2014 AACR: SGI-110 DNA HMA SGI-110 reverses Platinum resistance of ovarian cancer models
Summary
- Patients with advanced stage ovarian cancer (OC) have a 5-year survival rate of less than 25%. The most common treatment strategy comprises debulking surgery followed by platinum-based chemotherapy. Patients commonly respond to first-line chemotherapy, but >70% relapse, developing platinum-resistance.
There is evidence that the acquisition of platinum resistance is associated with the epigenetic silencing of specific genes by DNA methylation. - SGI110 is a novel second generation DNA hypomethylating agent, which is currently in a Phase II clinical trial in combination with carboplatin, in platinumresistant recurrent ovarian cancer patients (NCT01696032).
- SGI110 is a dinucleotide of decitabine and deoxyguanosine, which is resistant to modification by cytidine deaminase: a common pathway of decitabine metabolism and deactivation.
- Here we demonstrate that SGI110 reverses the cisplatin-resistance of the A2780 OC model, by abrogating the epigenetic silencing of MLH1. We demonstrate SGI110 activity in a panel of OC cell lines. We suggest that epigenetic silencing of ZIC1 is a mechanism of cisplatin resistance in the OAW28 and Ovcar8 cells and demonstrate that it is reversed by SGI110. SCID Beige mice bearing subcutaneous A2780 tumours. 2 mg/kg SGI110 was administered subcutaneously, once daily on days 1-5. A single dose of cisplatin was administered intraperitoneally on day 8, at 2 mg/kg or 4
mg/kg. Both agents were dosed either as single agent or in combination. Data represent mean ± SD (n=8). - SGI110 reverses the known cisplatin resistance mechanism (epigenetic silencing of MLH1) of A2780 cells by conferring MLH1 promoter demethylation and re-expression.
- SGI110 sensitises OAW28 and Ovcar8 cells to cisplatin. These models have distinct mechanisms of cisplatin resistance to the A2780 cells.
- We identify epigenetic silencing of ZIC1 as a potential cisplatin resistance mechanism in Ovcar8 and OAW28 cells and demonstrate that SGI110 restores ZIC1 expression.
- We demonstrate that SGI110 reverses the cisplatin resistance of OC models by restoring expression of epigenetically silenced genes. This supports our ongoing Phase II trial evaluating SGI110 in combination with carboplatin, in platinum-resistant recurrent ovarian cancer patients (NCT01696032).
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2014 AACR: SGI-110 DNA HMA SGI-110 reverses Platinum resistance of ovarian cancer models
