NIMG-28. HYPERPOLARIZED13C IMAGING OF D-2-HYDROXYGLUTARATE-INDUCED DOWNREGULATION OF PYRUVATE DEHYDROGENASE ACTIVITY PROVIDES AN EARLY READOUT OF RESPONSE TO VORASIDENIB IN MUTANT IDH GLIOMAS

Abstract Mutations in isocitrate dehydrogenase (IDHm) define a distinct class of gliomas. IDHm converts a-ketoglutarate (a-KG) to D-2-hydroxyglutarate (D-2HG), which inhibits a-KG-dependent histone/DNA demethylases and induces epigenetic alterations that drive tumorigenesis. The IDHm inhibitor vorasidenib extends progression-free survival in IDHm glioma patients and is expected to be widely used for this patient population. However, not all patients respond to vorasidenib, and magnetic resonance imaging (MRI) does not assess whether a patient is responding to vorasidenib. Therefore, the goal of this study was to identify metabolic alterations induced by D-2HG that can be leveraged for non-invasive imaging of IDHm gliomas. Using clinically relevant patient-derived models (BT257, BT142, BT54, SF10417, SF10602), we show that D-2HG downregulates the activity of pyruvate dehydrogenase (PDH), the rate-limiting enzyme for oxidation of glucose-derived pyruvate via the tricarboxylic acid cycle, by multiple mechanisms. Drug affinity target stability assays show that D-2HG directly binds to and inhibits PDH activity. D-2HG also inhibits a-KG-dependent prolyl hydroxylases that target hypoxia-inducible factor 1-a (HIF-1a) for degradation. As a result, D-2HG stabilizes HIF-1a and drives expression of pyruvate dehydrogenase kinase 3, which phosphorylates and inhibits PDH activity. Suppressing D-2HG using vorasidenib upregulates PDH activity in IDHm glioma cells and intracranial tumors. Next, we examined whether hyperpolarized 13C-MRS, which is an advanced MRI-based method of imaging metabolic activity, monitors PDH activity in IDHm gliomas. Following administration of hyperpolarized [2-13C]-pyruvate, metabolic conversion to [5-13C]-glutamate provides a readout of PDH activity. Our studies indicate that [5-13C]-glutamate production from hyperpolarized [2-13C]-pyruvate is upregulated in IDHm glioma cells treated with vorasidenib. Importantly, [5-13C]-glutamate production is elevated within 5 days of treatment with vorasidenib in rats bearing intracranial BT257 or BT142 xenografts, when changes cannot be observed by MRI. Collectively, our studies identify hyperpolarized [2-13C]-pyruvate as a unique probe of D-2HG-induced metabolic rewiring and highlight its ability to assess IDHm glioma response to therapy, which is a challenge in the clinic.