Oncotarget

Research Papers:

Decitabine reactivated pathways in platinum resistant ovarian cancer

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

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Oncotarget. 2014; 5:3579-3589. https://doi.org/10.18632/oncotarget.1961

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Abstract

Fang Fang1, Qingyao Zuo2, Jay Pilrose1, Yinu Wang1, Changyu Shen3,4, Meng Li5, Phillip Wulfridge1, Daniela Matei6,7,8,9, Kenneth P. Nephew1,6,8,10

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.


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