A pilot trial of perioperative IDH Inhibition in treatment-naïve IDH-mutant glioma
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PROVIDER: PRJNA1241178 | ENA |
REPOSITORIES: ENA
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Project description:Mutant-IDH (mIDH) inhibition significantly improves progression free survival in patients with mIDH WHO grade 2 glioma, however almost all patients will progress, and there is a lack of understanding on the mechanisms of adaptation to mIDH inhibition. In the first pre- and post-treatment perioperative trial in patients with mIDH1 low-grade glioma, we tested safusidenib (AB-218 / DS-1001b), an oral, blood brain barrier penetrant IDH1 R132X inhibitor, in a single arm, open label study. The primary endpoint demonstrated the feasibility and acceptability of conducting a two-stage perioperative trial and treatment was well tolerated, with ongoing follow-up for safety and efficacy. Tumor 2-hydroxyglutarate quantification revealed on-target activity, resulting in significant alterations in differentiation programs and neural excitability, functionally validated by patch clamp electrophysiology. Taken together, these results provide a detailed understanding on mechanisms of mIDH inhibition in glioma and the safety and feasibility of this perioperative approach, which can be applied broadly in clinical trial design, advancing drug development in glioma. Funded by AnHeart Therapeutics (a Nuvation Company) and the Victorian Government; ClinicalTrials.gov number NCT05577416.
2025-06-02 | GSE292732 | GEO
Project description:RNA-sequencing for myeloid inflammation-related genes was conducted on primary tumor samples from patients with IDH-wildtype glioblastoma (GBM) and grade 4 IDH-mutant astrocytoma (G4IMA). In addition, the IDH-wildtype murine glioma cell line GL261 and a strain of IDH-mutant GL261 were also sequenced using the murine counterpart of the RNA-sequencing myeloid innate immunity panel.
2024-05-29 | GSE268118 | GEO
Project description:Recent single-cell transcriptomic studies report that IDH-mutant gliomas share a common hierarchy of cellular phenotypes, independent of genetic subtype. However, the genetic differences between IDH-mutant glioma subtypes are prognostic, predictive of response to chemotherapy, and correlate with distinct tumor microenvironments. To reconcile these findings, we profiled 22 human IDH-mutant gliomas via single-cell assay for transposase-accessible chromatin (scATAC-seq). We determined the cell-type specific differences in transcription-factor expression and associated regulatory grammars between IDH-mutant glioma subtypes. We find that while IDH-mutant gliomas do share a common distribution of cell types, there are significant differences in the expression and targeting of transcription factors that regulate glial identity and cytokine elaboration. We knocked out the chromatin-remodeler ATRX, which suffers loss-of-function alterations in most IDH-mutant astrocytomas, in an IDH-mutant immunocompetent intracranial murine model. We find that both human ATRX-mutant gliomas and murine ATRX-knockout gliomas are more heavily infiltrated by immunosuppressive monocytic-lineage cells derived from circulation than ATRX-intact gliomas, in an IDH-mutant background. ATRX knockout in murine glioma recapitulates gene expression and open-chromatin signatures that are specific to human ATRX-mutant astrocytomas, including drivers of astrocytic lineage and immune-cell chemotaxis. ATRX knockout in murine glioma recapitulates gene expression and open chromatin signatures that are specific to human ATRX-mutant astrocytomas, including drivers of astrocytic lineage and immune-cell chemotaxis. Through single-cell cleavage under targets and tagmentation assays and meta-analysis of public data, we show that ATRX loss leads to a global depletion in CCCTC-binding factor association with DNA, gene dysregulation along associated chromatin loops, and protection from therapy-induced senescence.
2021-10-20 | GSE155430 | GEO
Project description:Discovering the cell-of-origin with the initial driver mutation provides fundamental basis for understanding tumor evolution and developing new treatments. In isocitrate dehydrogenase (IDH)-mutant gliomas, the most common malignant primary brain tumors in young adult under 50, its cell-of-origin remains poorly understood. Here, we used patient brain tissues and genome edited mice to identify glial progenitor cells (GPCs) including oligodendrocyte progenitor cells (OPCs) as the cell-of-origin harboring the IDH mutation as the initial driver mutation. We conducted comprehensive deep sequencing, including droplet digital PCR and deep panel and amplicon sequencing on 128 tissues from 62 patient (29 IDH-mutant gliomas and 33 IDH-negative controls), comprising tumors, normal cortex, or normal subventricular zone (SVZ), and blood. Surprisingly, we found low-level IDH mutation in the normal cortex away from the tumor, in 38.5% (10 of 26) of IDH-mutant glioma patients, while no IDH mutation was detected in the normal SVZ. Furthermore, through the analysis of cell-type-specific mutations, the direction of clonal evolution, and the single-cell transcriptome from patient brains as well as novel mouse model of IDH-mutant glioma arising from mutation-carrying OPCs, we determined that GPCs including OPCs with the initial driver mutation are responsible for the development and evolution to IDH-mutant gliomas. In summary, our results demonstrate that GPCs containing the IDH mutation are the cells-of-origin harboring the initial driver mutation in IDH-mutant gliomas.
