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

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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.