Defining and Therapeutically Targeting IDH1-WT Oncogenicity in GBM

Murnan, Kevin Michael

doi:https://doi.org/10.21985/n2-w941-cn10

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Defining and Therapeutically Targeting IDH1-WT Oncogenicity in GBM

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Glioblastoma multiforme (GBM) is the most prevalent primary central nervous system tumor, characterized by resistance to therapeutic intervention, inevitable recurrence, and ultimately patient death. The dismal prognosis is due in part to underlying molecular factors that promote an intratumoral cellular state heterogeneity and protect tumor cells from cell death pathways. Our group recently identified that upregulation of IDH1-WT is a unique molecular event in the context of GBM which promotes a stem like cellular state while producing NADPH reducing equivalents necessary for fueling de novo lipid biogenesis. Further, we have shown that genetic and pharmacological reduction of IDH1-WT function decreases tumor burden while extending survival in a patient-derived xenograft (PDX) mouse model of GBM. Based on these results, we hypothesized that IDH1-WT may regulate mechanisms of intratumoral heterogeneity while suppressing cellular death. By performing in vitro experiments coupled with TCGA analysis we have uncovered the role of IDH1-WT for maintaining GIC stemness and plasticity by promoting an outer radial glia (oRG)-like cellular state capable of contributing to intratumoral heterogeneity. We have further shown that IDH1-WT protects glioma cells from ferroptotic cell death by providing precursors and reducing equivalents necessary for master ferroptotic regulator GPX4 cofactor, GSH, production. In an effort to exploit this unique metabolic vulnerability, we have characterized a first-in-class, brain-penetrant IDH1-WT inhibitor, IDH1i-13. Treatment with IDH1i-13 resulted in decreased tumor burden and increased survival in a PDX model of GBM. To determine whether IDH1-WT dysregulation is a generalized mechanism of cancer pathogenesis, we performed TCGA analysis identifying a multitude of cancers codified by aberrant IDH1-WT expression and associated impact on patient survival. Collectively, our results further our understanding of IDH1-WT in GBM pathogenesis while providing a therapeutically viable modality for patient treatment.

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