EXTH-35. REPURPOSING OF CLINICALLY APPROVED GLUTAMATE ANTAGONISTS TO TREAT GLIOBLASTOMA

Abstract The neurotransmitter glutamate plays a fundamental role in promoting epilepsy and tumor progression in glioblastoma. Glioblastoma cells secrete glutamate into the tumor microenvironment via the cystine-glutamate antiporter system Xc, leading to neuronal hyperexcitability, excitotoxicity, and tumor cell invasion. Additionally, glutamatergic neuroglioma synapses drive glioma progression in preclinical tumor models. To pharmacologically counteract effects of glutamate in glioblastoma, we employed a triple combination of anti-glutamatergic drugs: gabapentin, sulfasalazine, and memantine, which target glutamate synthesis, release, and post-synaptic signaling, respectively. In genetically engineered murine glioblastoma models, daily treatment with this triple combination prolonged median survival. This survival benefit was not observed with single or double drug combinations, nor with the standard antiepileptic drug levetiracetam, indicating the potential synergy and efficacy of this drug combination beyond merely treating epilepsy. Importantly, these preliminary results support the rationale for the ongoing phase Ib/II randomized clinical trial GLUGLIO, which explores the efficacy of combined gabapentin, sulfasalazine, and memantine in conjunction with standard chemoradiotherapy in patients with newly diagnosed glioblastoma (NCT05664464).