Reference Detail

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	Vol	Issue	Date	Pages	Journal Short Title
Cancer research	70	22	2010 Nov 15	8981-7	Cancer Res

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	Glutaminase Inhibitor 3	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, PMID: 32450839).

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	high grade 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