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

项目总结/摘要 化疗引起的周围神经病变（CIPN）是一种严重的剂量限制性毒性， 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 它广泛用于乳腺癌、前列腺癌、肺癌、结肠直肠癌和血癌等。 CIPN不仅通过限制化疗剂量而增加死亡率，CIPN还影响行走，写作， 进食和穿衣时出现麻木、刺痛、疼痛、冷敏感和手脚抽筋。那里 没有FDA批准的CIPN治疗方法，因为我们需要更好地了解病理生理学， 的CIPN和有前途的治疗CIPN的作用机制。迄今为止，大多数关于CIPN的研究 病理生理学集中于外周感觉神经损伤。这个项目的动机是一个创新的 CIPN的症状不仅仅是由于周围神经损伤，而是CIPN 症状因内感受性脑系统的损伤而恶化（即，大脑对周围环境的反应 神经损伤）。该项目的长期愿景是基于机制的CIPN子类型和机制- 基于CIPN的治疗由大脑功能磁共振成像告知，就像在其他脑介导的疾病中所做的那样， 慢性疼痛和抑郁 这是一项II期随机临床试验，旨在评估内感受性大脑中的CIPN和fMRI大脑连接 系统中的66例CIPN患者从神经毒性化疗之前和之后6周的运动与平常 在乎本研究将作为临床试验URCC 19075的一部分。该项目的具体目标是 (1)获得CIPN和功能连接之间的关系的初步估计， CIPN患者的内感受性脑系统，以及（2）获得对CIPN影响的初步估计， 运动与不运动对CIPN严重程度和内感受性脑系统功能连接的影响， CIPN患者 这是第一个研究内感受性脑系统在CIPN的病理生理和治疗。 这项研究的结果将为R 01应用提供信息，以更明确地评估CIPN的这一理论， 锻炼的如果这项工作是成功的，它将揭示一种新的客观生物标志物的CIPN功能连接， 内感受性脑系统--利用神经内分泌系统改善CIPN的预测、跟踪、分型和治疗 运动或其他干预措施影响这个大脑系统。这最终将有助于减轻 化疗对癌症患者的治疗作用。 主席：Ian Kleckner

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