Jul 2026· Cancer Research· Vol 86, pp. A014-A014· 0 citations
TL;DR
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.
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.
Telomerase reverse transcriptase promoter (TERTp) mutations represent one of the most common non-coding alterations across cancers, yet their functional convergence between rare brain gliomas and colorectal cancer (CRC) remains poorly defined. We sought to identify shared TERTp-driven dependencies that could be therapeutically exploited.
We integrated whole-genome sequencing, RNA-seq, and targeted TERTp genotyping from a multi-institutional cohort encompassing rare glioma subtypes (gliosarcoma, pleomorphic xanthoastrocytoma, diffuse midline glioma) and CRC. TERTp-mutant cell lines from both tumor classes were profiled for transcriptional programs and subjected to drug sensitivity screens against epigenetic and transcription factor inhibitors.
TERTp mutations were present in 67% of rare gliomas and 52% of CRCs examined, and were associated with elevated telomerase activity. Cross-cancer transcriptomic analysis revealed convergent upregulation of the GABPA-GABPB1 complex downstream of mutant TERTp. Pharmacological inhibition of GABP using a small-molecule probe significantly reduced viability in TERTp-mutant organoids derived from both a rare gliosarcoma and a CRC liver metastasis, while TERTp wild-type counterparts were resistant. Moreover, the combination of a GABP inhibitor with a BET bromodomain inhibitor produced synergistic cytotoxicity across tumor types.
Our results establish GABP as a shared vulnerability in TERTp-mutant rare gliomas and CRC, nominating this axis for pan-cancer therapeutic development. Targeting the non-coding oncogenic pathway downstream of TERTp may bypass the limitations of direct telomerase inhibition.
Jinyu Lu. Pan-cancer dissection of TERT promoter mutations in rare gliomas and colorectal cancer: shared vulnerabilities and therapeutic implications [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 B031.
Glioblastoma (GBM) is a malignant brain tumor frequently driven by mutations in isocitrate dehydrogenase (IDH1 and IDH2) enzymes, which promote neomorphic synthesis of the oncometabolite 2-hydroxyglutarate (2-HG) and subsequent metabolic dysfunction. Although these mutations are associated with different clinical outcomes, therapeutic intervention remains challenging due to tumor heterogeneity, cellular plasticity, restricted blood-brain barrier permeability, drug efflux mechanisms, and effective DNA repair pathways. Therefore, this study aims to identify selective inhibitors of mutant IDH proteins by overcoming these challenges.
10,309 compounds from ChemFaces and MedChemExpress libraries are used for large-scale virtual screening and multi-level ADMET filtering, uncovering 19 lead compounds with favourable drug-likeness. Further, molecular docking followed by 300 ns of molecular dynamics simulations, PCA analysis, and MM-PBSA calculations were performed to explore conformational dynamics.
Molecular docking revealed strong binding affinities of PubChem ID 91457 (I1Hit1) as −7.57 kcal/mol and PubChem ID 4946 (I1Hit2) as −6.82 kcal/mol against IDH1, and PubChem ID 71550939 (I2Hit1) as −11.23 kcal/mol and PubChem ID 4946 (I2Hit2) as −7.87 kcal/mol against IDH2, by outperforming the standard (−6.17 kcal/mol). Molecular dynamics simulations, PCA analysis, and MM-PBSA calculations confirmed complex stability and inhibitory potential. Notably, I1Hit1 and I2Hit1 exhibited enhanced binding free energies of −20.67 ± 2.32 kcal/mol against IDH1 and -28.78 ± 2.67 kcal/mol against IDH2 respectively, compared to the standard, as further supported by computational pharmacophore evaluation.
Collectively, these findings highlight I1Hit1 and I2Hit1 as novel therapeutic compounds with efficient IDH-target inhibition to address epigenetic modification in GBM, and further experimental validation of these compounds is required to demonstrate potential inhibitors of IDH-driven metabolism in GBM.
