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

项目摘要 概况.化疗引起的周围神经病变（CIPN）是NCI的一个高优先级研究领域， 其高患病率、严重性和缺乏既定治疗。CIPN患者会出现麻木， 手脚神经性疼痛，尤其是冷刺激。虽然药物还没有证明 成功治疗CIPN，我们的初步数据表明，化疗期间6周的运动 减少患者报告的CIPN症状（麻木/刺痛）。锻炼可能是有效的，因为它的广泛 对CIPN病因学中涉及的多种途径的影响，包括炎症和大脑。我们的新型 理论框架提出化疗部分通过慢性炎症引起CIPN症状 以及干扰大脑对身体感觉的处理（内感受）。如果我们的理论正确， 未来的干预措施可以使炎症和内感受正常化， CIPN的治疗方案。本申请使用了一项为期12周的II期随机临床试验， 营养教育（对照），以评估运动对CIPN的初步疗效。 职业发展计划。Kleckner博士有研究内感受性大脑回路的经验， 最近开始研究癌症控制和CIPN。成为一名独立的研究者， 运动，以改善癌症治疗的毒性，如CIPN，他需要培训（1）设计和 对癌症患者进行临床试验，（2）设计和进行行为干预， 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）作为独立的研究者融入肿瘤学和症状管理。克莱克纳医生 指导团队在这些领域拥有专业知识，URMC的环境是世界一流的癌症控制。 研究计划。80名患有乳腺癌（非转移性，即将接受紫杉烷化疗， 试验期间未接受放疗或手术）将被随机分配至12周：第1组，标准治疗加 运动或组2：标准护理加营养教育（对照）。既定的运动干预 （EXCAP©®）由Mustian博士（导师）开发，包括面对面的指导和一个at- 家庭渐进式步行和阻力锻炼计划。营养教育（控制）涉及平等的时间 和注意力作为运动手臂，但涵盖了癌症患者的营养，缺乏运动处方。 测量包括患者报告的CIPN症状，以及CIPN、炎症和炎症的临床评估。 干预前、干预后和干预后3个月的内感受。 冲击Kleckner博士将获得成为独立研究员所需的关键培训，并将 数据，以支持未来的R 01赠款研究CIPN。这项工作将提供有价值的洞察力的影响， 练习CIPN，并将探索其与两个目前研究不足的生物途径的关系- 炎症和内感受。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.