Targeting the Epigenome in Ovarian Cancer

Authors and Disclosures

Susan K Murphy

Department of Obstetrics & Gynecology, Division of Gynecologic Oncology & Department of Pathology, Duke University Medical Center, PO Box 91012, Durham, NC 27708, USA. susan.murphy@duke.edu

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Executive Summary

Ovarian Cancer

• Ovarian cancer is the most lethal gynecological malignancy and is usually diagnosed at an advanced stage with 5-year overall survival rates of approximately 50%.

• Serous, endometrioid, mucinous and clear cell epithelial ovarian cancer comprise the four major histological types. Serous is the most common and most lethal.

Treatment

• Treatment consists of maximal surgical tumor debulking followed by a platinum and taxane regimen; clinical response is usually good.

• Remission can last months to years but recurrences are frequent.

• The expression and/or mutation status of several genes is known to influence response to therapy, including BRCA1/2 , TP53, YY1, PLK2 and SIK2.

• BRCA1 and PLK2 are often transcriptionally repressed through epigenetic modifications.

Potential for Epigenetic Therapies

• Epigenetic regulatory mechanisms change gene expression without altering the DNA sequence.

• Most current epigenetic therapies target reversal of aberrant DNA methylation and histone deacetylation.

• Recently elucidated DNA demethylation pathways may provide new opportunities for therapeutic targeting.

• Cancer stem-like cells are reliant on maintaining epigenetic plasticity and may therefore be particularly vulnerable to epigenetic therapies.

Epigenome Characterization & Clinical Utility

• Comprehensive epigenetic profiling is needed in ovarian cancer to help understand the genome-wide consequences of epigenetic therapies.

• Epigenetic biomarker panels may enable noninvasive detection and monitoring of disease.

Progress in Using Epigenetic Therapies

• Inhibitors of DNA methyltransferase and histone deacetylase activity induce nonspecific alleviation of transcriptional silencing.

• Combined use of DNA methyltransferase inhibitors and histone deacetylase inhibitors may be most effective at reversing transcriptional repression.

• Sequencing of drug treatment in platinum refractory disease, whereby epigenetic therapy is administered prior to platinum, shows promise in resensitizing ovarian cancer to treatment.

Current Limitations of Epigenetic Therapy

• Inhibitors of DNA methyltransferase and histone deacetylase activity act nonspecifically and, thus, may induce both beneficial as well as deleterious effects.