Nivedhitha Tamilazhagan, S. Arumugam· Frontiers in Bioinformatics· 0 citations
Background/Objectives: Isocitrate Dehydrogenase (IDH)1/2-mutant diffuse gliomas represent a biologically distinct subgroup of adult brain tumors in which eary metabolic reprogramming and accumulation of the oncometabolite D-2-hydroxyglutarate (D-2HG) drive epigenetic, immunologic, and clinical characteristics, including a high burden of glioma-associated epilepsy. This review summarizes the molecular and metabolic consequences of IDH mutations, their role in glioma-associated epilepsy, and the evolving impact of mutant IDH-targeted therapies in contemporary neuro-oncology. Methods: We conducted a narrative review of key molecular, translational, imaging, and clinical studies on IDH-mutant diffuse gliomas. The literature included the 2021 (World Health Organization) WHO Classification of Tumours of the Central Nervous System, studies investigating D-2HG biology and glioma-associated epilepsy, and prospective clinical trials and real-world evidence evaluating IDH-targeted therapies and contemporary antiseizure management. Particular emphasis was placed on vorasidenib, advanced metabolic imaging, and emerging liquid biopsy approaches. Results: IDH mutations are early driver events that promote D-2HG accumulation, resulting in widespread epigenetic reprogramming, metabolic dysregulation, and an immunosuppressive tumor microenvironment. D-2HG has also been implicated in the development of glioma-associated epilepsy, although the underlying mechanisms remain incompletely understood. Advances in integrated histomolecular diagnostics, magnetic resonance spectroscopy, amino acid positron emission tomography, and cerebrospinal fluid liquid biopsy have improved disease classification and treatment monitoring. Mutant IDH inhibitors, particularly vorasidenib, prolong progression-free survival, delay the need for subsequent treatment, and reduce intratumoral D-2HG concentrations, and have shown encouraging early signals of improved seizure control and preserved health-related quality of life in patients with grade 2 IDH-mutant gliomas, although this evidence remains preliminary and requires confirmation in larger prospective studies. Conclusions: IDH-mutant diffuse gliomas exemplify precision neuro-oncology, in which a single metabolic alteration informs diagnosis, disease monitoring, and targeted therapeutic approach. Additionally, ongoing studies are expected to further define the role of IDH inhibition across different disease stages and in combination with immunotherapy and standard treatments. Lastly, future clinical trials should systematically incorporate seizure outcomes, neurocognitive function, patient-reported outcomes, and immunologic endpoints to optimize both tumor control and quality of life.
T. Urbanic-Purkart· Journal of Clinical Medicine· 0 citations
Glioma-associated isocitrate dehydrogenase (IDH) mutations synthesize (R)-2-hydroxyglutarate (R2HG), which broadly inhibits 2-oxoglutarate-dependent enzymes. Given that mutant IDH inhibitors have limited efficacy in high-grade glioma subtypes, alternative treatment strategies are needed, such as therapies that exploit collateral vulnerabilities engendered by IDH mutations. In this vein, drugs that induce replication stress, such as Ataxia-telangiectasia and Rad3-related (ATR) inhibitors and dihydroorotate dehydrogenase (DHODH) inhibitors, have demonstrated efficacy in preclinical IDH-mutant glioma models. However, translation of this synthetic lethal framework to clinical testing has been limited in part by a lack of well-tolerated, effective, and on-target drugs that exploit this vulnerability. To address this need, we developed GLIO-1, a new small molecule inhibitor of DHODH. GLIO-1 preferentially killed IDH-mutant glioma cells in engineered, patient-derived, and orthotopic xenograft model systems. In a patient-derived orthotopic xenograft mouse model of IDH-mutant glioma, GLIO-1 displayed similar monotherapy antitumor efficacy and superior tolerability compared to a leading clinical-stage DHODH inhibitor (BAY 2402234). GLIO-1 also exhibited superior brain penetrance compared to BAY 2402234. The effects of GLIO-1 were on-target, as expression of a drug-resistant DHODH mutant (DHODH-A58T) completely rescued cell death induced by GLIO-1. To mechanistically understand how IDH-mutant gliomas are sensitized to DHODH inhibitors and replication stress, we performed forward genetic screens targeting all 2-oxoglutarate-dependent enzymes. Across six independent CRISPR screens using both DHODH and ATR inhibitors, we discovered that KDM6 histone demethylases play a vital role in protecting glioma cells from replication stress. Base editor screens directed against the KDM6A gene revealed that the demethylase activities of KDM6 enzymes are required for replication stress tolerance. Genetic or R2HG-dependent repression of KDM6 catalytic activity sensitized engineered, patient-derived, and xenograft models of glioma to both ATR and DHODH inhibitors. This liability was generalizable even to non-neural cells because KDM6A loss-of-function mutations commonly observed in urothelial carcinomas sensitized bladder cancer cells to DHODH inhibition including GLIO-1, thereby phenocopying IDH mutations in glioma. We developed an selective, on-target, and well-tolerated DHODH inhibitor, GLIO-1, that is effective in IDH-mutant gliomas. Moreover, we identify KDM6 enzymes as the mechanistic targets of R2HG that link IDH oncogenes with sensitivity to GLIO-1 and reveal KDM6 activity as a fundamental determinant of replication stress. Collectively, these results nominate a new pan-cancer biomarker and targeted therapy pairing, KDM6A inactivation and GLIO-1, that is poised for clinical translation.
