TMET-23. 2-Methylglutamate Prolongs Survival in a Mouse Model of Glioblastoma

Abstract Glutamate plays a central role in glioblastoma (GBM) pathophysiology, promoting tumor proliferation, excitotoxicity, and immune suppression. Emerging evidence also highlights that glioma cells integrate into normal neural circuits, and this neuronal activity drives GBM growth and progression through formation of direct glutamatergic synapses between neurons and glioma cells. Recent work by Wawro et al. (Sci Rep, 2021) demonstrated that enantiomers of 2-methylglutamate (2MeGlu), a glutamate analog, differentially modulate brain metabolism and behavior through stereoselective interactions with glutamate transport and glutamine metabolism. However, the impact of 2MeGlu on glioblastoma progression has not been studied. We employed two orthotopic mouse models of human GBM using luciferase-labeled U251 and GBM39 patient-derived xenograft cells. Approximately nine days post-implantation, mice received daily intraperitoneal injections of a racemic mixture of 2MeGlu (500 mg/kg) or vehicle control. Survival was monitored as the primary endpoint. The control and treatment groups were followed until humane endpoints were met. Tumor burden was assessed weekly using bioluminescence imaging (BLI). U251 glioma-bearing mice exhibited median survival of 26 and 35 days in the control and treatment groups, respectively (p = 0.0165). In GBM39 orthotopic xenografts, median survival of controls was 32 days. In contrast, mice treated with racemic 2MeGlu exhibited median survival of 51 days (p = 0.0004), representing a 59% increase in overall survival compared to controls. Longitudinal BLI revealed lower tumor-associated luminescence in treated animals relative to controls, consistent with reduced intracranial tumor burden. The substantial survival benefit suggests 2MeGlu may modulate glutamate-dependent metabolic or signaling pathways critical to glioblastoma growth or microenvironmental adaptation. These findings provide the first evidence that 2MeGlu confers a survival benefit in a preclinical GBM model. Given prior evidence of stereospecific effects of 2MeGlu on glutamate-glutamine cycling, future work will assess individual enantiomers for differential therapeutic efficacy and potential mechanisms of action, including altered tumor metabolism, immune microenvironment modulation, or excitotoxic stress. These studies may help establish new therapeutic vulnerabilities in glutamate-dependent glioblastoma progression.