Glutamate is a non-invasive metabolic biomarker of IDH1 mutant glioma response to temozolomide treatment.

Although lower-grade gliomas are driven by mutations in the isocitrate dehydrogenase 1 (IDH1) gene and are less aggressive than primary glioblastoma, they nonetheless generally recur. IDH1 mutant patients are increasingly being treated with temozolomide (TMZ), but early detection of response remains a challenge and there is a need for complementary imaging methods to assess response to therapy prior to tumor shrinkage. The goal of this study was to determine the value of magnetic resonance spectroscopy (MRS)-based metabolic changes for detection of response to TMZ in both genetically engineered and patient-derived mutant IDH1 models. Using 1H MRS in combination with chemometrics identified several metabolic alterations in TMZ-treated cells, including a significant increase in steady-state glutamate levels. This was confirmed in vivo, where the observed 1H MRS increase in glutamate/glutamine occurred prior to tumor shrinkage. Cells labeled with [1-13C]glucose and [3-13C]glutamine, the principal sources of cellular glutamate, showed that flux to glutamate both from glucose via the tricarboxylic acid cycle and from glutamine were increased following TMZ treatment. In line with these results, hyperpolarized [5-13C]glutamate produced from [2-13C]pyruvate and hyperpolarized [1-13C]glutamate produced from [1-13C]α-ketoglutarate were significantly higher in TMZ-treated cells compared to controls. Collectively, our findings identify 1H MRS-detectable elevation of glutamate and hyperpolarized 13C MRS-detectable glutamate production from either pyruvate or α-ketoglutarate as potential translatable metabolic biomarkers of response to TMZ treatment in mutant IDH1 glioma.