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Metabolomic and drug profiling of patient-derived glioblastoma models uncovers targetable vulnerabilities in IDH wild-type tumors
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DOI：10.1186/s40478-026-02396-7.png)
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Abstract
En 中文
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.
Keywords:
Glioma
Metabolomics
Drug screening
Patient derived tumor cells (PDCs)
Metabolic reprogramming
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