**1. Introduction**

### **1.1 Chemoresistance causes failure of classic ovarian cancer treatment**

Ovarian cancer, similar to other malignancies, is characterized by molecular changes in cells which result in unregulated proliferation and spread to other organs [1]. Normal regulatory processes are disrupted and therefore aberrant cells are able to bypass checkpoints and lead to widespread metastatic potential [2]. Malignant ovarian neoplasms contribute to the highest mortality rates among women with gynecologic cancers [3]. Among them, high grade serous histologic subtypes are the most aggressive with an estimated 21,410 new cases and 13,770 ovarian cancer deaths in the United States in 2021 according to the American Cancer Society [4]. Due to limited feasibility of screening modalities in low risk patients and vague generalized symptoms, many patients are diagnosed at advanced stages contributing to a higher rate of treatment failures and poorer prognosis [5]. Traditional initial therapy consists of a combination of cytoreductive surgical management and platinum/taxane based chemotherapy [6]. The recommended surgical procedure includes a total hysterectomy with removal of bilateral fallopian tubes and ovaries, lymph node evaluation

as well as evaluation and removal of all visible disease along the omentum and any peritoneal surfaces with full exploration of the abdomen and pelvis [7]. Despite the frequent initial success with the aforementioned approach, approximately 70% of patients develop recurrent disease either secondary to intrinsic or extrinsic causes of chemoresistance [8, 9]. Once the tumor is able to evade standard therapy, treatment options then become limited and the disease process is incurable [10]. As a result, chemoresistance is one of the leading causes of mortality among advanced stage and recurrent ovarian cancer patients. Multiple mechanisms are responsible for inducing chemoresistance, and a better understanding of these processes may lead to better treatment outcomes for patients with progressive disease [11].

## **1.2 Histologic subtypes and tumorigenesis**

Ovarian cancer can arise from several different cell types including epithelial, germ cell and mesenchymal (stromal) origins. These histological classifications vary widely with regard to treatment options and prognosis likely secondary to unique molecular and biologic features among each subtype [12, 13]. Epithelial ovarian cancer (EOC) accounts for 90% of ovarian cancer and can be subdivided into high grade serous, low grade serous, endometrioid, clear cell, mucinous, transitional cell, among several other subtypes with over two-thirds comprising high grade serous histology [14, 15]. Among high grade serous lesions, p53 mutations are typically omnipresent as well as other important germline and somatic mutations (BRCA 1, BRCA 2, and additional homologous recombinant genes), and tend to lead to more favorable treatment outcomes [16]. Although these gene mutations may induce chemoresistant disease, it is predominantly epimutations and their associated changes in gene expression which are thought to drive tumorigenesis. As chemoresistance may be innate or acquired even after an initial positive response to platinum therapy, it is plausible that genes involved in epigenetic reprogramming are controlled by specific transcription factors, and therefore may serve as a potential target for treatment [17, 18].

As with most malignancies, the staging of ovarian cancer and concurrent optimal cytoreduction plays a pertinent role in determining prognosis [19]. Ovarian neoplasms are staged surgically and according to the International Federation of Gynecology and Obstetrics (FIGO) classification. The 5-year overall survival rate differs significantly between early and advanced stage disease at 90% for Stage I disease and approximately 15–40% for Stage III/IV disease [20]. As most ovarian cancers are diagnosed in advanced stages, an individual's response to standard platinum chemotherapeutic agents becomes a major prognosticator in determining outcomes [21, 22].

### **1.3 Can epigenetic therapy overcome ovarian cancer chemoresistance?**

The mainstay approach to treatment of high grade serous carcinomas is with a platinum based chemotherapeutic agent whereas other histologic subtypes prove to be more chemoresistant [23]. As primary treatments involve a platinum and taxane chemotherapeutic agent, an important predictor of progression free and overall survival is the platinum-free interval [24]. Patients are classified as platinum sensitive should disease recurrence occur greater than 6 months from completion of therapy, platinum resistant if less than 6 months and refractory if progression occurs through therapy [25]. This subclassification is imperative to predicting which patients will likely recur after initial therapy and will require molecular analyses in order to determine a more targeted treatment approach. Unfortunately, only 15% of patients who develop chemoresistance respond to subsequent therapies and many

**237**

*Novel Indications of Epigenetic Therapy in Ovarian Cancer*

ultimately will succumb to their disease within one year [26]. Multiple mechanisms have been suggested for acquired chemoresistance such as mutations in the cancer

Another important component includes epigenetic modifications which result in silencing as well as activation of gene expression without DNA sequence alteration [36]. The majority of cancers, including ovarian cancer, have aberrant epigenetic modifications which result in the promotion of cancer growth, metastasis and