2026-01-13 | GSE275791 | GEO
Project description:A phase-1, multi-center study in recurrent non-enhancing gliomas with IDH1 R132H mutation for patients who require surgery. The purpose of this study is to evaluate the suppression of 2-HG (2-hydroxyglutarate) by comparing the concentration of 2-HG in resected tumors from IDH1 mutant glioma subjects following AG-120 or AG-881 treatment with the 2-HG concentration in untreated, control tumors. The safety, tolerability, PK/PD, and anti tumor activity data from the study in subjects with recurrent non-enhancing Grade 2/3 LGG with an IDH1 R132H mutation for whom surgical resection is indicated will identify the recommended dose of AG-120 and AG-881 for future studies in glioma. Vorasidenib and ivosidenib inhibit mutant forms of isocitrate dehydrogenase (mIDH) and have shown preliminary clinical activity against mIDHglioma. We evaluated both agents in a perioperative phase 1 trial to explore the mechanism of action in recurrent low-grade glioma (IGG) and select a molecule for phase 3 testing. Primary end-point was concentration ofD-2-hydroxyglutarate (2-HG), the metabolic product of mIDH enzymes, measured in tumor tissue from 49 patients with mIDH1-R132H nonenhancing gliomas following randomized treatment with vorasidenib (50 mg or 10 mg once daily, q.d.), ivosidenib (500 mg q.d. or 250 mg twice daily) or no treatment before surgery. Tumor 2-HG concentrations were reduced by 92.6% (95% credible interval (CrI), 76.1–97.6) and 91.1% (95% CrI, 72.0–97.0) in patients treated with vorasidenib 50 mg q.d. and ivosidenib 500 mg q.d., respectively. Both agents were well tolerated and follow-up is ongoing. In exploratory analyses, 2-HG reduction was associated with increased DNA 5-hydroxymethylcytosine, reversal of ‘proneural’ and ‘stemness’ gene expression signatures, decreased tumor cell proliferation and immune cell activation. Vorasidenib, which showed brain penetrance and more consistent 2-HG suppression than ivosidenib, was advanced to phase 3 testing in patients with mIDHLGGs. Funded by Agios Pharmaceuticals, Inc. and Servier Pharmaceuticals LLC; ClinicalTrials.gov number NCT03343197.
2023-05-11 | GSE232312 | GEO
Project description:Isocitrate dehydrogenase (IDH)-mutant gliomas are malignant brain tumors that typically arise in early- to mid-adulthood and nearly always recur following treatment. However, the genetic and cellular state changes that drive IDH-mutant glioma progression under treatment remain incompletely understood. Here, we integrated single-nucleus transcriptomic profiles, chromatin accessibility profiles and bulk DNA/RNA sequencing from 75 temporally separated gliomas across 35 patients comprising both the oligodendroglioma and astrocytoma IDH-mutant glioma tumor types. We show that malignant cell states transcriptionally resemble stages of normal glial-neuronal lineage development or a reactive mesenchymal-like state, mirroring states previously described in IDH-wildtype glioblastoma. Malignant cell states displayed distinct chromatin accessibility profiles that were comparable between both IDH-mutant glioma types. The abundance of less differentiated malignant cells increased with grade and with genetic alterations such as PDGFRA amplification. Longitudinal analysis highlighted two major malignant cell state transition patterns. First, reduced lineage differentiation and increased proliferative malignant cells at recurrence were pronounced in gliomas that acquired recurrence-associated genetic events, including treatment-associated hypermutation, increased copy number changes, and cell cycle alterations. Second, increased mesenchymal-like state abundance occurred independently of acquired genetic alterations and instead coincided with heightened macrophage expression. Overall, our findings provide an integrative model that traces the cell-intrinsic and extrinsic factors that shape cellular states during IDH-mutant glioma disease progression.
2026-04-20 | GSE324694 | GEO
Project description:Isocitrate dehydrogenase (IDH)-mutant gliomas are malignant brain tumors that typically arise in early- to mid-adulthood and nearly always recur following treatment. However, the genetic and cellular state changes that drive IDH-mutant glioma progression under treatment remain incompletely understood. Here, we integrated single-nucleus transcriptomic profiles, chromatin accessibility profiles and bulk DNA/RNA sequencing from 75 temporally separated gliomas across 35 patients comprising both the oligodendroglioma and astrocytoma IDH-mutant glioma tumor types. We show that malignant cell states transcriptionally resemble stages of normal glial-neuronal lineage development or a reactive mesenchymal-like state, mirroring states previously described in IDH-wildtype glioblastoma. Malignant cell states displayed distinct chromatin accessibility profiles that were comparable between both IDH-mutant glioma types. The abundance of less differentiated malignant cells increased with grade and with genetic alterations such as PDGFRA amplification. Longitudinal analysis highlighted two major malignant cell state transition patterns. First, reduced lineage differentiation and increased proliferative malignant cells at recurrence were pronounced in gliomas that acquired recurrence-associated genetic events, including treatment-associated hypermutation, increased copy number changes, and cell cycle alterations. Second, increased mesenchymal-like state abundance occurred independently of acquired genetic alterations and instead coincided with heightened macrophage expression. Overall, our findings provide an integrative model that traces the cell-intrinsic and extrinsic factors that shape cellular states during IDH-mutant glioma disease progression.
