DDDR-56. Single-cell analysis of drug perturbations in IDH-mutant glioma

Abstract IDH-mutant gliomas are the most common malignant brain tumor in patients under 50 years old and have no cure. A major challenge in treatment is intratumoral heterogeneity, where drug-resistant subpopulations drive recurrence. Ferroptosis, a form of iron-dependent cell death, and IDH inhibition both target metabolic vulnerabilities in glioma. Prior evidence in glioblastoma demonstrates that ferroptosis can selectively target vulnerable tumor subpopulations and may exploit metabolic shifts associated with IDH inhibition, a therapy now in clinical use. We have established methods to generate acute slices from human glioma surgical specimens, treat with drugs ex vivo, and assess drug responses by single-cell sequencing. This preserves tumor heterogeneity to enable identification of drug sensitivities in specific subpopulations, which is crucial for identifying effective molecular targets and therapeutic combinations. Using this platform, we tested drugs that induce ferroptosis via GPX4 inhibition and an IDH inhibitor in human IDH-mutant glioma samples. Our preliminary data suggests differential sensitivity to ferroptosis inducers and IDH inhibitors across tumor subpopulations, where responses correlate to metabolic state. These studies are especially timely and relevant for the growing subset of IDH-mutant glioma patients currently undergoing treatment with IDH inhibitors.