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Ref Type Journal Article
PMID (31727689)
Authors Machida Y, Nakagawa M, Matsunaga H, Yamaguchi M, Ogawara Y, Shima Y, Yamagata K, Katsumoto T, Hattori A, Itoh M, Seki T, Nishiya Y, Nakamura K, Suzuki K, Imaoka T, Baba D, Suzuki M, Sampetrean O, Saya H, Ichimura K, Kitabayashi I
Title A Potent Blood-Brain Barrier-Permeable Mutant IDH1 Inhibitor Suppresses the Growth of Glioblastoma with IDH1 Mutation in a Patient-Derived Orthotopic Xenograft Model.
Journal Molecular cancer therapeutics
Vol 19
Issue 2
Date 2020 02
URL
Abstract Text Gliomas are the second most common primary brain tumors in adults. They are treated with combination therapies, including surgery, radiotherapy, and chemotherapy. There are currently limited treatment options for recurrent gliomas, and new targeted therapies need to be identified, especially in glioblastomas, which have poor prognosis. Isocitrate dehydrogenase (IDH) mutations are detected in various tumors, including gliomas. Most patients with IDH mutant glioma harbor the IDH1R132H subtype. Mutant IDH catalyzes the conversion of α-ketoglutarate to the oncometabolite 2-hydroxyglutarate (2-HG), which induces aberrant epigenetic status and contributes to malignant progression, and is therefore a potential therapeutic target for IDH mutant tumors. The present study describes a novel, orally bioavailable selective mutant IDH1 inhibitor, DS-1001b. The drug has high blood-brain barrier (BBB) permeability and inhibits IDH1R132H. Continuous administration of DS-1001b impaired tumor growth and decreased 2-HG levels in subcutaneous and intracranial xenograft models derived from a patient with glioblastoma with IDH1 mutation. Moreover, the expression of glial fibrillary acidic protein was strongly induced by DS-1001b, suggesting that inhibition of mutant IDH1 promotes glial differentiation. These results reveal the efficacy of BBB-permeable DS-1001b in orthotopic patient-derived xenograft models and provide a preclinical rationale for the clinical testing of DS-1001b in recurrent gliomas.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
DS-1001b DS-1001b 6 1
Drug Name Trade Name Synonyms Drug Classes Drug Description
DS-1001b DS-1001|DS1001|Safusidenib|AB-218|AB218|AB 218 IDH1 Inhibitor 8 DS-1001b specifically targets IDH1 mutations, including at amino acid R132, which results in decreased 2HG production and potentially leads to increased differentiation and decreased proliferation of IDH1 mutant cancer cells (PMID: 31727689, PMID: 31406254).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
IDH1 R132G Advanced Solid Tumor predicted - sensitive DS-1001b Preclinical - Biochemical Actionable In a preclinical study, transformed human cells expressing IDH1 R132G demonstrated sensitivity to DS-1001b in culture, resulting in reduced production of the oncometabolite 2-hydroxyglutarate (2-HG) (PMID: 31727689). 31727689
IDH1 R132L Advanced Solid Tumor predicted - sensitive DS-1001b Preclinical - Biochemical Actionable In a preclinical study, transformed human cells expressing IDH1 R132L demonstrated sensitivity to DS-1001b in culture, resulting in reduced production of the oncometabolite 2-hydroxyglutarate (2-HG) (PMID: 31727689). 31727689
IDH1 R132H glioblastoma sensitive DS-1001b Preclinical - Pdx Actionable In a preclinical study, treatment with DS-1001b inhibited subcutaneous and intracranial tumor growth in a patient-derived xenograft (PDX) model of glioblastoma harboring IDH1 R132H, and also demonstrated reduced levels of the oncometabolite 2-hydroxyglutarate (2-HG) within tumors and plasma and increased expression of the astrocyte differentiation marker glial fibrillary acidic protein in tumor cells (PMID: 31727689). 31727689
IDH1 R132H Advanced Solid Tumor predicted - sensitive DS-1001b Preclinical - Biochemical Actionable In a preclinical study, DS-1001b inhibited IDH1 R132H enzymatic activity in an in vitro assay, and inhibited production of the oncometabolite 2-hydroxyglutarate (2-HG) in transformed human cells expressing IDH1 R132H in culture (PMID: 31727689). 31727689
IDH1 R132S Advanced Solid Tumor predicted - sensitive DS-1001b Preclinical - Biochemical Actionable In a preclinical study, transformed human cells expressing IDH1 R132S demonstrated sensitivity to DS-1001b in culture, resulting in reduced production of the oncometabolite 2-hydroxyglutarate (2-HG) (PMID: 31727689). 31727689
IDH1 R132C Advanced Solid Tumor predicted - sensitive DS-1001b Preclinical - Biochemical Actionable In a preclinical study, DS-1001b inhibited IDH1 R132C enzymatic activity in an in vitro assay, and inhibited production of the oncometabolite 2-hydroxyglutarate (2-HG) in transformed human cells expressing IDH1 R132C in culture (PMID: 31727689). 31727689