Assessing the role of the interoceptive brain system in the pathophysiology and treatment of chemotherapy-induced peripheral neuropathy

项目摘要/摘要 化疗引起的周围神经病(CIPN)是一种严重的剂量限制性毒性，影响65%以上的 每年大约有250,000名患者接受神经毒性化疗(例如紫杉烷、铂、长春花碱 生物碱)，广泛用于乳腺癌、前列腺癌、肺癌、结直肠癌和血癌等。 CIPN不仅通过限制化疗剂量增加死亡率，而且还影响行走、写作、 通过麻木、刺痛、疼痛、冷敏感和手脚抽筋来进食和穿衣。那里 没有FDA批准的治疗CIPN的方法，因为我们需要更多地了解病理生理学 CIPN的作用机制和有希望的治疗CIPN的机制。到目前为止，大多数关于CIPN的研究 病理生理学的研究重点是周围感觉神经损伤。这个项目的动机是一种创新的 观点认为，CIPN症状不是简单地由于周围神经损害，而是CIPN 大脑感觉间系统(即大脑对外周的反应)受损会使症状恶化 神经损伤)。该项目的长期愿景是基于机制的CIPN亚型和机制- 通过脑功能磁共振成像对CIPN进行的基础治疗，就像在其他脑介导的情况下所做的那样 作为慢性疼痛和抑郁。 这是一项II期随机临床试验，旨在评估CIPN和fMRI在感觉间脑中的脑连通性 66例神经毒性化疗后CIPN患者运动前、后6周与平时比较 关心。这项研究将作为临床试验URCC 19075的一部分。这个项目的具体目标是 (1)获得CIPN和功能连接之间关系的初步估计 CIPN患者的相互感觉脑系统，以及(2)获得对CIPN患者影响的初步估计 运动与不运动对大鼠感觉间脑系统CIPN严重性和功能连接性的影响 CIPN患者。 这是第一次研究CIPN的病理生理学和治疗中的相互感觉脑系统。 这项研究的结果将为R01应用程序提供信息，以更明确地评估CIPN和 锻炼身体。如果这项工作成功，它将揭示CIPN的一个新的客观生物标记物-功能连接性 相互感觉的大脑系统-使用以下技术改善CIPN的预测、跟踪、分型和治疗 运动或其他影响大脑系统的干预措施。这最终将有助于减轻 化疗对癌症患者的治疗作用。 主席：伊恩·克莱克纳

PROJECT SUMMARY/ABSTRACT Chemotherapy-induced peripheral neuropathy (CIPN) is a severe dose-limiting toxicity that affects over 65% of the roughly 250,000 patients per year receiving neurotoxic chemotherapy (e.g., taxane-, platinum-, vinca alkaloid-based), which is widely used for breast, prostate, lung, colorectal, and blood cancers among others. Not only does CIPN increase mortality by limiting the dose of chemotherapy, CIPN affects walking, writing, eating, and dressing via numbness, tingling, pain, cold sensitivity, and cramping in the hands and feet. There are no FDA-approved treatments for CIPN because we need a greater understanding of the pathophysiology of CIPN and mechanisms of action of promising treatments for CIPN. To date, most research on CIPN pathophysiology has focused on peripheral sensory nerve damage. This project is motivated by an innovative perspective that CIPN symptoms are not due simply to peripheral nerve damage, but rather that CIPN symptoms are worsened by damage to the interoceptive brain system (i.e., the brain’s reaction to peripheral nerve damage). The long-term vision for this project is mechanism-based CIPN sub-typing and mechanism- based treatments for CIPN informed by brain fMRI, as has been done in other brain-mediated conditions such as chronic pain and depression. This is a Phase II randomized clinical trial to assess CIPN and fMRI brain connectivity in the interoceptive brain system in 66 patients with CIPN from neurotoxic chemotherapy before and after 6 weeks of exercise vs. usual care. This study will be included as part of the clinical trial URCC 19075. The specific aims of this project are (1) to obtain preliminary estimates of the relationships between CIPN and functional connectivity in the interoceptive brain system in patients with CIPN, and (2) to obtain preliminary estimates of the effects of exercise vs. no exercise on both CIPN severity and functional connectivity in the interoceptive brain system in patients with CIPN. This is the first study to examine the interoceptive brain system in the pathophysiology and treatment of CIPN. Results from this study will inform an R01 application to more definitively assess this theory of CIPN and exercise. If this work is successful, it will reveal a novel objective biomarker of CIPN—functional connectivity in the interoceptive brain system—to improve prediction, tracking, sub-typing, and treatment of CIPN using exercise or other interventions that affect this brain system. This will ultimately help alleviate the burden of chemotherapy on treating patients with cancer. Chair: Ian Kleckner