Abstract B024: Targeting tmCLIC1 to overcome resistance across heterogeneous glioblastoma subtypes by exploiting metabolic vulnerabilities with synergistic combinatorial therapy

Abstract Glioblastoma (GB) remains one of the most lethal brain tumors, largely due to extensive inter- and intratumoral heterogeneity, which limits the efficacy of standard therapies and contributes to frequent recurrence. Tumor Treating Fields (TTFields) provide clinical benefit but fail to prevent tumor relapse, suggesting the presence of resistant subpopulations. Here, we modeled prolonged TTFields exposure in patient-derived GB cultures across multiple subtypes, revealing that a fraction of cells survives and adopts shared features of resistance, including enhanced OXPHOS metabolism and elevated tmCLIC1 expression, a regulator of GB cell metabolism and survival. We demonstrated that tmCLIC1 represents a targetable vulnerability in these resistant populations. Transcriptomic analysis of paired patient tumors pre- and post-TTFields treatment corroborated these findings, highlighting conserved molecular adaptations across subtypes. Pharmacological inhibition of tmCLIC1 with metformin synergizes with TTFields, suppressing proliferation in vitro and reducing tumor growth in vivo, even at low drug concentrations facilitated by TTFields-enhanced blood-brain barrier permeability. Collectively, our results indicate that tmCLIC1-targeted therapy can overcome resistance in heterogeneous GB populations and suggest a rational combinatorial strategy to improve clinical outcomes. Citation Format: Francesca Cianci, Guido Rey, Elisa Meraviglia, Antonio Maria. Polito, Michele Mazzanti. Targeting tmCLIC1 to overcome resistance across heterogeneous glioblastoma subtypes by exploiting metabolic vulnerabilities with synergistic combinatorial therapy [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Brain Cancer; 2026 Mar 23-25; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(6_Suppl):Abstract nr B024.