Abstract
Simple SummaryHigh-grade serous ovarian cancer (HGSOC) is the most common ovarian cancer subtype. While 60–80% of HGSOC patients initially respond to treatment, the majority of patients will eventually become platinum resistant. Epigenetic modifications are mechanisms that alter the expression of a gene but do not change the DNA sequence itself. Several types of epigenetic modifications, including DNA methylation, histone deacetylation, and microRNA expression, have been implicated in the progression of HGSOC to chemoresistance. These modifications can be targeted by epigenetic modulating therapies to overcome chemoresistance. This review summarises the epigenetic modifications identified in chemoresistant HGSOC and clinical trials utilizing epigenetic therapies in HGSOC.High-grade serous ovarian cancer (HGSOC) is the most common ovarian cancer subtype, and the overall survival rate has not improved in the last three decades. Currently, most patients develop recurrent disease within 3 years and succumb to the disease within 5 years. This is an important area of research, as the major obstacle to the treatment of HGSOC is the development of resistance to platinum chemotherapy. The cause of chemoresistance is still largely unknown and may be due to epigenetics modifications that are driving HGSOC metastasis and treatment resistance. The identification of epigenetic changes in chemoresistant HGSOC enables the development of epigenetic modulating drugs that may be used to improve outcomes. Several epigenetic modulating drugs have displayed promise as drug targets for HGSOC, such as demethylating agents azacitidine and decitabine. Others, such as histone deacetylase inhibitors and miRNA-targeting therapies, demonstrated promising preclinical results but resulted in off-target side effects in clinical trials. This article reviews the epigenetic modifications identified in chemoresistant HGSOC and clinical trials utilizing epigenetic therapies in HGSOC.
Highlights
Standard-of-care treatment for high-grade serous ovarian cancer (HGSOC) consists of combination carboplatin and paclitaxel chemotherapy
The homologous recombination (HR) pathway is involved in repairing double-strand breaks that occur at sites of DNA crosslinks caused by platinum chemotherapy during DNA replication [4,6]
This pathway is regulated by BRCA1 and BRCA2 proteins that are involved in homologous recombination, which are deficient in approximately 50% of HGSOC patients [12], and results in increased double-strand breaks (DSBs) after platinum chemotherapy
Summary
Standard-of-care treatment for high-grade serous ovarian cancer (HGSOC) consists of combination carboplatin and paclitaxel chemotherapy. The exact mechanisms of platinum resistance are still unknown, cancer stem cells, epithelial-to-mesenchymal transition, and dysfunctional DNA repair pathways are thought to aid in the development of chemoresistance in HGSOC [2,3,4]. This pathway is regulated by BRCA1 and BRCA2 proteins that are involved in homologous recombination, which are deficient in approximately 50% of HGSOC patients [12], and results in increased double-strand breaks (DSBs) after platinum chemotherapy While this initially increases sensitivity to platinum treatments [13], HR-deficient patients eventually become platinum resistant as well [14]
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