Alexander C-Y. Tsai, Mathew D. Lin, Vinesh T. Puliyappadamba, Dorothy M. Junginger, Victoria G. Donovan, Eleanor G. Kaplan, Laura M. Drepanos, Hiroaki Wakimoto, Daniel P. Cahill, Julie A. Losman, Kent W. Mouw, Kalil G. Abdullah, John G. Doench, Duane Nash, Daniel Vitt, Christian Gege, Hella Kohlhof, Samuel K. McBrayer, William G. Kaelin Jr., Diana D. Shi. GLIO-1 is a selective DHODH inhibitor that is effective in IDH-mutant gliomas and KDM6-mutated cancers [abstract]. In: Proceedings of AACR Drug Discovery and Development (AACR D3) Conference; 2026 Jul 21-24; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(14_Suppl):Abstract nr B083.
Alexander C-Y. Tsai, Mathew D. Lin, V. Puliyappadamba et al.· Clinical Cancer Research· 0 citations
Glioma-associated isocitrate dehydrogenase (IDH) mutations synthesize (R)-2-hydroxyglutarate (R2HG), which broadly inhibits 2-oxoglutarate-dependent enzymes. Given that mutant IDH inhibitors have limited efficacy in high-grade glioma subtypes, alternative treatment strategies are needed, such as therapies that exploit collateral vulnerabilities engendered by IDH mutations. In this vein, drugs that induce replication stress, such as Ataxia-telangiectasia and Rad3-related (ATR) inhibitors and dihydroorotate dehydrogenase (DHODH) inhibitors, have demonstrated efficacy in preclinical IDH-mutant glioma models. However, translation of this synthetic lethal framework to clinical testing has been limited in part by a lack of well-tolerated, effective, and on-target drugs that exploit this vulnerability. To address this need, we developed GLIO-1, a new small molecule inhibitor of DHODH. GLIO-1 preferentially killed IDH-mutant glioma cells in engineered, patient-derived, and orthotopic xenograft model systems. In a patient-derived orthotopic xenograft mouse model of IDH-mutant glioma, GLIO-1 displayed similar monotherapy antitumor efficacy and superior tolerability compared to a leading clinical-stage DHODH inhibitor (BAY 2402234). GLIO-1 also exhibited superior brain penetrance compared to BAY 2402234. The effects of GLIO-1 were on-target, as expression of a drug-resistant DHODH mutant (DHODH-A58T) completely rescued cell death induced by GLIO-1. To mechanistically understand how IDH-mutant gliomas are sensitized to DHODH inhibitors and replication stress, we performed forward genetic screens targeting all 2-oxoglutarate-dependent enzymes. Across six independent CRISPR screens using both DHODH and ATR inhibitors, we discovered that KDM6 histone demethylases play a vital role in protecting glioma cells from replication stress. Base editor screens directed against the KDM6A gene revealed that the demethylase activities of KDM6 enzymes are required for replication stress tolerance. Genetic or R2HG-dependent repression of KDM6 catalytic activity sensitized engineered, patient-derived, and xenograft models of glioma to both ATR and DHODH inhibitors. This liability was generalizable even to non-neural cells because KDM6A loss-of-function mutations commonly observed in urothelial carcinomas sensitized bladder cancer cells to DHODH inhibition including GLIO-1, thereby phenocopying IDH mutations in glioma. We developed an selective, on-target, and well-tolerated DHODH inhibitor, GLIO-1, that is effective in IDH-mutant gliomas. Moreover, we identify KDM6 enzymes as the mechanistic targets of R2HG that link IDH oncogenes with sensitivity to GLIO-1 and reveal KDM6 activity as a fundamental determinant of replication stress. Collectively, these results nominate a new pan-cancer biomarker and targeted therapy pairing, KDM6A inactivation and GLIO-1, that is poised for clinical translation.
