Leveraging reactive metabolite generation in brain tumors

PROJECT SUMMARY Gliomas rank among the deadliest forms of cancer. Mutations in isocitrate dehydrogenase 1 or 2 (IDHm) define a molecular subtype of adult gliomas that typically afflict younger patients. Standard of care includes surgical resection, radiation, and chemotherapy. However, this regimen only delays progression and patients inevitably face tumor recurrence and premature death. There is a need for novel therapies for IDHm glioma patients. IDHm produces the oncometabolite D-2-hydroxyglutarate, which disrupts redox homeostasis by depleting glutathione (GSH). GSH is essential for the detoxification of methylglyoxal (MGO), a reactive metabolite that is spontaneously produced during glycolysis. Unless detoxified, MGO induces apoptosis by irreversibly damaging proteins and DNA. Tumors adapt to MGO production by upregulating glyoxalase 1 (GLO1), which uses GSH to eliminate MGO. Our studies with patient-derived IDHm glioma models and patient biopsies indicate that D-2HG acts via the NRF2 transcription factor to upregulate GLO1 expression. Inhibiting GLO1 using the potent brain penetrant GLO1 inhibitor S-p-bromobenzylglutathione cyclopentyl diester (BBG) abrogates MGO detoxification and arrests tumor growth in mice bearing orthotopic patient-derived IDHm gliomas. Importantly, radiation depletes GSH, and combined treatment with BBG and radiation causes massive MGO accumulation, macromolecular glycation, and tumor regression in vivo. Based on these results, we will test the hypothesis that targeting GLO1 in combination with radiation is lethal for IDHm gliomas. In Aim 1, we will determine whether the combination of BBG with radiation is an actionable therapeutic strategy in patient-derived IDHm glioma models. In Aim 2, we will delineate the molecular mechanisms governing reactive metabolite generation in IDHm gliomas. Deuterium magnetic resonance spectroscopy is a novel, clinically translatable method of visualizing the metabolism of 2H-labeled substrates in vivo. Our studies indicate that MGO glycates the glycolytic enzyme phosphoglycerate kinase 1, thereby reducing lactate production from [6,6-2H]-glucose in IDHm tumor-bearing mice. Therefore, in Aim 3, we will determine whether [6,6-2H]-glucose provides an early readout of response to combined BBG and radiation in mice bearing IDHm gliomas in vivo. Our proposal is innovative because we will, for the first time, mechanistically validate reactive metabolite generation as a druggable vulnerability in IDHm gliomas. This project is significant because our studies will set the stage for clinical translation of the combination of BBG and radiation to IDHm glioma patients. Concomitantly, [6,6-2H]-glucose will enable early assessment of efficacy in clinical trials. In essence, by simultaneously targeting metabolism and imaging treatment response, we will deliver precision medicine that enhances outcomes and quality of life for IDHm glioma patients.