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

基本信息

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
项目类别：
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&apos 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

项目摘要

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% 被诊断患有癌症的儿童在诊断后至少可以存活 10 年，但到 50 岁时。每位幸存者平均经历 >4 次严重或危及生命（CTCAE 3-4 级）的慢性健康的情况（通常发生在年长数十岁的人中）引起人们对早发性生理衰弱的担忧。虚弱是指生理能力的丧失，干扰正常功能，最常见于老年人成人，其特征（油炸标准）具有以下三个或三个以上：1) 瘦肌肉质量低，2) 强度降低，3) 步行速度慢，4）能量消耗低，5）一般人群会感到虚弱。然而，幸存者的平均年龄仅为 33 岁（范围为 18-50 岁），其中 8% 的幸存者身体虚弱，另有 22.2% 的幸存者身体虚弱。符合脆弱前的定义（五个标准中的两个），比率与 65 岁以上的成年人相似，代表细胞复制或生长能力丧失的静止状态是一个重要且已确定的状态衰老过程中的机制与身体虚弱和衰老生物标志物密切相关。现在有证据表明，接受化疗和治疗的幸存者中 p16INK4A 升高。放射治疗，并且升高的程度与衰弱程度相关。因此，细胞衰老。可能提供一种有针对性的途径来改善衰老指标，例如达沙替尼和类黄酮。（槲皮素；非瑟酮，可作为营养补充剂）干扰该途径，因此具有“抗衰老”作用。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）和体弱人群，包括成年骨髓移植受者安全性和耐受性以及 senolytics 可以缓解身体功能障碍的证据然而，迄今为止，还没有试验。为了弥补这一知识空白，对儿童癌症成年幸存者的抗衰老药物进行了评估。我们利用圣裘德生命队列研究的良好表型群体提出了一个双组、随机、对体弱的儿童癌症幸存者（弗里德标准）进行的开放标签试点干预试验，这些幸存者的病情已经减少步行速度和细胞衰老增加（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 senolytic 方案的功效：1）达沙替尼加组合。槲皮素和 2) 单独使用非瑟酮，可减少血液中衰老细胞的丰度并提高步行速度（1° 次要终点包括：步行速度之外的其他虚弱指标（即额外的 Fried）。虚弱标准）、炎症、胰岛素抵抗、骨吸收和认知功能的标志物。促进衰老疗法将减少衰老的生物标志物和临床指标。如果成功，我们将测试这些 senolytic 疗法的安全性和耐受性。将：1）提供首个幸存者证据，表明针对细胞衰老途径可以改变虚弱和使用短暂（每月两天）接触 senolytic 方案来检测衰老的生物标志物，以及 2) 提供大规模临床疗效试验的有力科学前提。