Decitabine reactivated pathways in platinum resistant ovarian cancer

Fang Fang*, Qingyao Zuo, Jay Pilrose, Yinu Wang, Changyu Shen, Meng Li, Phillip Wulfridge, Daniela Matei, Kenneth P. Nephew

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

24 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)3579-3589
Number of pages11
JournalOncotarget
Volume5
Issue number11
DOIs
StatePublished - 2014

Keywords

  • Chemosensitization
  • DNA methylation
  • Decitabine
  • Gene expression
  • Pathway analysis
  • Platinum resistant ovarian cancer

ASJC Scopus subject areas

  • Oncology

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