The field of epigenetics has gained heightened interest in the field of oncology over the years. This new concept of study was first described by Conrad Waddington in 1942 where he demonstrated the inheritance of an acquired characteristic in a particular population [38]. Although the definition has evolved over the years, the overall essence of epigenetics involves the alterations in gene expression without modification of the DNA sequence itself [39]. In other words, these aberrant changes are maintained through cell division without producing a change in the overall genetic information [40]. As stated previously, epigenetic alterations affect chromatin structure through a variety of mechanisms, altering patterns of gene expression. Disruptions in these epigenetic processes can in turn lead to altered gene function and further, malignant transformation through oncogene activation or tumor suppressor gene silencing [41]. As human cancer cells harbor aberrant epigenetic abnormalities, cancer progression is then enabled and mechanisms of resistance develop, which creates an opportunity for targeted therapy

Promoter hypermethylation silences crucial genes including but not limited to p16, SPARC, CTGF, CDH1 and ICAM-1. Other genes involved in methylation dysregulation include PTEN (seen in type 1 ovarian cancers), and those involved with suppression of metastasis [42]. Several studies have utilized DNA methylation assays in order to identify potential epigenetic biomarkers in cell free DNA for ovarian cancer in order to improve on early screening challenges [43–45]. This method of identification and targeting of differentially methylated regions (DMRs) has the potential to identify populations of at-risk patients for the development of

Moreover, epigenetic agents have already proved effective in acting as chemotherapy sensitizers by essentially improving or re-establishing tumor sensitivity as well as reversing resistant disease in a multitude of studies [46–48]. Where patients may ultimately be classified as platinum resistant, the use of epigenetic agents have the potential to reinvoke a response to platinum agents with one study demonstrating

cells themselves, DNA repair failures as well as epigenetic changes [27–29]. For example, cancer stem cells (CSCs) which are capable of self-renewal, differentiation and tumorigenicity have been indicated in the development of platinum resistance disease [30, 31]. One particular study demonstrated upregulated expression of stem cell markers CD44, CD133, and ALDH1A1 in recurrent ovarian cancer in comparison to primary tumors [32]. DNA repair failures may also occur in nucleotide excision, recombination, and mismatch repair pathways enabling cancer cells to exploit repair mechanisms and therefore induce an acquired chemoresistance [33]. Point of nonsense mutations in oncogenes such as Ras or ERK signaling and/or DNA repair genes such as p53, PARP, BRCA 1 and 2 have been evidenced to cause chemoresistance and subsequent failure in standard oncologic treatments [34]. All in all, cancer renewal and heterogeneity are the main reasons for the development of chemoresistance and subsequent failure in standard onco-

*DOI: http://dx.doi.org/10.5772/intechopen.98187*

logic treatments [35].

chemoresistance [37].

using epigenetic inhibitors.

epithelial ovarian cancers.

**1.4 Epigenetics**

### *Novel Indications of Epigenetic Therapy in Ovarian Cancer DOI: http://dx.doi.org/10.5772/intechopen.98187*

ultimately will succumb to their disease within one year [26]. Multiple mechanisms have been suggested for acquired chemoresistance such as mutations in the cancer cells themselves, DNA repair failures as well as epigenetic changes [27–29].

For example, cancer stem cells (CSCs) which are capable of self-renewal, differentiation and tumorigenicity have been indicated in the development of platinum resistance disease [30, 31]. One particular study demonstrated upregulated expression of stem cell markers CD44, CD133, and ALDH1A1 in recurrent ovarian cancer in comparison to primary tumors [32]. DNA repair failures may also occur in nucleotide excision, recombination, and mismatch repair pathways enabling cancer cells to exploit repair mechanisms and therefore induce an acquired chemoresistance [33]. Point of nonsense mutations in oncogenes such as Ras or ERK signaling and/or DNA repair genes such as p53, PARP, BRCA 1 and 2 have been evidenced to cause chemoresistance and subsequent failure in standard oncologic treatments [34]. All in all, cancer renewal and heterogeneity are the main reasons for the development of chemoresistance and subsequent failure in standard oncologic treatments [35].

Another important component includes epigenetic modifications which result in silencing as well as activation of gene expression without DNA sequence alteration [36]. The majority of cancers, including ovarian cancer, have aberrant epigenetic modifications which result in the promotion of cancer growth, metastasis and chemoresistance [37].

### **1.4 Epigenetics**

*Ovarian Cancer - Updates in Tumour Biology and Therapeutics*

treatment outcomes for patients with progressive disease [11].

