Dissecting the Determinants of IDH-mutant Gliomas Response to Mutant IDH Inhibitors

Abstract This proposal focuses on IDH-mutant gliomas, a leading cause of cancer-related death in people under 45-years old. IDH mutations result in profound distortions in metabolism, chromatin structure and the epigenetic control of gene expression. The oncogenicity of mutant IDH, together with its ubiquitous

expression across malignant cells in IDH-mutant gliomas make it an attractive therapeutic target. However, we and others have found that the responses of IDH-mutant cancers to mutant IDH inhibitors (IDHi) are mixed: some tumors show growth inhibition in the presence of IDHi, while others do not. Clinically, studies in patients with progressive high-grade gliomas have shown scant signs of activity,

but recent data showed signs of objective tumor responses in subset of patients with low-grade gliomas. The basis for this differential response in patients and in models is unknown. Our hypothesis, based on our preliminary data, is that IDHi may act as a differentiation therapy in subsets of glioma

patients by inducing the differentiation of glioma progenitor cells towards mature glial lineages; we further hypothesize that both intrinsic and extrinsic factors will influence the capacity of glioma cells to respond to IDHi. To rigorously test our hypotheses, we propose (Aim 1) to perform single-cell multi-omics analysis in a cohort of IDH-mutant gliomas with and without clinical response to

IDHi. We propose to profile IDHi-treated tumor specimen, and include matched pre- and on-treatment sample pairs. Leveraging novel human and murine low-grade glioma models, we then suggest to dissect how mutations associated with glioma progression (Aim 2) and how extrinsic microenvironmental factors (Aim 3) are affecting the tumor’s response to IDHi. Altogether, this co-PI

R01 research proposal seeks to systematically dissect the neurodevelopmental, genetic and microenvironmental cues that determine IDH-mutant glioma’s response to IDHi throughout their progression.