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Oncotarget. 2014 Jun 15;5(11):3579-89.

Decitabine reactivated pathways in platinum resistant ovarian cancer.

Author information

1
Medical Sciences, Indiana University School of Medicine, Bloomington, IN, USA.
2
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.
3
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.

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.

PMID:
25003579
PMCID:
PMC4116504
DOI:
10.18632/oncotarget.1961
[Indexed for MEDLINE]
Free PMC Article

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