title: Decitabine reactivated pathways in platinum resistant ovarian cancer.
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>6 months) and "non-responders" (PFS< 6 months). 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.
authors.affiliation: Medical Sciences, Indiana University School of Medicine, Bloomington, IN, USA.
authors.forename: Fang
authors.initials: F
authors.lastname: Fang
authors.forename: Qingyao
authors.initials: Q
authors.lastname: Zuo
authors.forename: Jay
authors.initials: J
authors.lastname: Pilrose
authors.forename: Yinu
authors.initials: Y
authors.lastname: Wang
authors.forename: Changyu
authors.initials: C
authors.lastname: Shen
authors.forename: Meng
authors.initials: M
authors.lastname: Li
authors.forename: Phillip
authors.initials: P
authors.lastname: Wulfridge
authors.affiliation: Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN, USA; VA Roudebush Hospital, Indianapolis, IN, USA; Department of Obstetrics and Gynecology; Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Daniela
authors.initials: D
authors.lastname: Matei
authors.affiliation: Medical Sciences, Indiana University School of Medicine, Bloomington, IN, USA; Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN, USA; Department of Obstetrics and Gynecology; Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Kenneth P
authors.initials: KP
authors.lastname: Nephew
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001374:Azacitidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D016190:Carboplatin / Q000008:administration & dosage / Q000494:pharmacology*; D045744:Cell Line, Tumor; D019175:DNA Methylation / Q000187:drug effects; D000077209:Decitabine; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D020869:Gene Expression Profiling; D006801:Humans; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics
chemical_list: D000964:Antimetabolites, Antineoplastic; D000077209:Decitabine; D016190:Carboplatin; D001374:Azacitidine