Characterizing the Risk of Chemotherapy Side Effects Based on Epigenetic Age and Modification by Resistance Training Intervention

根据表观遗传年龄表征化疗副作用的风险并通过抗阻训练干预进行修改

• 批准号: 10280002
• 负责人: Alexandra Margaret Lynn Binder
• 金额: $ 54.94万
• 依托单位: UNIVERSITY OF HAWAII AT MANOA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-08 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10280002
• 关键词: Acceleration; Acute; Address; Adjuvant; Age; Aging; Attenuated; Biological Aging; Biological Assay; Biological Markers; Biological Process; Blood; Body Composition; Body Size; Body measure procedure; Breast Cancer Treatment; Cancer Patient; Cancer Survivor; Cell Aging; Chemotherapy-Oncologic Procedure; Chronology; Clinical Trials; Collaborations; Collection; Colon Carcinoma; Colorectal Cancer; Cyclin-Dependent Kinase Inhibitor 2A; DNA; DNA Damage; DNA Methylation; Diagnosis; Diet; Disease; Dose; Early treatment; Educational Intervention; Elderly; Epigenetic Process; Face; Geriatric Assessment; Health; High Prevalence; Incidence; Individual; Intervention; Malignant Neoplasms; Measures; Modification; Morbidity - disease rate; Muscle function; Muscular Atrophy; Outcome; Participant; Patients; Pattern; Phenotype; Physical Fitness; Physical Function; Physical activity; Prognosis; Recording of previous events; Resources; Risk; Shapes; Telomerase; Thinness; Time; Toxic effect; Toxicity due to chemotherapy; Training; Treatment-related toxicity; United States; Woman; age related; base; cancer diagnosis; cancer therapy; chemotherapy; cohort; colon cancer patients; colon cancer treatment; colorectal cancer treatment; comorbidity; experience; frailty; functional decline; functional disability; health related quality of life; high risk; improved; insight; malignant breast neoplasm; men; mortality; multimodality; muscle form; novel; personalized approach; physical conditioning; prevent; prognostic; rate of change; reduced muscle mass; risk minimization; sarcopenia; side effect; skeletal muscle wasting; strength training; tool; treatment as usual

There is strong evidence that cancer treatment contributes to increased co-morbidity, functional decline, and accelerated biologic aging. Resistance training (RT) interventions may help to minimize this functional decline by increasing lean mass and strength. Patients diagnosed with colon cancer are particularly likely to benefit from RT interventions given the high prevalence of involuntary loss of skeletal muscle mass (sarcopenia) at diagnosis, which is associated with chemotherapy-associated toxicities, and poor prognosis. Geriatric assessment, which measures facets of functional aging, can improve the prediction of chemotoxicity risk to guide treatment decisions. However, application of this tool is frequently limited by the resources required for assessment. Epigenetic clocks, which predict chronologic or phenotypic age based on specific patterns of DNA methylation (DNAm), are easy to assay, well-validated markers of biologic aging. Epigenetic age acceleration (AgeAccel; DNAm-estimated age adjusting for chronologic age) has been associated with indicators of decreased muscle mass and function. We hypothesize that colon cancer patients with increased AgeAccel will be at greater risk for chemotherapy toxicities, dose reductions, and delays, that AgeAccel will increase during colon cancer chemotherapy, and that a RT intervention can reduce the rate of epigenetic aging. We plan to address this scientific premise in collaboration with the Resistance Training to Reduce Chemotoxicity in Colon Cancer (FORCE) clinical trial. This clinical trial of RT in stage II and III colon cancer patients includes DNA and multi-modal measures of body composition collected at the beginning and end of chemotherapy. Our first primary aim will evaluate the relationship between several measures of AgeAccel at baseline and incidence of grade 3 and 4 chemotoxicities, dose reductions, and delays among FORCE participants. We anticipate that increased baseline AgeAccel will be associated with an increased incidence of these outcomes, and that RT can reduce the strength of these associations. Our second primary aim will assess the rate of epigenetic aging during treatment, and whether this rate is modified by RT. We expect that AgeAccel will be higher at the end of chemotherapy relative to the beginning, and that the rate of epigenetic aging will be attenuated in the RT group. Together, these analyses will provide novel insight into the biologic processes of aging that predict tolerance of cancer treatment, and inform appraisal of whether AgeAccel may serve as a useful tool to guide treatment decisions.

有充分的证据表明癌症治疗有助于增加合并症，功能性 下降和加速生物衰老。抵抗训练（RT）干预可能有助于 通过增加瘦肉质量和强度来最大程度地减少功能下降。诊断出患者 鉴于较高的患病率，结肠癌尤其有可能受益 诊断时的骨骼肌质量（肌肉减少症）的非自愿丧失 化学疗法相关的毒性和预后不良。老年评估，测量 功能衰老的方面可以改善指导治疗的趋化风险的预测 决定。但是，该工具的应用通常受到所需资源的限制 评估。表观遗传时钟，基于特定的年龄或表型年龄 DNA甲基化（DNAM）的模式易于测定，生物衰老的验证标记。 表观遗传年龄的加速度（AGEACCEL； DNAM估计的年龄调节年龄）具有 与肌肉质量和功能降低的指标有关。我们假设这一点 AGEACCEL升高的结肠癌患者将面临化学疗法毒性的风险更大， 减少剂量和延误，在结肠癌化学疗法期间，AgeACCEL将增加 RT干预可以降低表观遗传衰老的速度。我们计划解决这一科学 与阻力训练合作的前提，以降低结肠癌的介毒性 （力）临床试验。 II期和III结肠癌患者中RT的这项临床试验包括 在开始和末端收集的身体成分的DNA和多模式测量 化学疗法。我们的第一个主要目的将评估几种措施之间的关系 基线和3级和4级化学毒性的发生率，降低剂量和延迟的发生率 在力量参与者中。我们预计基线的AGEACCEL将会增加 随着这些结果的发生率增加，RT可以降低这些结果的强度 协会。我们的第二个主要目的将评估治疗过程中表观遗传衰老的速率， 以及该速率是否通过RT修改。我们希望Ageaccel在结束时会更高 相对于开始的化学疗法，并且表观遗传衰老的速率将减弱 RT组。这些分析将共同提供对生物过程的新见解 预测癌症治疗耐受性的衰老，并告知Ageaccel是否可以 用作指导治疗决策的有用工具。