Abstract A014: Targeting shared metabolic vulnerabilities in IDH-mutant gliomas and colorectal cancer: a new therapeutic angle for rare brain tumors

Abstract

Gain-of-function mutations in isocitrate dehydrogenase 1/2 (IDH1/2) produce the oncometabolite 2-hydroxyglutarate (2-HG) and occur in the majority of lower-grade gliomas as well as in a subset of colorectal cancers. We sought to identify conserved metabolic addictions in IDH-mutant gliomas and CRC that could be pharmacologically targeted, with special emphasis on rare glioma variants. Untargeted metabolomics and 13C-glutamine isotope tracing were performed on a panel of IDH1-mutant oligodendroglioma, astrocytoma, and CRC cell lines, alongside matched wild-type controls. A CRISPR-Cas9 metabolic gene knockout screen was conducted in IDH1-mutant models. Therapeutic vulnerabilities were validated in vitro and in orthotopic xenografts, including a model derived from a rare IDH-mutant primary spinal cord glioma. Metabolomic profiling revealed a shared dependence on glutamine anaplerosis to sustain the tricarboxylic acid cycle and 2-HG production in both IDH-mutant gliomas and CRC. CRISPR screening identified glutaminase (GLS) and glutamate dehydrogenase (GLUD1) as essential nodes for mutant cell survival. Pharmacological inhibition of GLS with CB-839 induced metabolic crisis and apoptosis selectively in IDH-mutant cells. Strikingly, the combination of the mutant IDH inhibitor ivosidenib and CB-839 produced synergistic growth inhibition and durable 2-HG reduction in intracranial and subcutaneous tumor models, including complete remission in the rare spinal cord glioma xenograft. IDH-mutant brain and colorectal tumors converge on glutamine metabolism as a critical liability. Dual blockade of mutant IDH and glutaminolysis represents a novel, cross-entity therapeutic regimen and offers a promising treatment avenue for rare, surgically challenging IDH-mutant gliomas. Lei Li. Targeting shared metabolic vulnerabilities in IDH-mutant gliomas and colorectal cancer: a new therapeutic angle for rare brain tumors [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Breaking Barriers in the Fight against Rare Cancers; 2026 Jul 18-20; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(14_Suppl):Abstract nr A014.