Alexander C-Y. Tsai, Mathew D. Lin, Vinesh T. Puliyappadamba, Dorothy M. Junginger, Victoria G. Donovan, Eleanor G. Kaplan, Laura M. Drepanos, Hiroaki Wakimoto, Daniel P. Cahill, Julie A. Losman, Kent W. Mouw, Kalil G. Abdullah, John G. Doench, Duane Nash, Daniel Vitt, Christian Gege, Hella Kohlhof, Samuel K. McBrayer, William G. Kaelin Jr., Diana D. Shi. GLIO-1 is a selective DHODH inhibitor that is effective in IDH-mutant gliomas and KDM6-mutated cancers [abstract]. In: Proceedings of AACR Drug Discovery and Development (AACR D3) Conference; 2026 Jul 21-24; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(14_Suppl):Abstract nr PR012.
Alexander C-Y. Tsai, Mathew D. Lin, V. Puliyappadamba et al.· Clinical Cancer Research· 0 citations
Astrocytoma and oligodendroglioma are initiated by missense mutations in isocitrate dehydrogenase 1 and 2 genes (IDH1/2). The mutant IDH1 protein acquires neomorphic activity, producing (R)-2-hydroxyglutarate, which interferes with α-ketoglutarate-dependent epigenetic processes. These effects result in metabolic and epigenetic changes that impair cellular differentiation and promotes tumorigenesis Whole-genome CRISPR/Cas9 knockout screens were conducted using isogenic IDH1-mutant and wild-type (WT) U-87 MG cells and identified the thioredoxin reductase 1 gene (TXNRD1) as a selective dependency in IDH1-mutants. This work sought to validate this dependency and detail the underlying mechanism using thioredoxin reductase 1 (TrxR1) inhibitors and TXNRD1 knockout (KO) models. Antiproliferative potency of TrxR1 inhibitors (auranofin, TRi-1) were similar in IDH1 WT and mutant cells when assessed in both 2D monolayer and 3D soft agar colony assays. Glutathione levels and reduced:oxidized glutathione ratios were decreased similarly in IDH1-mutant and WT cells following TrxR1 inhibition, consistent with increased oxidative stress. Reactive oxygen species (ROS) measured using ROS-Glo™ or CM-H2DCFDA dye were increased following acute treatment with TRi-1 or auranofin. In the ROS-Glo™ studies, ROS levels were modestly higher in IDH1-mutant compared with WT cells. Loss of membrane integrity prevented CM-H2DCFDA dye retention and decreased the ability to accurately assess intracellular ROS. This observed change was consistent with induction of disulfidptosis, which was supported by rapid morphological rounding of cells upon TrxR1 inhibitor treatment, suggestive of actin cytoskeletal collapse. Rescue of TrxR1 inhibitor-treated cultures was achieved using co-treatment with reducing agents (NAC, DTT or TCEP), supporting disulfidptosis as the cell death mechanism. Overall, both IDH1-mutant and WT cells displayed similar sensitivity to TrxR1 inhibition. To confirm the effect of TXNRD1 KO observed in the screen, multiguide RNA-Cas9 ribonucleoproteins were used to generate TXNRD1 knockouts. Neither IDH1-mutant nor WT cells tolerated acute TXNRD1 KO, although some surviving clonal KO lines were developed after several weeks. These KO clones displayed slower growth kinetics and impaired growth in soft agar. In contrast to TrxR1 inhibition, TXNRD1 KO clones displayed decreased CM-H2DCFDA signal compared with unedited cells, suggesting lower basal ROS levels. Quantitative proteomics implicated changes in several metabolic pathways, including amino acid, fatty acid and NRF2 activity, as compensatory mechanisms of TXNRD1 loss in both IDH1-mutant and WT cells. Despite these changes, glutathione levels and reduced:oxidized glutathione ratios were similar in TXNRD1 KO and unedited cell lines. These findings demonstrate that glioma models are dependent on TXNRD1 for survival, but acquire adaptive antioxidant changes to survive TXNRD1 loss. TrxR1 inhibition is acutely cytotoxic, via induction of disulfidptosis, with similar effects in IDH1-mutant and WT models.
Sophia F. O'Brien-Gortner, Dinar Rani K, Daniel Conole, Tet-Woo Lee, Stephen MF. Jamieson, Dean C. Singleton. CRISPR screens identify thioredoxin reductase 1 as a target for inducing disulfidptosis in IDH1-mutant glioma models [abstract]. In: Proceedings of AACR Drug Discovery and Development (AACR D3) Conference; 2026 Jul 21-24; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(14_Suppl):Abstract nr B027.
S. O’Brien-Gortner, Dinar Rani K, D. Conole et al.· Clinical Cancer Research· 0 citations