2026-04-20 | GSE324481 | GEO
Project description:Isocitrate dehydrogenase (IDH)-mutant gliomas are malignant brain tumors that typically arise in early- to mid-adulthood and nearly always recur following treatment. However, the genetic and cellular state changes that drive IDH-mutant glioma progression under treatment remain incompletely understood. Here, we integrated single-nucleus transcriptomic profiles, chromatin accessibility profiles and bulk DNA/RNA sequencing from 75 temporally separated gliomas across 35 patients comprising both the oligodendroglioma and astrocytoma IDH-mutant glioma tumor types. We show that malignant cell states transcriptionally resemble stages of normal glial-neuronal lineage development or a reactive mesenchymal-like state, mirroring states previously described in IDH-wildtype glioblastoma. Malignant cell states displayed distinct chromatin accessibility profiles that were comparable between both IDH-mutant glioma types. The abundance of less differentiated malignant cells increased with grade and with genetic alterations such as PDGFRA amplification. Longitudinal analysis highlighted two major malignant cell state transition patterns. First, reduced lineage differentiation and increased proliferative malignant cells at recurrence were pronounced in gliomas that acquired recurrence-associated genetic events, including treatment-associated hypermutation, increased copy number changes, and cell cycle alterations. Second, increased mesenchymal-like state abundance occurred independently of acquired genetic alterations and instead coincided with heightened macrophage expression. Overall, our findings provide an integrative model that traces the cell-intrinsic and extrinsic factors that shape cellular states during IDH-mutant glioma disease progression.
2026-04-23 | GSE324860 | GEO
Project description:Isocitrate dehydrogenase (IDH)-mutant gliomas are malignant brain tumors that typically arise in early- to mid-adulthood and nearly always recur following treatment. However, the genetic and cellular state changes that drive IDH-mutant glioma progression under treatment remain incompletely understood. Here, we integrated single-nucleus transcriptomic profiles, chromatin accessibility profiles and bulk DNA/RNA sequencing from 75 temporally separated gliomas across 35 patients comprising both the oligodendroglioma and astrocytoma IDH-mutant glioma tumor types. We show that malignant cell states transcriptionally resemble stages of normal glial-neuronal lineage development or a reactive mesenchymal-like state, mirroring states previously described in IDH-wildtype glioblastoma. Malignant cell states displayed distinct chromatin accessibility profiles that were comparable between both IDH-mutant glioma types. The abundance of less differentiated malignant cells increased with grade and with genetic alterations such as PDGFRA amplification. Longitudinal analysis highlighted two major malignant cell state transition patterns. First, reduced lineage differentiation and increased proliferative malignant cells at recurrence were pronounced in gliomas that acquired recurrence-associated genetic events, including treatment-associated hypermutation, increased copy number changes, and cell cycle alterations. Second, increased mesenchymal-like state abundance occurred independently of acquired genetic alterations and instead coincided with heightened macrophage expression. Overall, our findings provide an integrative model that traces the cell-intrinsic and extrinsic factors that shape cellular states during IDH-mutant glioma disease progression.
2026-04-23 | GSE327580 | GEO
Project description:Isocitrate dehydrogenase (IDH)-mutant gliomas are malignant brain tumors that typically arise in early- to mid-adulthood and nearly always recur following treatment. However, the genetic and cellular state changes that drive IDH-mutant glioma progression under treatment remain incompletely understood. Here, we integrated single-nucleus transcriptomic profiles, chromatin accessibility profiles and bulk DNA/RNA sequencing from 75 temporally separated gliomas across 35 patients comprising both the oligodendroglioma and astrocytoma IDH-mutant glioma tumor types. We show that malignant cell states transcriptionally resemble stages of normal glial-neuronal lineage development or a reactive mesenchymal-like state, mirroring states previously described in IDH-wildtype glioblastoma. Malignant cell states displayed distinct chromatin accessibility profiles that were comparable between both IDH-mutant glioma types. The abundance of less differentiated malignant cells increased with grade and with genetic alterations such as PDGFRA amplification. Longitudinal analysis highlighted two major malignant cell state transition patterns. First, reduced lineage differentiation and increased proliferative malignant cells at recurrence were pronounced in gliomas that acquired recurrence-associated genetic events, including treatment-associated hypermutation, increased copy number changes, and cell cycle alterations. Second, increased mesenchymal-like state abundance occurred independently of acquired genetic alterations and instead coincided with heightened macrophage expression. Overall, our findings provide an integrative model that traces the cell-intrinsic and extrinsic factors that shape cellular states during IDH-mutant glioma disease progression.
2026-04-23 | GSE326221 | GEO