Epigenetic therapies for chemoresensitization of epithelial ovarian cancer

Abstract

Epigenetic drugs have been shown to enhance gene expression and drug sensitivity in ovarian cancer cell lines and animal models. Based on promising preclinical studies, DNA methylation inhibitors in combination with existing chemotherapeutic agents have the potential for overcoming acquired drug resistance, laying the foundation for this specific class of epigenetic drug in ovarian cancer clinical trials. The recent completion of phase I trials of decitabine has yielded important information on dosing schedules and biological endpoints for evaluating patient responses. In addition, epigenetic drug effects on pharmacodyamic targets are beginning to emerge, and predictive epigenetic biomarkers and next generation epigenome therapeutics are being developed for application in clinical settings for ovarian cancer patients.

Figure 1

Resensitization of chemoresistant ovarian tumors to carboplatin by epigenetic drug therapy. A. DNA methylation inhibitors (DNMTIs) or histone deacetylase inhibitors (HDACIs), alone or in combination, can reverse platinum resistance in chemoresistant ovarian cancer Additive or synergistic effects of DNMTI and HDACI combinations on silenced gene reexpression have been demonstrated. B. This chemosensitization is hypothesized to be due to the derepression of tumor suppressor genes (TSG) that were previously silenced by promoter DNA methylation or a transcriptionally repressed (closed) chromatin environment. Epigenetic therapies restore TSG gene expression by creating a more active (open) chromatin environment, reestablishing chemotherapy drug response cascades. See text for details. Black circles, methylated DNA; white circles, unmethylated DNA; green circles, repressive histone modification; stars, activating histone modifications;