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.