Austin L. Brown - US grants

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.

Project Summary This proposal seeks to integrate clinical, demographic, metabolomic, and genomic data to advance our understanding of ethnic disparities in treatment-related hepatoxicity (TAH) during induction therapy for pediatric acute lymphoblastic leukemia (ALL). Improved treatment regimens for pediatric (ALL) have resulted in survival rates exceeding 90%; however, nearly a quarter of patients experience TAH. Emerging evidence from our group has identified striking ethnic disparities in the incidence of TAH. Specifically, Latino patients with ALL appear particularly vulnerable to dose-limiting TAH, potentially compromising treatment efficacy during the critical initial induction phase and contributing to well-established disparities in pediatric ALL relapse and survival. This proposal pursues the central hypothesis that risk of TAH is greater in Latino patients as compared to non-Latino patients due to a combination of inherited and potentially modifiable risk factors. Our preliminary data suggest ethnic disparities in TAH incidence are exacerbated but not fully explained by ethnic variation in obesity and that the abundance of key metabolites in the blood associated with liver function, which are likely influenced by treatment exposures and inherited genetic variation, may serve as powerful biomarkers of TAH risk. Informed by our preliminary data, the specific research aims of this Project will examine: 1) to what extent ethnic variability in obesity and associated hepatic dysfunction contribute to ethnic differences in the incidence of TAH during pediatric ALL induction therapy; 2) whether consistent and recognizable changes induced by ALL chemotherapy in the metabolomic pathways involved in liver function are predictive of TAH; and 3) how genetic variation modifies individual susceptibility to TAH. This Project, which is jointly led by investigators with expertise in pediatric oncology (Drs. Huynh and Orgel) and molecular epidemiology (Dr. Brown), builds on the rich resources available in the ethnically diverse, multi-institutional Reducing Ethnic Disparities in Acute Leukemia (REDIAL) consortium. Leveraging the Retrospective (n=2,958) and Prospective (n=1,369) REDIAL Cohorts, this project will systematically evaluate and follow an additional 600 newly diagnosed cases of pediatric ALL. Thus, this innovative proposal will establish one of the largest prospective investigations of TAH in a multi-ethnic cohort of pediatric patients with ALL. The comprehensive research plan outlined here will address key gaps in our understanding of ethnic disparities in the incidence and etiology of TAH and serve as a unique resource of preliminary data to support future research endeavors. Ultimately, we anticipate that this work will inform risk- stratified approaches to safely deliver curative induction chemotherapy to Latino children and adolescents treated for ALL to improve their overall survival.