Background: Ovarian cancer (OC) progression is associated with accumulation of epigenetic changes leading to transcriptional silencing of tumor suppressor and chemo-responsiveness associated genes. We recently demonstrated for the first time in a clinical trial that therapeutic interventions targeting the OC methylome reverse drug resistance and induce meaningful clinical responses. While the FDA-approved demethylating agent decitabine is prone to deamination by cytidine deaminase, SGI-110 (Astex Pharmaceuticals, Inc.), a dinucleotide analogue of decitabine, is more stable, less toxic, and a promising alternative to restoring silenced TSG expression in cancer cells by reversal of DNA methylation. Our previous preclinical evaluation demonstrated that SGI-110 resensitized platinum-resistant OC cell lines to cisplatin (CDDP) (3-fold reduction in IC50) and reduced the CDDP IC50 by >2-fold in the A2780 platinum sensitive OC cell line. SGI-110 treatment induced significant demethylation and subsequent transcriptional derepression of tumor suppressors and differentiation-associated genes in A2780 ovarian cancer cells. In addition, non-tumor bearing mice tolerated SGI-110 alone or in combination with CDDP. Methods: In the current study, we assessed the activity of SGI-110 in combination with CDDP to retard the growth of platinum sensitive or drug resistant human ovarian cancer xenografts. Mice were injected with SGI-110 (2 mg/kg or 5 mg/kg, SQ.) or CDDP (2 mg/kg or 4 mg/kg, IP.) treatment or in combination in a biweekly or QD5 regimen. Results: Significant antitumor activity was observed in the single SGI-110 and SGI-110 + CDDP treatment in both the biweekly and QD5 regimen mice bearing a subcutaneous A2780 OC xenograft. The effect of SGI-110 treatment alone was greater than CDDP treatment alone. Pyrosequencing analysis was use to reaffirm global demethylation by SGI-110 treatment, based on significant demethylation of LINE1 in peripheral blood mononuclear cells. As expected, SGI-110 treatment resulted in derepression of TSGs (MLH1 and RASSF1A), HOXA10 and HOXA11 (differentiation-associated genes), CSNK1D (DNA repair), IL2RG (receptor subunit in Jak/STAT pathway), and STAT5B (transcription factor) in tumors (as observed in the in vitro study). To test the hypothesis that SGI-110 treatment influenced DNA adduct formation and repair of cisplatin-DNA damage, we are currently analyzing the amount of platinum-DNA damage induced by CDDP treatment using mass spectrometry. Conclusions: The results of our preclinical study support our recently activated clinical trial using SGI-110 in combination with carboplatin in patients with recurrent, platinum-resistant OC.

Citation Format: Jessica Tang, Fang Fang, Yinu Wang, Pietro Taverna, David F.B. Miller, Gavin Choy, Mohammad Azab, Daniela Matei, Katherine S. Pawelczak, Pamela VanderVere-Carozza, Michael Wagner, John J. Turchi, Kenneth P. Nephew. The novel, small molecule DNA methylation inhibitor SGI-110 as an ovarian cancer chemosensitizer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4623. doi:10.1158/1538-7445.AM2013-4623