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: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:Single-Cell Sequencing of IDH-Mutant Glioma
| PRJNA1125010 | ENA
Project description:Adult-type diffuse gliomas comprise IDH-mutant astrocytomas, IDH-mutant 1p/19q codeleted oligodendrogliomas (ODG), and IDH-wildtype glioblastomas (GBM). GBM display genome instability, which may result from two genetic events leading to massive chromosome alterations: chromothripsis (CT) and whole-genome duplication (WGD). The better prognosis of the latter may be related to their genome stability compared to GBM. Pangenomic profiles of 297 adult diffuse gliomas were analyzed at initial diagnosis using SNP arrays, including 192 GBM and 105 IDH-mutant gliomas (61 astrocytomas and 44 ODG). Tumor ploidy was assessed with Genome Alteration Print and CT events with CTLPScanner and through manual screening.
2024-12-24 | E-MTAB-13542 | biostudies-arrayexpress
Project description:This multi-site, Phase 1/2 clinical trial is an open-label study to identify the safety, pharmacokinetics, and efficacy of a repeated dose regimen of NEO212 for the treatment of patients with radiographically-confirmed progression of Astrocytoma IDH-mutant, Glioblastoma IDH-wildtype, and the safety, pharmacokinetics and efficacy of a repeated dose regimen of NEO212 when given with select SOC for the treatment of solid tumor patients with radiographically confirmed uncontrolled brain metastasis. The study will have three phases, Phase 1, Phase 2a and Phase 2b.
| 92735 | ecrin-mdr-crc
Project description:Background. High-grade transformation (HT) is common in IDH-mutant glioma, which is inevitable and unpredictable. Both genomic and metabolomic landscapes are going through dynamic processes during the transformation. Although HT phenomena have been observed clinically, the research of mechanisms underlying HT have been limited by the lack of preclinical models that can recapitulate the evolution of malignant transformation. Methods. Here we established a unique pair of matched cell lines, 403L and 403H, by utilizing tumor samples of an IDH-mutant astrocytoma from the same patient when the tumor was diagnosed as WHO grade 2 and 4, respectively. Using genetic, epigenetic, and metabolomic analyses, the two cell models have been characterized extensively. The cell lines have been used to establish orthotopic xenograft models of the disease.
2025-05-15 | GSE267615 | GEO
Project description:Expression profile for hemocytes from hml-Gal4, UAS-2xEGFP larvae were compared to hemocytes from hml-Gal4, UAS-2xEGFP; UAS-Idh-R195H larvae We sought to determine which genes and pathways were upregulated or downregulated in hemocytes expressing Idh-R195H, the Drosophila homolog of the human cancer-associated IDH1-R132H mutant, in vivo. We sought to obtain homogeneous populations of hemocytes from each genotype. We compared larvae expressing Idh-R195H from the hml-Gal4 driver to larvae with the hml-Gal4 driver alone.
2014-10-03 | E-GEOD-62008 | biostudies-arrayexpress
Project description:A perioperative study of Safusidenib in Patients with IDH1-mutated glioma
| PRJNA1235854 | ENA