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Ref Type Journal Article
PMID (21045145)
Authors Seltzer MJ, Bennett BD, Joshi AD, Gao P, Thomas AG, Ferraris DV, Tsukamoto T, Rojas CJ, Slusher BS, Rabinowitz JD, Dang CV, Riggins GJ
Title Inhibition of glutaminase preferentially slows growth of glioma cells with mutant IDH1.
Journal Cancer research
Vol 70
Issue 22
Date 2010 Nov 15
URL
Abstract Text Mutation at the R132 residue of isocitrate dehydrogenase 1 (IDH1), frequently found in gliomas and acute myelogenous leukemia, creates a neoenzyme that produces 2-hydroxyglutarate (2-HG) from α-ketoglutarate (α-KG). We sought to therapeutically exploit this neoreaction in mutant IDH1 cells that require α-KG derived from glutamine. Glutamine is converted to glutamate by glutaminase and further metabolized to α-KG. Therefore, we inhibited glutaminase with siRNA or the small molecule inhibitor bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide (BPTES) and found slowed growth of glioblastoma cells expressing mutant IDH1 compared with those expressing wild-type IDH1. Growth suppression of mutant IDH1 cells by BPTES was rescued by adding exogenous α-KG. BPTES inhibited glutaminase activity, lowered glutamate and α-KG levels, and increased glycolytic intermediates while leaving total 2-HG levels unaffected. The ability to selectively slow growth in cells with IDH1 mutations by inhibiting glutaminase suggests a unique reprogramming of intermediary metabolism and a potential therapeutic strategy.

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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
BPTES BPTES 2 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
BPTES bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide BPTES is a small molecule that inhibits glutaminase, which results in decreased conversion of glutamine to glutamate, and potentially leads to decreased tumor cell growth (PMID: 21045145, PMID: 25915584).
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 R132H malignant glioma sensitive BPTES Preclinical - Cell culture Actionable In a preclinical study, a glioma cell line expressing IDH1 R132H demonstrated increased sensitivity to growth inhibition by BPTES compared to a cell line expressing wild-type IDH1 in culture (PMID: 21045145). 21045145