Work

Decitabine reactivated pathways in platinum resistant ovarian cancer

Year: 2014

Type: article

Abstract: // Fang Fang 1 , Qingyao Zuo 2 , Jay Pilrose 1 , Yinu Wang 1 , Changyu Shen 3,4 , Meng Li 5 , Phillip Wulfridge 1 , Daniela Matei 6,7,8,9 , Kenneth P. Nephew 1,6,8,10 1 Medical Sciences, Indiana University School of Medicine, Bloomington, IN, USA 2 Department of Endocrinology, Beijing Jishuitan Hospital, Beijing, P.R. China 3 Department of Biostatistics, Indiana University, Indianapolis, IN, USA 4 Computational Biology & Bioinformatics, Indiana University, Indianapolis, IN, USA 5 Norris Medical Library, University of Southern California, Los Angeles, CA, USA 6 Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN, USA 7 VA Roudebush Hospital, Indianapolis, IN, USA 8 Department of Obstetrics and Gynecology 9 Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA 10 Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, IN, USA Correspondence: Fang Fang, email: // Daniela Matei, email: // Kenneth P. Nephew, email: // Keywords : platinum resistant ovarian cancer, decitabine, gene expression, chemosensitization, DNA methylation, pathway analysis Received : March 10, 2014 Accepted: May 12, 2014 Published: May 13, 2014 Abstract Combination therapy with decitabine, a DNMTi and carboplatin resensitized chemoresistant ovarian cancer (OC) to platinum inducing promising clinical activity. We investigated gene-expression profiles in tumor biopsies to identify decitabine-reactivated pathways associated with clinical response. Gene-expression profiling was performed using RNA from paired tumor biopsies before and 8 days after decitabine from 17 patients with platinum resistant OC. Bioinformatic analysis included unsupervised hierarchical-clustering, pathway and GSEA distinguishing profiles of “responders” (progression-free survival, PFS>6months) and “non-responders” (PFS<6months). Functional validation of selected results was performed in OC cells/tumors. Pre-treatment tumors from responders expressed genes associated with enhanced glycosphingolipid biosynthesis, translational misregulation, decreased ABC transporter expression, TGF-β signaling, and numerous metabolic pathways. Analysis of post-treatment biopsies from responders revealed overexpression of genes associated with reduced Hedgehog pathway signaling, reduced DNA repair/replication, and cancer-associated metabolism. GO and GSEA analyses revealed upregulation of genes associated with glycosaminoglycan binding, cell-matrix adhesion, and cell-substrate adhesion. Computational findings were substantiated by experimental validation of expression of key genes involved in two critical pathways affected by decitabine (TGF-β and Hh). Gene-expression profiling identified specific pathways altered by decitabine and associated with platinum-resensitization and clinical benefit in OC. Our data could influence patient stratification for future studies using epigenetic therapies.

Source: Oncotarget

DOI: 10.18632/oncotarget.1961