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Series GSE83479 Query DataSets for GSE83479
Status Public on Jun 18, 2016
Title Three different in vivo models of synovial sarcoma (xenograft: Fuji; PDX: CTG-0331 and CTG-0771) treated with or without the indicated dose of the EZH2 inhibitor, tazemetostat
Organism Homo sapiens
Experiment type Expression profiling by high throughput sequencing
Summary 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.
 
Overall design Three different in vivo models of synovial sarcoma (xenograft: Fuji; PDX: CTG-0331 and CTG-0771) treated with or without the indicated dose of the EZH2 inhibitor, tazemetostat
 
Contributor(s) Grassian AR, Ribich S
Citation(s) 27391784
Submission date Jun 17, 2016
Last update date Oct 03, 2019
Contact name Igor Feldman
E-mail(s) ifeldman@epizyme.com
Organization name Epizyme
Street address 400 Technology Square
City Cambridge
ZIP/Postal code 02130
Country USA
 
Platforms (1)
GPL11154 Illumina HiSeq 2000 (Homo sapiens)
Samples (57)
GSM2204076 CTG-0331 Vehicle 35 day treatment BID 0331-1_L5.D703
GSM2204077 CTG-0331 400mg/kg Tazemetostat 35 day treatment BID 0331-10_L6.D712
GSM2204078 CTG-0331 Vehicle 35 day treatment BID 0331-2_L5.D704
Relations
BioProject PRJNA326108
SRA SRP076716

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SOFT formatted family file(s) SOFTHelp
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Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE83479_rsem_gfpkm_matrix.paper.txt.gz 3.4 Mb (ftp)(http) TXT
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Processed data are available on Series record
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