title: Preclinical Evidence of Anti-Tumor Activity Induced by EZH2 Inhibition in Human Models of Synovial Sarcoma.
abstract: The catalytic activities of covalent and ATP-dependent chromatin remodeling are central to regulating the conformational state of chromatin and the resultant transcriptional output. The enzymes that catalyze these activities are often contained within multiprotein complexes in nature. Two such multiprotein complexes, the polycomb repressive complex 2 (PRC2) methyltransferase and the SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeler have been reported to act in opposition to each other during development and homeostasis. An imbalance in their activities induced by mutations/deletions in complex members (e.g. SMARCB1) has been suggested to be a pathogenic mechanism in certain human cancers. Here we show that preclinical models of synovial sarcoma-a cancer characterized by functional SMARCB1 loss via its displacement from the SWI/SNF complex through the pathognomonic SS18-SSX fusion protein-display sensitivity to pharmacologic inhibition of EZH2, the catalytic subunit of PRC2. Treatment with tazemetostat, a clinical-stage, selective and orally bioavailable small-molecule inhibitor of EZH2 enzymatic activity reverses a subset of synovial sarcoma gene expression and results in concentration-dependent cell growth inhibition and cell death specifically in SS18-SSX fusion-positive cells in vitro. Treatment of mice bearing either a cell line or two patient-derived xenograft models of synovial sarcoma leads to dose-dependent tumor growth inhibition with correlative inhibition of trimethylation levels of the EZH2-specific substrate, lysine 27 on histone H3. These data demonstrate a dependency of SS18-SSX-positive, SMARCB1-deficient synovial sarcomas on EZH2 enzymatic activity and suggests the potential utility of EZH2-targeted drugs in these genetically defined cancers.
authors.affiliation: Eisai Co., Ltd., Tsukuba, Ibaraki, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kawano
authors.affiliation: Epizyme Inc., Cambridge, Massachusetts, United States of America.
authors.forename: Alexandra R
authors.initials: AR
authors.lastname: Grassian
authors.affiliation: Department of Cancer Pathology, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido, Japan.
authors.forename: Masumi
authors.initials: M
authors.lastname: Tsuda
authors.affiliation: Epizyme Inc., Cambridge, Massachusetts, United States of America.
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Knutson
authors.affiliation: Epizyme Inc., Cambridge, Massachusetts, United States of America.
authors.forename: Natalie M
authors.initials: NM
authors.lastname: Warholic
authors.affiliation: Eisai Inc., Andover, Massachusetts, United States of America.
authors.forename: Galina
authors.initials: G
authors.lastname: Kuznetsov
authors.affiliation: Eisai Inc., Andover, Massachusetts, United States of America.
authors.forename: Shanqin
authors.initials: S
authors.lastname: Xu
authors.affiliation: Epizyme Inc., Cambridge, Massachusetts, United States of America.
authors.forename: Yonghong
authors.initials: Y
authors.lastname: Xiao
authors.affiliation: Epizyme Inc., Cambridge, Massachusetts, United States of America.
authors.forename: Roy M
authors.initials: RM
authors.lastname: Pollock
authors.affiliation: Epizyme Inc., Cambridge, Massachusetts, United States of America.
authors.forename: Jesse S
authors.initials: JS
authors.lastname: Smith
authors.affiliation: Epizyme Inc., Cambridge, Massachusetts, United States of America.
authors.forename: Kevin K
authors.initials: KK
authors.lastname: Kuntz
authors.affiliation: Epizyme Inc., Cambridge, Massachusetts, United States of America.
authors.forename: Scott
authors.initials: S
authors.lastname: Ribich
authors.affiliation: Eisai Co., Ltd., Tsukuba, Ibaraki, Japan.
authors.forename: Yukinori
authors.initials: Y
authors.lastname: Minoshima
authors.affiliation: Eisai Co., Ltd., Tsukuba, Ibaraki, Japan.
authors.forename: Junji
authors.initials: J
authors.lastname: Matsui
authors.affiliation: Epizyme Inc., Cambridge, Massachusetts, United States of America.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Copeland
authors.affiliation: Department of Cancer Pathology, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Tanaka
authors.affiliation: Epizyme Inc., Cambridge, Massachusetts, United States of America.
authors.forename: Heike
authors.initials: H
authors.lastname: Keilhack
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D000071221:Enhancer of Zeste Homolog 2 Protein / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism; D063151:Polycomb Repressive Complex 2 / Q000235:genetics / Q000378:metabolism; D000071796:SMARCB1 Protein / Q000235:genetics / Q000378:metabolism; D013584:Sarcoma, Synovial / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D015514:Oncogene Proteins, Fusion; D000071796:SMARCB1 Protein; C513266:SMARCB1 protein, human; C587877:SS18-SSX1 fusion protein; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2