SGI-110, is a novel second generation DNA hypomethylating agent, which shows promising single agent activity in leukaemia patients (NCT01261312) and is currently under investigation as a priming agent in solid tumors. There is evidence that the acquisition of platinum resistance in ovarian cancer is associated with DNA methylation changes that result in epigenetic silencing of specific genes. Pre-clinical studies suggest that DNA hypomethylating agents can reverse such resistance. SGI-110 is currently in a Phase II clinical trial in combination with carboplatin, in platinum-resistant recurrent ovarian cancer patients (NCT01696032). SGI-110 is a dinucleotide of decitabine and deoxyguanosine, which is resistant to modification by cytidine deaminase: a common pathway of decitabine metabolism and deactivation.
We demonstrated that SGI-110 conferred global LINE1 de-methylation and re-expression of epigenetically silenced genes in a panel of ovarian cancer cell lines. We identified three cell lines, A2780, OVCAR8 and OAW28, which were sensitised to cisplatin following SGI-110 treatment (4-fold, 9-fold and 3-fold sensitisation, respectively). It has previously been demonstrated that epigenetic silencing of the mismatch repair protein MLH1 contributes to the cisplatin resistance of A2780 cells. Using pyrosequencing, we confirmed MLH1 promoter hypermethylation (96.2% methylation) and silencing of MLH1 expression in A2780 cells. Treatment with 0.1 µM SGI-110 conferred 25% MLH1 promoter de-methylation and MLH1 re-expression. We demonstrated that MLH1 is not epigenetically silenced in OVCAR8 or OAW28 cells. This suggests that the cisplatin resistance of these cell lines are due to distinct epigenetic mechanisms, which we are currently investigating.
We assessed SGI-110 activity in an in vivo A2780 xenograft model. Mice bearing subcutaneous xenografts were treated with SGI-110 (2 mg/kg, s.c, daily x5), either as single agent or prior to treatment with cisplatin (2 mg/kg, or 4 mg/kg cisplatin i.p). Cisplatin treatment alone had no anti-tumor activity. Single agent SGI-110 conferred moderate anti-tumor activity. However, the combination of SGI-110 with 4 mg/kg cisplatin, conferred even greater anti-tumor activity than either agent alone (p<0.05). Since single agent cisplatin had no anti-tumor activity, this demonstrates that priming with SGI-110 reversed the intrinsic cisplatin resistance of the A2780 tumors. SGI-110 conferred 11% LINE1 de-methylation, 2.2% MLH1 promoter de-methylation and a 3-fold increase in MLH1 mRNA levels in tumors.
These data suggest that SGI-110 can reverse the cisplatin resistance of ovarian cancer models by restoring the expression of epigenetically silenced genes and supports our ongoing Phase II trial evaluating SGI-110 in combination with carboplatin, in platinum-resistant recurrent ovarian cancer patients
Citation Format: Joanne M. Munck, John Lyons, Neil T. Thompson, Nicola G. Wallis, Pietro Taverna. The DNA hypomethylating agent SGI-110, reverses the platinum resistance of ovarian cancer models. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3756. doi:10.1158/1538-7445.AM2014-3756