Targeting the Epigenome in Ovarian Cancer

Susan K Murphy

Future Oncol. 2012;8(2):151-164.

Abstract and Introduction

Abstract

Epithelial ovarian cancer is the leading cause of death from gynecological cancers, largely owing to the development of recurrent intractable disease. Only a small number of distinct genetic mutations are known to contribute to ovarian carcinogenesis. Furthermore, understanding mechanistic genotype–phenotype links is complicated by frequent aneuploidy. Epigenetic deregulation is even more prominent, and ovarian cancers are replete with such aberrations that repress tumor suppressors and activate proto-oncogenes. Epigenetic therapies are emerging as promising agents for resensitizing platinum-resistant ovarian cancers. These drugs may also have the potential to alter epigenetic programming in cancer progenitor cells and provide a strategy for improving therapy of ovarian cancer.

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Next Section

Abstract and Introduction
Ovarian Cancer
Treatment
Potential for Epigenetic Therapies
Epigenome Characterization & Clinical Utility
Progress in Using Epigenetic Therapies
Current Limitations of Epigenetic Therapy
Conclusion
Future Perspective
References
Sidebar

Table 1. Epithelial ovarian cancers
	Genetic alterations	Origin	Characteristics
*Type I tumors*
Low-grade serous	KRAS, BRAF, ERBB and PIK3CA	Fallopian tube epithelium	Usually confined to one ovary Usually large Indolent Good prognosis Relative genetic stability
Clear cell	ARID1A, PIK3CA, ZNF217 and PPP2R1A	Endometriosis
Endometrioid	ARID1A, CTNNB1, PTEN, PIK3CA and PPP2R1A	Endometriosis
Mucinous	KRAS	Borderline tumors
*Type II tumors*
High-grade serous	TP53 and BRCA1/2 Chromosome instability	Fallopian tube epithelium	Usually present at advanced stage Rapid growth Aggressive Genetically unstable TP53 mutated BRCA often inactivated
High-grade endometrioid		Endometriosis
Carcinosarcomas		Unknown
Undifferentiated carcinomas		Unknown

Sidebar

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.

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