207 Poster Session 2 - Connective Tissue Oncology Society

Scientific Posters – Poster Session 2Poster #165HDAC INHIBITION; A NOVEL THERAPY FOR THETREATMENT OF EPITHELIOID SARCOMAGonzalo Lopez 1 ; Yechun Song 1 ; Quan-Sheng Zhu 1 ;Ryan Lam 1 ; Roman Belousov 1 ; Davis R. Ingram 1 ;Torsten O. Nielsen 3 ;Chad Creighton 2 ; Dina Lev 11MDACC, Houston, TX, USA; 2 Baylor College of Medicine,Houston, TX, USA; 3 University of British Columbia,Vancouver, BC, CanadaObjective: There is a critical need for improved therapeuticstrategies for the treatment of epithelioid sarcoma (ES).Loss of INI1 expression is the molecular hallmark of theseunique malignancies resulting in a potential disruption inthe cellular epigenetic landscape. The goal of the currentstudy was to evaluate the effects of the epigenetic modifiers,HDAC inhibitors (HDACi), on the protumorigenicproperties of ES cells in vitro and in vivo.Methods: Three human ES cell lines were included(VAESBJ, Epi544, and HS-ES) and three HDACis weretested (PCI24781, SAHA, and MS275). Effects on growthwere assessed by MTS and clonogenic assays; cell cycleprogression was determined by PI staining FACS analysesand apoptosis by Annexin V/PI FACS analysis and WBfor cleaved caspase 3 and cleaved PARP. In vivo growtheffects of PCI24781 were evaluated using SCID mouse ESxenograft models. An Illumina gene array was used todetermine HDACi-induced gene expression signatures.Genes of interest were validated via WB and qPCR.Results: HDACis induced target acetylation in ES cellsand abrogated their growth and colony formation. Furthermore,G2 cell cycle arrest and enhanced apoptosis wasnoted. PCI24781 markedly inhibited ES xenograft growthand induced apoptosis in vivo. Gene expression profilingidentified an ES HDACi-induced genetic signature consistingof multiple up- and down- regulated genes (~5%of genes on the platform exhibited reproducibly changedexpression). Bioinformatic analyses identified enrichmentof genes associated with cell death, cell cycle progression,and differentiation. Furthermore, multiple transcriptionalregulators, epigenetic modifiers, and post-translationaleffectors were found to exhibit changed expression, highlightingthe complexity of- and the interaction amongstnodesmaking up the cellular molecular landscape. Ourstudies further demonstrated HDACi induced reduction inthe expression of one particular epigenetic enzyme, EZH2.Enhanced EZH2 expression was demonstrated in humanES specimens and studies to unravel the pro-ES effects ofthis protein are currently ongoing.Conclusion: Studies presented here identified moleculesof potential contribution to the development and progressionof ES. Most importantly, pre-clinical investigationsidentified HDAC inhibition as a possibly effective anti-EStherapeutic strategy supporting further investigation ofthis approach in the clinical setting.Poster #166TRABECTEDIN ACTIVITY IN SOFT TISSUESARCOMAS OF VASCULAR AND PERIVASCULARCELLS (STS-V/PV): A RETROSPECTIVE POOLEDANALYSISJean-Yves Blay 1 ; Ian Judson 2 ; Robert G. Maki 3 ;Xavier García del Muro 4 ; María José Pontes 5 ; Patrik Zintl 5 ;George D. Demetri 61Centre Leon Berard, Lyon, France; 2 Royal Marsden Hospital,London, United Kingdom; 3 Sloan-Kettering Institute,New York, NY, USA; 4 Institut Catala d’Oncologia, Barcelona,Spain; 5 PharmaMar, Madrid, Spain; 6 Dana-Farber CancerInstitute, Boston, MA, USAObjective: Trabectedin is approved in >70 countries worldwidefor the treatment of advanced soft tissue sarcomas(STS). It has demonstrated activity in several phase IIstudies as well as compassionate use programs. STS-V/PVrepresent 3 cycles).One patient with solitary fibrous tumor achieved partialresponse (8%), 5 patients had stable disease (39%; in 4 lasting≥3 months), 7 patients (54%) had progressive disease asbest response. Median PFS was 1.9 months (CI95%:1.5-3.3)and 38.5% patients (CI95% 12-64.9) were progression-freeat 3 months. Median OS was 8.8 months; OS at 12 and 24months was 40.5% (CI95% 8-72.9) and 27% (CI95% 0-57.5),respectively. There were no unexpected toxicities: grade3/4 toxicities included neutropenia (58% of the patients),thrombocytopenia (25%), anemia (8 %), fatigue (8%),254