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Ref Type Journal Article
PMID (28978137)
Authors Miele E, Valente S, Alfano V, Silvano M, Mellini P, Borovika D, Marrocco B, Po A, Besharat ZM, Catanzaro G, Battaglia G, Abballe L, Zwergel C, Stazi G, Milite C, Castellano S, Tafani M, Trapencieris P, Mai A, Ferretti E
Title The histone methyltransferase EZH2 as a druggable target in SHH medulloblastoma cancer stem cells.
Journal Vol Issue Date Pages Journal Short Title
Oncotarget 8 40 2017 Sep 15 68557-68570 Oncotarget
URL
Abstract Text The histone methyltransferase EZH2 plays a role in maintenance of the stem component of cancer, and its overexpression and/or mutation typically drives tumor aggressiveness, drug resistance and patients' poor prognosis. In this study, we use mouse and human medulloblastoma stem-like cells belonging to the Sonic Hedgehog subgroup (SHH MB-SLCs) and demonstrate that genetic suppression of EZH2 reduces the level of its histone mark H3K27me3 and lowers proliferation and self-renewal. We designed an EZH2 inhibitor (EZH2i) as a simplified analog of EPZ005687 and GSK2816126, MC3629, and we tested its biological activity in SHH MB-SLCs. Pharmacological inhibition of EZH2 impairs SHH MB cells proliferation and self-renewal, and induces apoptosis in vitro. Finally, we generated xenograft MB-SLCs orthotopic tumors in nude mice to test MC3629 in vivo. In treated mice, we observed impairment of tumor growth, together with induction of apoptosis and reduction of proliferation and stemness. Overall, these findings describe EZH2 as a druggable target in MB and provide insight into the biological activity of MC3629 as an EZH2i.

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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
MC3629 MC3629 0 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
MC3629 EZH2 inhibitor 20 MC3629 inhibits EZH2, which results in decreased H3K27 trimethylation, and potentially leads to decreased proliferation and increased apoptosis of tumor cells and reduced tumor growth (PMID: 28978137).
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