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 长期目标：诺埃尔博士的长期职业目标是减少痛苦，最大限度地 通过确定转化性治疗策略在青少年和年轻成人(AYA)中进行化疗剂量 用于化疗引起的周围神经病(CIPN)。 临床问题：CIPN(如手脚麻木/刺痛)是一种常见的并发症 与化疗剂量减少相关的长春新碱/紫杉醇化疗，从而 增加了死亡的风险。然而，目前还没有推荐的预防CIPN的治疗方法，而且几乎没有 了解AYAS中的CIPN以指导临床试验的发展。 候选人背景：诺埃尔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 管理试验通过进行随机对照试验来测试在线自我管理的有效性 慢性疼痛CIPN的管理干预。诺埃尔博士目前是达纳-法伯大学的博士后研究员。 癌症研究所(DFCI)，并已获得内部资金，用于研究临床医生决策支持的有效性 改进CIPN评估的算法；以及探索瑜伽对CIPN的影响的外部资金。 职业发展计划：这项K23计划的实施将进一步推动候选人实现他的目标 通过为他提供特定的培训，成为一名独立的、翻译症状科学研究人员 1)代谢和基因组中间体的测量和分析；2)CIPN的作用机制 开发，以及3)临床试验中患者报告结果的设计、测量和分析。DFCI 是一个最佳的培训环境，因为候选人将能够获得专家、课程和资源 与研究和培训目标保持一致。 具体目标：这项纵向研究的总体目标是确定对设计 CIPN预防AYA癌症的临床试验。主要目的是确定两者之间的关联 血清烟酰胺核苷二核苷酸水平与CIPN严重程度及相关功能 干扰。次要目标是1)评估高危CEP72(位于rs924607的TT)之间的关联 基因和CIPN严重程度及相关功能损害2)检查患者的心理测量学特性 生活质量问卷-化疗所致周围神经病(QLQ-CIPN20)。 预期结果：将NAD+确立为CIPN发展的生理影响因素将直接 今后的工作是测试干预措施，以促进CIPN预防的NAD+。身份的鉴定 CEP72作为CIPN的生物标志物将增加统计能力，并允许AYA检查的分层 未来试验中的治疗反应。确定QLQ-CIPN20的心理测量学特性将有助于 AYAS中有效的CIPN干预措施的确定。

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.