**5. Epigenetic biomarkers for ovarian cancer**

As mentioned above, the development of ovarian cancer is well characterized by a range of combinatorial epigenetic aberrations distinct from this malignancy, including but not limited to RASSF1A, DAPK, H-Sulf-1, BRCA1, and HOXA10 DNA methylation. As a result, these methylated DNA sequences represent potential diagnostic, staging, prognostic, and therapy response monitoring (predictive biomarkers) biomarkers [29]. DNA methylation biomarkers have several advantages over other types of biomarkers, such as proteins, gene expression, and DNA mutations, including their stability, ability to amplify (thus greatly enhancing detection sensitivity), relatively low cost of the assessment, and restriction to small DNA regions (CpG islands) [30]. It also acts as a biomarker to predict response to platinum-based chemotherapy regimen and the poly-ADP ribose polymerase inhibitor (PARPi). In the future, DNA methylation tests of resected ovarian tumors are highly likely to be used to customize care individually, similar to the recently discovered predictive markers of non-small cell lung cancer in stage I [31]. While single-gene methylation evaluation lacks adequate specificity for ovarian cancer diagnosis, it is believed that multiple methylation biomarker panels will achieve the precision needed for widespread population screening [30, 32]. To that end, a panel of 112 methylated DNA markers was found to correlate progression-free survival with ovarian cancer [33].

### **6. Clinical trials of epigenetic therapeutic in ovarian cancer**

DNA methylation inhibitor and HDAC inhibitor are cancer therapeutics, begins primarily as a treatment for hematological disorders in the early 2000s. The FDA

**57**

*Epigenetic Events in Ovarian Cancer*

**7. Future prospects**

**8. Conclusion**

the existing challenges to precision medicine.

treatment have emerged as promising drug targets.

*DOI: http://dx.doi.org/10.5772/intechopen.95472*

approved 5-Azacytidine (AZA) and 5-aza-2′-deoxycytidine (decitabine) for myelodysplastic syndrome (MDS) in 2004 and 2006, while the HDAC suberoylanilide hydroxamic acid (SAHA) inhibitor was approved in 2006 for the treatment of persistent or cutaneous T cell lymphoma [34]. Epigenetic therapy was initially performed in a clinical trial. It was setting either alone or with the standard in combination care to resensitize either the tumor to anticancer treatment or avoid therapy resistance production. Ultimately, these medications have been tested against resilient OC tumors, like both SAHA and AZA clinical trials, ovarian cancer, which is platinum-resistant. Although there are no antitumors, the behavior was detected after SAHA treatment, and AZA demonstrated the partial reaction. Still, it was correlated with significant adverse effects such as tiredness and myelosuppression [35]. The HDAC inhibitor, in a related analysis Belinostat, was given to platinumresistant patients with ovarian tumors. Still, they have similarly caused significant adverse reaction events such as thrombocytopenia, neutropenia, and vomiting, leading to the end of the analysis with no clinical advantage over conventional therapy [34]. Similarly, in a phase I study, the vorinostat pan-HDACi carboplatin or gemcitabine was administered despite the extreme hematological toxicities caused and caused observed partial response, leading to the termination of the study [36].

Exponential advancement in DNA methylation-based biomarker growth has been observed over the last decade. A variety of cfDNA and tissue-dependent screening assays have paved their way into clinics due to the consistency of DNA and methylation patterns. Several tests for early detection of colon, lung, and prostate cancer are commercial success based on DNA methylation biomarkers. New technologies that enable the rapid identification of methylation signatures directly from the blood can promote sample-to-respond solutions, allowing molecular diagnostics for the next-generation point of care. Besides, ongoing work on liquid biopsies together with the latest advanced technologies such as digital PCR, bisulfite sequencing, methyl immune precipitation coupled with next-generation sequencing, and methylation arrays together with advanced statistical data analysis will mitigate the complicated problems of non-invasive system creation by overcoming

Ovarian cancer causes substantial morbidity and mortality. Owing to unspecific signs at the early stage of the disease, their appearance at an advanced stage, and poor survival, the difficulty of promptly diagnosing ovarian cancer at its early stage remains difficult. Improved methods of detection are, therefore, urgently needed. This chapter identifies the possible clinical usefulness of epigenetic signatures such as DNA methylation, modifications of histones, and microRNA dysregulation, which play an essential role in ovarian carcinogenesis and its use in the development of diagnosis, prognosis, and biomarkers for prediction. New treatment options separate from conventional treatment options chemotherapy that benefits from developments in the understanding of ovarian cancer pathophysiology to enhance performance, they are required. Recent work has shown that mutations in epigenetic regulator-encoding genes are mutated in ovarian cancer, driving tumorigenesis and drug resistance. Several of these modifiers of epigenetics for ovarian cancer