**1.2 Histologic subtypes and tumorigenesis**

tial target for treatment [17, 18].

outcomes [21, 22].

as well as evaluation and removal of all visible disease along the omentum and any peritoneal surfaces with full exploration of the abdomen and pelvis [7]. Despite the frequent initial success with the aforementioned approach, approximately 70% of patients develop recurrent disease either secondary to intrinsic or extrinsic causes of chemoresistance [8, 9]. Once the tumor is able to evade standard therapy, treatment options then become limited and the disease process is incurable [10]. As a result, chemoresistance is one of the leading causes of mortality among advanced stage and recurrent ovarian cancer patients. Multiple mechanisms are responsible for inducing chemoresistance, and a better understanding of these processes may lead to better

Ovarian cancer can arise from several different cell types including epithelial, germ cell and mesenchymal (stromal) origins. These histological classifications vary widely with regard to treatment options and prognosis likely secondary to unique molecular and biologic features among each subtype [12, 13]. Epithelial ovarian cancer (EOC) accounts for 90% of ovarian cancer and can be subdivided into high grade serous, low grade serous, endometrioid, clear cell, mucinous, transitional cell, among several other subtypes with over two-thirds comprising high grade serous histology [14, 15]. Among high grade serous lesions, p53 mutations are typically omnipresent as well as other important germline and somatic mutations (BRCA 1, BRCA 2, and additional homologous recombinant genes), and tend to lead to more favorable treatment outcomes [16]. Although these gene mutations may induce chemoresistant disease, it is predominantly epimutations and their associated changes in gene expression which are thought to drive tumorigenesis. As chemoresistance may be innate or acquired even after an initial positive response to platinum therapy, it is plausible that genes involved in epigenetic reprogramming are controlled by specific transcription factors, and therefore may serve as a poten-

As with most malignancies, the staging of ovarian cancer and concurrent optimal cytoreduction plays a pertinent role in determining prognosis [19]. Ovarian neoplasms are staged surgically and according to the International Federation of Gynecology and Obstetrics (FIGO) classification. The 5-year overall survival rate differs significantly between early and advanced stage disease at 90% for Stage I disease and approximately 15–40% for Stage III/IV disease [20]. As most ovarian cancers are diagnosed in advanced stages, an individual's response to standard platinum chemotherapeutic agents becomes a major prognosticator in determining

**1.3 Can epigenetic therapy overcome ovarian cancer chemoresistance?**

The mainstay approach to treatment of high grade serous carcinomas is with a platinum based chemotherapeutic agent whereas other histologic subtypes prove to be more chemoresistant [23]. As primary treatments involve a platinum and taxane chemotherapeutic agent, an important predictor of progression free and overall survival is the platinum-free interval [24]. Patients are classified as platinum sensitive should disease recurrence occur greater than 6 months from completion of therapy, platinum resistant if less than 6 months and refractory if progression occurs through therapy [25]. This subclassification is imperative to predicting which patients will likely recur after initial therapy and will require molecular analyses in order to determine a more targeted treatment approach. Unfortunately, only 15% of patients who develop chemoresistance respond to subsequent therapies and many

**236**

The field of epigenetics has gained heightened interest in the field of oncology over the years. This new concept of study was first described by Conrad Waddington in 1942 where he demonstrated the inheritance of an acquired characteristic in a particular population [38]. Although the definition has evolved over the years, the overall essence of epigenetics involves the alterations in gene expression without modification of the DNA sequence itself [39]. In other words, these aberrant changes are maintained through cell division without producing a change in the overall genetic information [40]. As stated previously, epigenetic alterations affect chromatin structure through a variety of mechanisms, altering patterns of gene expression. Disruptions in these epigenetic processes can in turn lead to altered gene function and further, malignant transformation through oncogene activation or tumor suppressor gene silencing [41]. As human cancer cells harbor aberrant epigenetic abnormalities, cancer progression is then enabled and mechanisms of resistance develop, which creates an opportunity for targeted therapy using epigenetic inhibitors.

Promoter hypermethylation silences crucial genes including but not limited to p16, SPARC, CTGF, CDH1 and ICAM-1. Other genes involved in methylation dysregulation include PTEN (seen in type 1 ovarian cancers), and those involved with suppression of metastasis [42]. Several studies have utilized DNA methylation assays in order to identify potential epigenetic biomarkers in cell free DNA for ovarian cancer in order to improve on early screening challenges [43–45]. This method of identification and targeting of differentially methylated regions (DMRs) has the potential to identify populations of at-risk patients for the development of epithelial ovarian cancers.

Moreover, epigenetic agents have already proved effective in acting as chemotherapy sensitizers by essentially improving or re-establishing tumor sensitivity as well as reversing resistant disease in a multitude of studies [46–48]. Where patients may ultimately be classified as platinum resistant, the use of epigenetic agents have the potential to reinvoke a response to platinum agents with one study demonstrating

a 35% objective response rate after administration of decitabine followed by carboplatin among platinum resistant ovarian cancer patients [48]. Therefore, current research is concentrated on the development of treatment methodologies involving the use of classic chemotherapy in combination or sequentially with epigenetic regimens in order to overcome chemoresistance and improve outcomes.
