Reference Detail

Ref Type

Journal Article

PMID

(38334611)

Authors

Sprinzen L, Garcia F, Mela A, Lei L, Upadhyayula P, Mahajan A, Humala N, Manier L, Caprioli R, Quiñones-Hinojosa A, Casaccia P, Canoll P

Title

EZH2 Inhibition Sensitizes IDH1R132H-Mutant Gliomas to Histone Deacetylase Inhibitor.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cells	13	3	2024 Jan 25		Cells

URL

Abstract Text

Isocitrate Dehydrogenase-1 (IDH1) is commonly mutated in lower-grade diffuse gliomas. The IDH1R132H mutation is an important diagnostic tool for tumor diagnosis and prognosis; however, its role in glioma development, and its impact on response to therapy, is not fully understood. We developed a murine model of proneural IDH1R132H-mutated glioma that shows elevated production of 2-hydroxyglutarate (2-HG) and increased trimethylation of lysine residue K27 on histone H3 (H3K27me3) compared to IDH1 wild-type tumors. We found that using Tazemetostat to inhibit the methyltransferase for H3K27, Enhancer of Zeste 2 (EZH2), reduced H3K27me3 levels and increased acetylation on H3K27. We also found that, although the histone deacetylase inhibitor (HDACi) Panobinostat was less cytotoxic in IDH1R132H-mutated cells (either isolated from murine glioma or oligodendrocyte progenitor cells infected in vitro with a retrovirus expressing IDH1R132H) compared to IDH1-wild-type cells, combination treatment with Tazemetostat is synergistic in both mutant and wild-type models. These findings indicate a novel therapeutic strategy for IDH1-mutated gliomas that targets the specific epigenetic alteration in these tumors.

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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

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

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	decreased response	Panobinostat	Preclinical - Cell culture	Actionable	In a preclinical study, mouse glioma cells expressing IDH1 R132H were less sensitive to Farydak (panobinostat) compared to IDH1 wild-type cells in culture (PMID: 38334611).	38334611
IDH1 R132H	high grade glioma	sensitive	Panobinostat + Tazemetostat	Preclinical - Cell culture	Actionable	In a preclinical study, cotreatment with Tazverik (tazemetostat) sensitized mouse glioma cells expressing IDH1 R132H to Farydak (panobinostat) in culture, resulting in synergistic inhibition of cell viability (PMID: 38334611).	38334611