Integrative Molecular Epidemiology of Neurocognitive Outcomes in Acute Lymphoblastic Leukemia

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Project Summary/Abstract This K07 Career Development Award proposal details the rigorous training, research, and mentorship program that will provide a foundation for Dr. Brown to launch a successful independent research career. Dr. Brown’s long-term career goal is to establish a productive independent research program, with an emphasis on identifying novel biomarkers and modifiable therapeutic targets to reduce the burden of treatment-related toxicity among pediatric cancer patients. Therefore, the research goal for this proposal is to characterize early phenotypic, metabolomic, and genomic biomarkers of chemotherapy-associated neurocognitive impairment in pediatric acute lymphoblastic leukemia (ALL) patients. Although improved treatment regimens for pediatric ALL have resulted in survival rates exceeding 90%, nearly half of patients experience chronic treatment-related neurocognitive dysfunction. This proposal pursues the hypothesis that central nervous system-directed ALL chemotherapy disrupts the equilibrium of cerebral spinal fluid (CSF) metabolome, manifesting as acute symptom toxicity and long-term neurocognitive dysfunction. Because genetic factors likely control the CSF metabolomic response to therapy, we further hypothesize that integrating genetic and metabolomics data will lead to the discovery of causal genetic pathways. The specific research aims of this proposal will evaluate whether: 1) Symptom toxicity during the post-induction phase of ALL therapy reflects chemotherapy-directed neurologic damage and serves as an early marker of post-treatment neurocognitive performance; 2) ALL chemotherapy induces consistent and recognizable changes to CSF metabolomic pathways involved in normal neurocognitive function and development; and 3) Genetic variation modifies individual susceptibility to neurocognitive impairment. Leveraging two NIH-funded studies with rich phenotype data and biospecimen repositories, this innovative proposal will establish one of the largest prospective investigations of neurocognitive outcomes in pediatric ALL patients. The research experience gained during the course of this study complements the proposed career development goals. Specifically, didactic training and interaction with experienced mentors in molecular epidemiology (Dr. Scheurer), symptoms research (Dr. Hockenberry), metabolomics (Dr. Devaraj), and neuropsychology (Dr. Ris) will enhance Dr. Brown’s: 1) Content area expertise in patient-reported symptoms and neurocognitive evaluation; 2) Understanding of metabolomics research methods; and 3) Proficiency in grant and scientific writing. The comprehensive career development and research plan outlined in this proposal will address key gaps in Dr. Brown’s training, provide additional research experience, and serve as a unique resource of preliminary data to support future research endeavors.