Immunomodulatory action of demethylating agent SGI-110 in ovarian cancer

Ovarian cancer (OC) is regarded as being an immunogenic cancer, however, the bulk of the immune responses associated with OC are inflammatory and suppressive in nature. This suggests that strategies to overcome these suppressive mechanisms and enhance immune function in patients will confer benefit and improve prognosis. Immunotherapy has been shown to be most promising when combined with other therapeutic approaches to combat the disease.

Recent evidence in the field and preliminary data from our group suggest that treatment with epigenetic drugs, such as cytidine analogs, can lead to improved immune activation in several cancers including ovarian. We hypothesise that the global demethylating and DNA damaging effects of treatment with cytidine analogs can induce the re-expression of immunomodulatory genes and endogenous retroviral elements (ERVs), which shifts ovarian cancer cells towards a more immunogenic expression profile.

We plan to identify and validate such immunomodulatory genes and ERVs by RNA-sequencing of ovarian cancer cell lines treated with novel cytidine analog SGI-110; to investigate the contribution of DNA demethylation and DNA damage in the proposed immunomodulatory effect of this class of epigenetic drugs and to test a novel combination epigenetic-immunotherapeutic strategy for the treatment of ovarian cancer using SGI-110 and T-cells. This project will, for the first time, use a genomic approach to study the immunomodulatory potential of SGI-110 and provide genome-wide transcriptional data for previously unstudied ovarian cancer cell lines which better represent the real disease. Additionally, it will identify potential gene targets and/or biomarkers and test a novel combination therapy which may, ultimately, be developed into a clinical trial.