De Novo Nucleotide Synthesis as a Mediator of Radiation Resistance and a Therapeutic Target in Glioblastoma

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This K08 proposal will complete Dr. Daniel R. Wahl, MD, PhD’s training towards his long-term career goal of directing an independent research program that aims to improve treatments for patients with glioblastoma (GBM) by understanding interactions between abnormal GBM metabolism and the radiation response. Dr. Wahl is an Assistant Professor of Radiation Oncology in the Department of Radiation Oncology at the University of Michigan with established success in the field of radiation oncology. This proposal builds on Dr. Wahl’s previously acquired expertise in radiation biology and the mechanisms of metabolically-targeted drugs to develop expertise in flux-based metabolomics studies, bioinformatics analyses of large data sets and advanced mouse modeling of GBM. These established and newly-acquired skills will be integrated to improve our understanding of how metabolic adaptation interactions with the radiation response and to test new therapeutic options for patients with GBM. The work proposed herein will be conducted under the guidance of primary mentor Theodore S. Lawrence, MD, PhD and co-mentors Maria Castro PhD and Charles A. Burant MD, PhD and an advisory team of accomplished investigators with expertise in the fields of metabolomics, mouse modeling of GBM and computational biology as well as a long track record of mentroring success. This 5-year plan includes formal coursework, professional development and progressively independent research, with defined milestones to ensure productivity and a successful transition to independence. Nearly all glioblastoma (GBM) recur within the high dose radiation field. We previously showed that inhibiting abnormal metabolism in GBM is an effective strategy to abrogate radiation-resistance. We have since performed an unbiased metabolomic analysis of 23 genetically distinct GBM cell lines, which has implicated de novo purine and pyrimidine synthesis as the metabolic pathways most associated with radiation resistance in GBM. For the work proposed in this K08 Award, we will use flux-based metabolomics, patient-derived xenograft models of GBM and FDA-approved inhibitors of de novo nucleotide synthesis to test the hypothesis that ionizing radiation directly increases the activity of de novo purine and pyrimidine synthesis in GBM and that inhibition of these pathways will augment radiotherapy by blunting the DNA damage response. Because the terminally-differentiated cells that comprise normal brain predominantly rely on nucleotide salvage rather than de novo synthesis and because already FDA approved drugs targeting these pathways are well-tolerated in patients, we believe that de novo nucleotide synthesis may be a promising therapeutic target for selective radiosensitization in GBM.