Abstract
Abstract Deoxycytosine methylation of CpG islands within promoter regions of tumor suppressor genes (TSGs) plays a prominent role in the development and progression of drug-resistant epithelial ovarian cancer (OC). Recently, in a phase I/II trial of the DNA methylation inhibitor decitabine in combination with carboplatin in platinum-resistant OC patients (NCT00477386), we demonstrated that decitabine-altered DNA methylation resulted in platinum resensitization and significant clinical activity, with a response rate of 35% and median PFS of 10 months (ASCO abstract #79158). The objective of the current study was to investigate the molecular basis underlying the clinical response observed. For this, we compared differential gene expression in paired tumor biopsies and ascitic fluid collected before and one week after decitabine treatment. Of the 17 patients enrolled in NCT00477386, samples evaluable from 14 patients were subjected to global gene expression profiling using GeneChip Human Gene 1.0 St arrays, and selected genes were validated by quantitative RT-PCR. Data analysis was performed using significance of microarray analysis (SAM), clustering, functional pathway prediction using DAVID, gene ontology (GO), and gene set enrichment analysis (GSEA). In the patients with progression free survival (PFS) greater than six months (n=6), 274 genes were uniquely upregulated by decitabine. Enriched signaling pathways included Hedgehog, focal adhesion, and gap junction. Specifically, genes upregulated (fold change >1.2, P < 0.05) in the Hedgehog pathway included PTCH2 (a putative TSG), the hedgehog antagonist HHIP, and BAALC (with the latter two genes frequently silenced by DNA methylation in cancer), and MMP8 (associated with decreased lung cancer risk). Expression of AKT1 was higher in patients with PFS > 6 months compared to patients with PFS < 6 months (fold change 1.9 vs. 1.2 compared to baseline). MLH1 (mismatch repair gene) expression was increased (1.3 fold-change compared to baseline) in patients with PFS > 6 months and decreased in patients with PFS < 6 months (-1.2 fold-change). Furthermore, 394 genes were downregulated (FC < –1.2, P < 0.05) by decitabine in patients with PFS > 6 months, including 33 genes of the “stemness” and chemoresistance-associated Wnt pathway. Notably, underexpression of those 33 genes has been correlated with prolonged survival in previous ovarian cancer studies. In summary, these findings show that repetitive low-dose decitabine reactivates silenced genes and restores sensitivity to carboplatin, providing strong clinical and biological support for further study of hypomethylating agents in heavily pre-treated, platinum-resistant ovarian cancer patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4081. doi:1538-7445.AM2012-4081
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