The Effects of Exercise on Chemotherapy-Induced Peripheral Neuropathy, Inflammation, and Interoceptive Brain Circuitry

项目总结 概述。化疗引起的周围神经病变(CIPN)是NCI给予的一个高度优先的研究领域 它的高患病率、严重程度和缺乏既定的治疗方法。CIPN患者出现麻木和 手和脚的神经性疼痛，尤其是由于冷刺激。尽管药物还没有证明 成功治疗CIPN，我们的初步数据显示，化疗期间进行6周的锻炼 减少患者报告的CIPN症状(麻木/刺痛)。运动可能是有效的，因为它广泛存在 对参与CIPN病因学的多个途径的影响，包括炎症和大脑。我们的小说 理论框架认为，化疗导致CIPN症状的部分原因是慢性炎症 并通过扰乱大脑对来自身体的感觉的处理(内感)。如果我们的理论是正确的， 未来的干预措施可以量身定做，以使炎症和内感觉正常化，作为全面 CIPN的治疗计划。该应用程序使用了为期12周的运动与 营养教育(对照)，评价运动对CIPN的初步疗效。 职业发展计划。克莱克纳博士有研究内感大脑回路的经验，他有 最近开始研究癌症控制和CIPN。成为学习和使用的独立调查者 为了减少癌症治疗的毒性，如CIPN，他需要在(1)设计和 对癌症患者进行临床试验，(2)设计和实施行为干预， 特别是运动；(3)研究和治疗CIPN及其病因，特别是炎症和大脑， 以及(4)作为独立的调查者融入肿瘤学和症状管理领域。克莱克纳医生的 指导团队在这些领域拥有专业知识，URMC的环境在癌症控制方面是世界级的。 研究计划。80名乳腺癌患者(非转移性，即将接受紫杉烷化疗，以及 试验期间没有放射或手术)将被随机分配到12周：ARM 1，标准护理加 运动或手臂2：标准护理加营养教育(对照)。既定的运动干预 (EXCAP©®)，由Mustian博士(Mentor)开发，包括面对面的指导和AT- 居家渐进式步行和抵抗力训练计划。营养教育(控制)包括平等的时间 和注意力就像运动手臂一样，但涵盖了癌症患者的营养，缺乏运动处方。 措施包括患者报告的CIPN症状，以及对CIPN、炎症和 干预前、干预后、干预后3个月的内感。 冲击力。克莱克纳博士将获得成为独立研究人员所需的关键培训，并将拥有 支持未来研究CIPN的R01拨款的数据。这项工作将为我们深入了解 在CIPN上进行练习，并将探索其与目前研究不足的两条生物途径的关系- 炎症和内感。这项工作特别重要，因为CIPN没有有效的治疗方法。

PROJECT SUMMARY Overview. Chemotherapy-induced peripheral neuropathy (CIPN) is a high-priority research area for NCI given its high prevalence, severity, and lack of established treatments. Patients with CIPN suffer from numbness and neuropathic pain in their hands and feet, especially from cold stimulation. Although drugs have not proven successful for treating CIPN, our preliminary data suggest that 6 weeks of exercise during chemotherapy reduces patient-reported CIPN symptoms (numbness/tingling). Exercise may be effective due to its widespread effects on multiple pathways involved in the etiology of CIPN, including inflammation and the brain. Our novel theoretical framework proposes that chemotherapy causes CIPN symptoms partly via chronic inflammation and by disrupting the brain’s processing of sensations from the body (interoception). If our theory is correct, future interventions can be tailored to normalize inflammation and interoception as part of a comprehensive treatment plan for CIPN. This application uses a 12-week phase II randomized clinical trial of exercise vs. nutrition education (control) to assess the preliminary efficacy of exercise on CIPN. Career Development Plan. Dr. Kleckner has experience studying interoceptive brain circuitry, and has recently begun studying cancer control and CIPN. To become an independent investigator studying and using exercise to ameliorate toxicities from cancer treatment, such as CIPN, he needs training in (1) designing and conducting clinical trials with cancer patients, (2) designing and conducting behavioral interventions, specifically exercise, (3) studying and treating CIPN and its etiology, specifically inflammation and the brain, and (4) integrating into oncology and symptom management as an independent investigator. Dr. Kleckner’s mentoring team has expertise in these areas and the environment at URMC is world-class for cancer control. Research Plan. Eighty women with breast cancer (non-metastatic, about to receive taxane chemotherapy, and no radiation or surgery during the trial) will be randomly assigned to 12 weeks of: Arm 1, standard care plus exercise or Arm 2: standard care plus nutrition education (control). The established exercise intervention (EXCAP©®), developed by Dr. Mustian (mentor), involves face-to-face instruction and a prescription for an at- home progressive walking and resistance exercise program. Nutrition education (control) involves equal time and attention as the exercise arm, but covers nutrition for cancer patients and lacks an exercise prescription. Measures include patient-reported CIPN symptoms, and clinical assessments of CIPN, inflammation, and interoception at pre-intervention, post-intervention, and 3 months post-intervention. Impact. Dr. Kleckner will obtain critical training required to become an independent researcher and will have data to support a future R01 grant studying CIPN. This work will provide valuable insight into the effects of exercise on CIPN and will explore its relationship with two currently understudied biological pathways— inflammation and interoception. This work is particularly important because CIPN has no effective treatments.