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

摘要 超过80%被诊断患有癌症的儿童在诊断后至少存活十年。然而，到了50岁， 每名幸存者平均经历> 4次严重或危及生命（CTCAE 3 - 4级）的慢性健康 疾病（通常见于几十岁以上的人）引起了对生理脆弱早期发作的关注。 虚弱是一种生理能力的丧失，干扰了正常的功能，最常见于老年人。 成年人和特征（弗里德标准）的三个或更多的：1）低瘦肌肉质量，2）减少的力量，3） 步行速度慢，4）能量消耗低，和5）疲劳。在一般人群中， 老人然而，在中位年龄只有33岁（范围18 - 50），8%的幸存者是虚弱的，额外的22.2%， 符合虚弱前期的定义（五项标准中的两项），比率与65岁以上的成年人相似。细胞衰老， 静止状态代表细胞复制或生长能力的丧失，是一个重要的和既定的 老化过程中的机制。衰老与身体虚弱和衰老生物标志物密切相关， 老年人口。现在有证据表明，p16INK4A在接受化疗的幸存者中升高， 放射治疗，并且升高的幅度与虚弱的测量相关。因此，细胞衰老 可以提供一个有针对性的途径，以改善老化的措施。药物如达沙替尼和类黄酮 （槲皮素;非瑟酮，可作为营养补充剂获得）干扰该途径，因此是"衰老清除剂"。六 目前正在与衰老相关的慢性疾病状态（例如特发性 肺纤维化）和虚弱人群，包括表现出初始 安全性和耐受性的证据，以及senolytics减轻身体功能障碍。然而，迄今为止， 评估了儿童癌症成年幸存者的衰老清除剂。为了弥补这一知识差距， 我们利用St.Jude Life队列研究的良好表型人群，提出了一个两组，随机， 一项在儿童癌症的虚弱幸存者（Fried标准）中进行的开放标签试点干预试验， 步行速度和增加的细胞衰老（外周血中p16INK4a mRNA表达水平增加 T淋巴细胞）。我们的目的是测试两种衰老清除方案的疗效：1）达沙替尼+ 槲皮素和2）单独的非瑟酮，以减少血液中衰老细胞的丰度并提高步行速度（1 ° Aim）。次要终点包括：步行速度以外的其他虚弱指标（即额外的Fried 虚弱标准）、炎症标志物、胰岛素抵抗、骨吸收和认知功能。我们 假设衰老清除疗法将减少衰老的生物标志物和临床测量。此外，本发明还 我们将测试这些衰老清除疗法的安全性和耐受性。如果成功，这项单一机构的试点研究 将：1）提供第一个幸存者证据，证明靶向细胞衰老途径可以改变脆弱性， 使用短暂（每月两天）暴露于衰老清除方案的衰老生物标志物，以及2）提供 为大规模临床疗效试验提供了强有力的科学前提。

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.