Glutamine antagonists disrupt the epigenetically maintained embryonic stem cell like state in AT/RT

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PROJECT SUMMARY/ABSTRACT: Childhood brain tumors are the leading cause of mortality in pediatric cancer patients. My overall career goal is to become an independent, physician-scientist working to identify and advance novel therapies to improve these outcomes. One such avenue is to identify specific metabolic antagonists to target and disrupt the epigenetic abnormalities, common to many childhood brain tumors, which transform cancers and drive poor prognoses. Our understanding of the epigenetic consequences of metabolic therapies, especially in pediatric brain tumors, is nascent. This proposal outlines a 5-year career development program to develop my expertise and independence performing translational metabolomics research and epigenetic analysis to fill this gap in childhood brain tumor research. To date, my work has focused on the impact of glutamine antagonism on the embryonic stem cell (ESC)-like state in atypical teratoid/rhabdoid tumors (AT/RT), an aggressive infantile brain tumor. We have previously shown that glutamine antagonists decrease the methylation index in AT/RT, leading to histone hypomethylation, decreased expression of cancer stem cell factors, and increased expression of neuronal differentiating genes. In this proposal, I will carry out in vivo metabolomics and metabolic flux experiments to identify the metabolic pathways disrupted by glutamine antagonists and lead to these changes in histone methylation. I will then determine the consequences on the epigenetic regulation of gene expression involved in the maintenance of an ESC-like state using CHIPSeq, RNASeq, and whole genome bisulfite sequencing (WGBS). Finally, I will use magnetic resonance spectroscopy to identify a metabolic signature that predicts ongoing tumor sensitivity to glutamine antagonism in growing orthotopic tumors. Insights gained will inform the use of glutamine antagonists to treat AT/RT as well as other epigenetically driven tumors, such as medulloblastoma and diffuse midline gliomas. Funding from this mentored award will support development of the skills I need to run an independent metabolomics laboratory, tools to analyze the epigenetic consequences of metabolic antagonists, and metabolic imaging techniques that will enable real-time metabolic analyses of growing orthotopic tumors in murine models of patient-derived xenografts. My team of mentors comprises investigators who are at the forefront of cancer research, each having longstanding records of NIH funding, high-impact publications, and translation of their research to new drug development in human clinical trials. Collectively, they have mentored numerous young researchers who successfully developed into independently funded PIs. Their enthusiasm for both my grant proposal and career development will provide a strong environment ensuring my rapid scientific development. The skills I gain will help me establish one of very few metabolomics laboratories dedicated to pediatric brain tumor research and achieve my career goal as a physician-scientist determined to improve treatment strategies for childhood brain tumors.