### *Epigenetic Events in Ovarian Cancer DOI: http://dx.doi.org/10.5772/intechopen.95472*

*Ovarian Cancer - Updates in Tumour Biology and Therapeutics*

**4. MicroRNA dysregulation in ovarian cancer**

**5. Epigenetic biomarkers for ovarian cancer**

The most recently discovered epigenetic miRNAs represent ovarian tumors have recently become a phenomenon, and it was found to substantially up-regulate miR-199a, miR-200a, miR-200a, miR-214, and down-regulate miR-100 and, precisely, miR-100 and miR-214 to target the tumor suppressor, miR-214 was shown to PTEN and is associated with resistance to platinum [21, 22]. Let-7 miRNA family as one of the regulator of the MYCN pathway that linking to the platinum-resistant trait. It was recently discovered that miRNA let-7i was a tumor substantially down-regulated suppressor in platinum-resistant ovarian tumors, and restored let-7i gain-of-function chemoresistant ovarian cancer drug sensitivity cells, thus representing a biomarker and therapeutic candidate goal [23]. MiR-429, miR-200a, and miR-200b, respectively a single primary transcript was found to be clustered on epithelial-to-mesenchymal transition-regulated (EMT, a metastatic phenotype) ZEB1/SIP1 repressor, with negative regulation of miR-200a and miR-200b ZEB1/SIP1 and the development of a loop of double-negative feedback [24]. In another study, 27 miRNAs were substantially correlated with chemotherapy response, indicating a chemotherapy response miRNA (similar to DNA methylation) represent potential biomarkers for ovarian prognosis and diagnosis [25]. Regarding the regulation of miRNA genes, a group of six chromosomes, 19 miRNAs clustered on chromosome 19, and seven clusters were up-regulated on chromosome 14, DNMT-inhibitor decitabine inhibitor, showing that miRNAs can be controlled by DNA methylation [26]. What's more, an overall, collective tumor—MiRNAs' suppressive effect has been suggested by Drosha and Dicer down-regulation, involving two enzymes in the processing of miRNA, being significantly connected with an early stage of ovarian cancer and poor prognosis [27, 28].

As mentioned above, the development of ovarian cancer is well characterized by a range of combinatorial epigenetic aberrations distinct from this malignancy, including but not limited to RASSF1A, DAPK, H-Sulf-1, BRCA1, and HOXA10 DNA methylation. As a result, these methylated DNA sequences represent potential diagnostic, staging, prognostic, and therapy response monitoring (predictive biomarkers) biomarkers [29]. DNA methylation biomarkers have several advantages over other types of biomarkers, such as proteins, gene expression, and DNA mutations, including their stability, ability to amplify (thus greatly enhancing detection sensitivity), relatively low cost of the assessment, and restriction to small DNA regions (CpG islands) [30]. It also acts as a biomarker to predict response to platinum-based chemotherapy regimen and the poly-ADP ribose polymerase inhibitor (PARPi). In the future, DNA methylation tests of resected ovarian tumors are highly likely to be used to customize care individually, similar to the recently discovered predictive markers of non-small cell lung cancer in stage I [31]. While single-gene methylation evaluation lacks adequate specificity for ovarian cancer diagnosis, it is believed that multiple methylation biomarker panels will achieve the precision needed for widespread population screening [30, 32]. To that end, a panel of 112 methylated DNA markers was found to correlate progression-free survival with ovarian cancer [33].

**6. Clinical trials of epigenetic therapeutic in ovarian cancer**

DNA methylation inhibitor and HDAC inhibitor are cancer therapeutics, begins primarily as a treatment for hematological disorders in the early 2000s. The FDA

**56**

approved 5-Azacytidine (AZA) and 5-aza-2′-deoxycytidine (decitabine) for myelodysplastic syndrome (MDS) in 2004 and 2006, while the HDAC suberoylanilide hydroxamic acid (SAHA) inhibitor was approved in 2006 for the treatment of persistent or cutaneous T cell lymphoma [34]. Epigenetic therapy was initially performed in a clinical trial. It was setting either alone or with the standard in combination care to resensitize either the tumor to anticancer treatment or avoid therapy resistance production. Ultimately, these medications have been tested against resilient OC tumors, like both SAHA and AZA clinical trials, ovarian cancer, which is platinum-resistant. Although there are no antitumors, the behavior was detected after SAHA treatment, and AZA demonstrated the partial reaction. Still, it was correlated with significant adverse effects such as tiredness and myelosuppression [35]. The HDAC inhibitor, in a related analysis Belinostat, was given to platinumresistant patients with ovarian tumors. Still, they have similarly caused significant adverse reaction events such as thrombocytopenia, neutropenia, and vomiting, leading to the end of the analysis with no clinical advantage over conventional therapy [34]. Similarly, in a phase I study, the vorinostat pan-HDACi carboplatin or gemcitabine was administered despite the extreme hematological toxicities caused and caused observed partial response, leading to the termination of the study [36].
