BI-07 * HYPERPOLARIZED [1-13C] GLUTAMATE: A METABOLIC IMAGING BIOMARKER OF IDH1 MUTATIONAL STATUS IN GLIOMA

Abstract

Mutations of the isocitrate dehydrogenase 1 (IDH1) gene are among the most prevalent in low-grade glioma and secondary glioblastoma, represent an early pathogenic event and are being considered a promising therapeutic target. Consequently, non-invasive imaging methods are needed to monitor IDH1 status. Amongst these, we previously demonstrated the use of 13C MR spectroscopic imaging of hyperpolarized [1-13C] α-ketoglutarate (α-KG) to non-invasively assess IDH1 status through the detection of the conversion of hyperpolarized α-ketoglutarate to 2-hydroxyglutarate (2-HG) catalyzed by mutant IDH1. Importantly, in addition to its oncogenic role, IDH1 mutation is also associated with global modulations in metabolism. Interestingly, a study recently uncovered a relationship between presence of IDH1 mutation and decreased activity of the branched chained amino acid transaminase 1 (BCAT1) enzyme, which transaminates amino acids while converting α-KG to glutamate. Given this new study, we decided to expand on our previous findings and investigated the potential of hyperpolarized α-KG as an imaging probe to monitor BCAT1-driven α-KG-to-glutamate conversion and its modulation in the presence of IDH1 mutation. We investigated two isogenic glioblastoma lines that differed only in their IDH1 status, and performed experiments in live cells and in vivo in rat orthotopic tumors. Following injection of hyperpolarized α-KG, hyperpolarized glutamate production was detected both in cells and in vivo, and the level of hyperpolarized glutamate was significantly lower in mutant IDH1 cells and tumors compared to their IDH1-wild-type counterparts. Importantly however, the observed drop in hyperpolarized glutamate was likely mediated not only by a drop in BCAT1 activity, but also by reductions in aspartate transaminase and glutamate dehydrogenase activities, suggesting additional metabolic reprogramming at least in our model. Hyperpolarized glutamate could thus inform on multiple mutant IDH1-associated metabolic events and serve as a secondary metabolic biomarker of IDH1 mutational status in gliomas, together with 2-HG.