Metabolomic and Drug Profiling of Patient-Derived Glioblastoma Models Uncovers Targetable Vulnerabilities in IDH Wild-Type Tumors

IDH (isocitrate dehydrogenase) wild-type gliomas (glioblastomas) exhibit rapid progression and poor prognosis compared to their IDH mutant counterparts, highlighting an urgent need for novel, biology-informed therapies. We performed an integrative analysis combining tissue metabolomics and ex vivo drug screening in matched patient-derived tumor cells (PDCs) to uncover IDH-relevant vulnerabilities. IDH wild-type tumors showed metabolic reprogramming marked by upregulation of nucleotide metabolism, central carbon metabolism, fatty acid β-oxidation, and redox mechanisms relative to IDH mutant tumors, consistent with enhanced proliferation and tumor plasticity. Strikingly, microbiota-derived metabolites (p-cresyl sulphate and indoxyl sulphate) were enriched in IDH wt tumor tissues in relation to IDH mut, suggesting altered blood-brain barrier permeability. A machine learning classifier trained in metabolic profiles distinguished IDH status with high accuracy. Drug response profiles across 66 compounds revealed significantly higher efficacy (p < 0.05) of HDAC inhibitors (panobinostat, vorinostat), MDM2 inhibitors (AMG232, R7112) and nuclear export/mTOR inhibitors (selinexor, temsirolimus) in IDH wild-type PDCs. Importantly, drug responses aligned with metabolic signatures, indicating that metabolic context shapes therapeutic susceptibility. Our integrative approach reveals fundamental metabolic differences between IDH wild-type and mutant gliomas, and links these to differential drug responses. These findings underscore the potential of metabolism informed precision oncology strategies for glioblastomas.