Determining Mechanisms and Measures for the Design of Chemotherapy-Induced Peripheral Neuropathy Clinical Trials in Adolescents and Young Adults with Cancer

项目摘要 长期职业目标：Knoerl博士的长期职业目标是减少痛苦， 通过确定转化治疗策略，在青少年和年轻人（AYAs）中进行化疗给药 化疗引起的周围神经病变（CIPN）。 临床问题：CIPN（例如，手/脚麻木/刺痛）是一种常见的并发症， 长春新碱/紫杉醇化疗与化疗剂量减少相关，因此 增加死亡的风险。然而，没有推荐的治疗CIPN预防和小 了解AYA中的CIPN，以指导临床试验的发展。 候选人背景：Knoerl博士曾在密歇根大学接受培训，并获得了领导CIPN的专业知识 通过进行随机对照试验来测试在线自我管理的功效， 慢性疼痛性CIPN的管理干预。Knoerl博士目前是Dana-Farber的博士后 癌症研究所（DFCI），并赢得了内部资金，以研究临床医生决策支持的疗效 算法，以改善CIPN评估;和校外资金，以探索瑜伽对CIPN的影响。 职业发展计划：K23提案的实施将进一步推动候选人实现其目标， 成为一个独立的，翻译症状科学调查员，为他提供具体的培训， 1)代谢和基因组中介物的测量和分析，2）CIPN的机制 开发，以及3）临床试验中患者报告结局的设计、测量和分析。DFCI 是一个最佳的培训环境，因为候选人将有机会获得专家，课程和资源 符合研究和培训目标。 具体目的：本纵向研究的总体目标是确定对设计 CIPN预防癌症AYA的临床试验。主要目的是确定以下之间的关联 血清烟酰胺核苷二核苷酸（NAD+）水平和CIPN严重程度及相关功能 干扰次要目的是：1）评价高风险CEP 72（rs 924607处的TT） 基因型和CIPN的严重程度和相关的功能障碍2）检查的心理测量特性， 化疗诱发的周围神经病变的生活质量（QLQ-CIPN 20）。 预期结果：确立NAD+作为CIPN发展的生理影响因素将指导 未来的工作是测试干预措施，以提高NAD+预防CIPN。的识别 CEP 72作为CIPN的生物标志物将增加统计功效，并允许AYA检查分层 在未来的试验中治疗反应。确定QLQ-CIPN 20的心理测量特性将有助于 在AYA中识别有效的CIPN干预措施。

Project Summary Long-TermCareer Goal: Dr. Knoerl’s long-term career goal is to decrease suffering and maximize chemotherapy dosing in adolescents and young adults (AYAs) by identifying translational treatment strategies for chemotherapy-induced peripheral neuropathy (CIPN). Clinical Problem: CIPN (e.g., numbness/tingling in hands/feet) is a common complication of vincristine/paclitaxel chemotherapy that is associated with reductions in chemotherapy dosing, thereby increasing the risk of mortality. Yet, there are no recommended treatments for CIPN prevention and little is known about CIPN in AYAs to guide the development of clinical trials. Candidate Background: Dr. Knoerl trained at the University of Michigan and gained expertise leading CIPN management trials by conducting a randomized controlled trial to test the efficacy of an online self- management intervention for chronic painful CIPN. Dr. Knoerl is currently a postdoctoral fellow at Dana-Farber Cancer Institute (DFCI) and has earned internal funding to study the efficacy of a clinician decision support algorithm to improve CIPN assessment; and extramural funding to explore the impact of yoga for CIPN. Career Development Plan: The conduct of this K23 proposal will further advance the candidate to his goal of becoming an independent, translational symptom science investigator by providing him with specific training in 1) the measurement and analysis of metabolic and genomic intermediaries, 2) mechanisms of CIPN development, and 3) the design, measurement, and analysis of patient-reported outcomes in a clinical trial. DFCI is an optimal environment for training as the candidate will have access to experts, coursework, and resources aligned with the research and training aims. Specific Aims: The overall objective of this longitudinal study is to determine factors crucial to the design of CIPN prevention clinical trials for AYAs with cancer. The primary aim is to determine the association between serum nicotinamide riboside dinucleotide (NAD+) levels and CIPN severity and associated functional interference. Secondary aims are to 1) evaluate the association between the high risk CEP72 (TT at rs924607) genotype and CIPN severity and associated functional impairment 2) examine the psychometric properties of the Quality of Life Questionnaire-Chemotherapy-Induced Peripheral Neuropathy (QLQ-CIPN20). Expected Outcomes: Establishing NAD+ as a physiological influencing factor of CIPN development will direct future work towards the testing of interventions to boost NAD+ for CIPN prevention. The identification of CEP72 as a biomarker of CIPN will increase statistical power and allow for the stratification of AYAs examine treatment response in future trials. Determining the psychometric properties of the QLQ-CIPN20 will aid in the identification of efficacious CIPN interventions in AYAs.