Biosynthetic Metabolic Pathway Regulation of Glioma Growth

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ABSTRACT Biosynthetic metabolic pathways provide the building blocks required for cell growth and generate important cell signaling molecules, including reactive species. When dysregulated, these pathways can contribute to brain pathologies including brain tumors. We determined that one biosynthetic pathway involving GTP cyclohydrolase I (GCH1) as the rate-limiting step contributes to the growth of brain tumors and is elevated in the neoplastic stem cell subpopulation. In patient sample datasets, increased levels of GCH1 also correlate with poor outcomes. These data suggest the importance of understanding the biological and molecular roles of GCH1. We have therefore proposed to determine if GCH1 is critical for regulating reactive species balance in glioma and maintaining neoplastic stem cell characteristics. Potential novel downstream mediators of GCH1 effects will be validated. Pharmacologic and genetic inhibition of GCH1 will determine if targeting of GCH1 is sufficient to decrease glioma growth alone or in combination with standard of care. We anticipate these studies will determine if GCH1 or another molecule in the same biosynthetic pathway should be a further investigated as a biomarker for either outcome or therapeutic response. We hope that our studies will provide a greater understanding of the mechanisms through which metabolism is altered in brain disease and inform future novel treatment strategies.