**6. Conclusion**

*Ovarian Cancer - Updates in Tumour Biology and Therapeutics*

treatment arm was not found to be statistically significant [74].

**4.2 The administration of epigenetic therapy – better together?**

**5. Future directions in improving patents care outcomes**

There is biologic plausibility that epigenetic therapies can prime tumors for a better response to immunotherapy and turn "cold" tumors into "hot" ones [68]. For example, in one murine model, the combination of decitabine and anti-CTLA-4 significantly shrunk tumors and prolonged survival as compared to either agent alone [77]. There is additional preclinical data suggesting that AZA can upregulate T-cells in murine models [78]. Additionally, two clinical trials are currently underway. The results from one study of 75 patients are expected in March 2022 (NCT03206047). Its investigators are looking at AZA and atezolizumab with or without the anti-NY-ESO-1 vaccine (a biologic agent) in women with recurrent platinum resistant ovarian cancer. The other study is looking at guadecitabine with pembrolizumab for

(topotecan, pegylated liposomal doxorubicin, paclitaxel or gemcitabine) until disease progression or unacceptable toxicity. Cross-over was allowed from the standard arm to the experimental arm and 27 patients crossed-over. The combination of guadecitabine and carboplatin was found to be effective, however the median progression free survival of 16 weeks when compared to the 9 weeks in the standard

One approach to utilizing epigenetic therapy effectively up front is in alternating treatments of classic chemotherapy and epigenetic therapy. This method was found to be effective and less toxic in clinical translational studies [73, 74]. Sequential administration of classic chemotherapy and epigenetic drugs not only suppresses ovarian cancer growth *in vitro*, but also spares toxicity to normal cells and preserves the healing ability of stem cells [75]. Furthermore, chemotherapy and epigenetic therapy act synergistically allowing smaller doses of both to be administered. In turn, this decreases the toxicity of both chemotherapy and epigenetic therapy [69]. This methodology has yet to be broadly adopted in clinical trials involving epigen-

For recurrent disease, epigenetic therapy may have utility. Epigenetic therapy restores platinum sensitivity as both hypermethylation and histone modification contribute to chemoresistance, reversing these epigenetic changes, should reverse the chemoresistance [64]. This has been borne out in the literature as less than 10 percent of platinum resistant patients would be expected to respond to platinum again, yet pretreatment with AZA yields a 22 percent response and decitabine, a 35 percent response [64]. Taxol resistance has not been as heavily explored in the literature as platinum resistance, however, epigenetic therapy, may re-sensitize ovarian cancer to paclitaxel as it does cisplatin. In one preclinical study, the HDACi panobinostat was used to re-sensitize ovarian cancer cell lines that had become resistant to paclitaxel [76]. These researchers were further able to demonstrate that when human ovarian cancer xenografts were implanted in a murine model, panobinostat in combination with cisplatin and paclitaxel was superior in efficacy to cisplatin-paclitaxel or panobinostat alone [76]. Thus, epigenetics may possibly be used upfront to "prime" or increase the efficacy of classic chemotherapy. Additionally, they may be sequenced in between classic chemotherapy and again when patients recur to re-sensitize them to platinum

**242**

etic therapy.

and taxol agents.

**5.1 Epigenetics and immunotherapy**

Platinum resistant and recurrent ovarian cancer patients have very little in the way of highly effective treatment. Chemotherapy may be effective for a period of months or a few years for these patients, but it is rarely if ever curable. Epigenetic therapies hold promise, especially in conjunction with other mechanisms, like PARP inhibitors and immunotherapy, but the timing, dosing and patient selection must be fine-tuned before they can enter the mainstream of treatment for ovarian cancer.
