Epigenetic resensitization to platinum in ovarian cancer

Daniela Matei, Fang Fang, Changyu Shen, Jeanne Schilder, Alesha Arnold, Yan Zeng, William A. Berry, Tim Huang, Kenneth Nephew

Research output: Contribution to journalArticle

215 Citations (Scopus)

Abstract

Preclinical studies have shown that hypomethylating agents reverse platinum resistance in ovarian cancer. In this phase II clinical trial, based upon the results of our phase I dose defining study, we tested the clinical and biologic activity of low-dose decitabine administered before carboplatin in platinum-resistant ovarian cancer patients. Among 17 patients with heavily pretreated and platinum-resistant ovarian cancer, the regimen induced a 35% objective response rate (RR) and progression-free survival (PFS) of 10.2 months, with nine patients (53%) free of progression at 6 months. Global and gene-specific DNA demethylation was achieved in peripheral blood mononuclear cells and tumors. The number of demethylated genes was greater (P < 0.05) in tumor biopsies from patients with PFS more than 6 versus less than 6 months (311 vs. 244 genes). Pathways enriched at baseline in tumors from patients with PFS more than 6 months included cytokine-cytokine receptor interactions, drug transporters, and mitogen-activated protein kinase, toll-like receptor and Jak-STAT signaling pathways, whereas those enriched in demethylated genes after decitabine treatment included pathways involved in cancer, Wnt signaling, and apoptosis (P < 0.01). Demethylation of MLH1, RASSF1A, HOXA10, and HOXA11 in tumors positively correlated with PFS (P < 0.05). Together, the results of this study suggest that low-dose decitabine altered DNA methylation of genes and cancer pathways, restoring sensitivity to carboplatin in patients with heavily pretreated ovarian cancer and resulting in a high RR and prolonged PFS.

Original languageEnglish
Pages (from-to)2197-2205
Number of pages9
JournalCancer Research
Volume72
Issue number9
DOIs
StatePublished - May 1 2012

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decitabine
Platinum
Epigenomics
Ovarian Neoplasms
Disease-Free Survival
Carboplatin
Neoplasms
Genes
Phase II Clinical Trials
Cytokine Receptors
Toll-Like Receptors
Neoplasm Genes
DNA Methylation
Mitogen-Activated Protein Kinases
Drug Interactions
Blood Cells
Apoptosis
Cytokines
Biopsy
DNA

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Epigenetic resensitization to platinum in ovarian cancer. / Matei, Daniela; Fang, Fang; Shen, Changyu; Schilder, Jeanne; Arnold, Alesha; Zeng, Yan; Berry, William A.; Huang, Tim; Nephew, Kenneth.

In: Cancer Research, Vol. 72, No. 9, 01.05.2012, p. 2197-2205.

Research output: Contribution to journalArticle

Matei, D, Fang, F, Shen, C, Schilder, J, Arnold, A, Zeng, Y, Berry, WA, Huang, T & Nephew, K 2012, 'Epigenetic resensitization to platinum in ovarian cancer', Cancer Research, vol. 72, no. 9, pp. 2197-2205. https://doi.org/10.1158/0008-5472.CAN-11-3909
Matei, Daniela ; Fang, Fang ; Shen, Changyu ; Schilder, Jeanne ; Arnold, Alesha ; Zeng, Yan ; Berry, William A. ; Huang, Tim ; Nephew, Kenneth. / Epigenetic resensitization to platinum in ovarian cancer. In: Cancer Research. 2012 ; Vol. 72, No. 9. pp. 2197-2205.
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