy of two senolytic regimens: 1) combination of Dasatinib plus Quercetin, and 2) Fisetin alone, to reduce senescent cell abundance in blood and improve walking speed (1° Aim). Secondary endpoints include: additional measures of frailty beyond walking speed (i.e. additional Fried Frailty Criteria), markers of inflammation, insulin resistance, bone resorption and cognitive function. We hypothesize that senolytic therapy will reduce biological markers and clinical measures of aging. Additionally, we will test the safety and tolerability of these senolytic therapies. If successful, this single-institution pilot study will: 1) provide first-in-survivor evidence that targeting cellular senescence pathways can modify frailty and biological markers of aging using brief (two days per month) exposure to senolytic regimens, and 2) provide strong scientific premise for a large-scale clinical trial of efficacy.

抽象的 超过80％的被诊断患有癌症的儿童将在诊断后至少十年生存。但是，到50岁 每年的幸存者，平均经历> 4严重或威胁生命（CTCAE 3-4年级）健康慢性 条件（通常在数十年以上的人中看到的速度）提出了对生理脆弱早期发作的关注。 脆弱是损失生理能力，会干扰正常功能，最常见于较老的生理能力 成人和特征（油炸标准）的三个或更多：1）低瘦肌肉质量，2）降低强度，3） 步行速度缓慢，4）低能量消耗和5）疲劳。在一般人口中，脆弱的 老年。但是，中位年龄仅为33岁（范围18-50），有8％的表面是脆弱的，另外22.2％ 满足预货车的定义（五个标准中的两个），类似于成年人> 65岁的成年人。细胞感应， 静态状态，代表了一个细胞复制或生长的能力，是一个重要而建立的 衰老过程中的机制。衰老与脆弱和衰老的生物标志物密切相关 老年人。现在有证据表明，用化学疗法治疗和 放射疗法和海拔高度与脆弱的措施有关。那就是细胞感应 可能会提供有针对性的途径来改善衰老的测量。 dasatinib和类黄酮等特工 （槲皮素； fisetin，可作为营养补充）中断该途径，因此是“鼻溶剂”。六 与感应相关的慢性疾病状态中，效率的临床试验正在进行中（例如特发性 肺纤维化）和体弱的种群，包括成年骨髓移植受者 证据证明了安全性和耐受性的证据，并且可以缓解身体功能障碍。但是，迄今为止没有试用 已经评估了儿童癌症成人生存中的鼻溶剂。为了解决这一知识的差距， 我们利用圣裘德生活队列研究的良好型人群提出了一个随机的两臂， 儿童癌症的脆弱生存期（油炸标准）的开放标签飞行员干预试验已减少 步行速度和增加的细胞感应（p16Ink4a mRNA表达水平升高 T淋巴细胞）。我们旨在测试两种鼻溶剂方案的效率：1）达沙替尼加的组合 槲皮素和2）单独的fisetin，以减少血液中的感觉细胞丰度并提高步行速度（1° 目的）。次要终点包括：超出步行速度的其他脆弱措施（即其他油炸 脆弱的标准），炎症，胰岛素抵抗，骨骼分辨率和认知功能的标记。我们 假设鼻溶疗法将减少生物学标记和衰老的临床指标。此外， 我们将测试这些塞溶性疗法的安全性和耐受性。如果成功，这项单身试点研究 意志：1）提供首先活生生的证据，表明靶向细胞感应途径可以改变脆弱和 使用短暂（每月两天）暴露于鼻溶剂方案的衰老的生物标志物，2） 强大的科学前提，用于大规模的效率临床试验。