Development of novel approaches for the treatment of recurrent ovarian cancer

Obeid Mohammadali Pourmalekshah
2020
Ovarian cancer is among the five leading types of cancer incidence and has the highest mortality rate of all gynecologic malignancies in the US. The standard of care for this type of cancer is debulking surgery, followed by chemotherapy with a combination of platinum-based anticancer drugs and paclitaxel. Even though most ovarian tumors are sensitive to chemotherapy at the time of diagnosis, approximately 90% of patients after suboptimal resection and 70% of patients after optimal cytoreduction
more » ... timal cytoreduction go on to experience relapse within 18–24 months. The main reason for this outcome is the late-stage diagnosis of ovarian cancer, which leads to tumor cell metastasis into the peritoneal cavity and the creation of tumorspheres. These tumorspheres are rich in cancer stem‐like cells (CSCs), are resistant to therapy, and are considered a significant source of relapse. Therefore, to tackle these challenges, we aimed at developing treatment methods than can eradicate the peritoneal CSC‐rich tumorspheres and inhibit relapse.The first part of this dissertation describes the development of a safe chemotherapeutic approach for patients who are candidates for debulking surgery. To achieve this goal, OVASC‐1 that is resistant to standard‐of‐care chemotherapy was obtained from a patient with ovarian carcinoma and recurrent disease. The most effective combination of drugs that could eradicate CSC‐rich tumorspheres at nanomolar levels was identified. Luciferase‐expressing OVASC‐1 cells were used to produce an ovarian cancer xenograft in the peritoneal cavity of nude mice and treated with the selected drug combination. Quantitative imaging was used to study the progression of the disease, and its response to therapy and histopathology was used to study abdominal tissues for any sign of toxicity. Our low‐dose intraperitoneal (IP) therapy approach effectively restricted the cytotoxic effects to the tumor cells in the peritoneal cavity, provided a complete response, and eliminated the chance of cancer relapse. These results encourage further [...]
doi:10.7282/t3-rgt2-xh42 fatcat:r7r7sdsb4zbtpbwueainf6x3ja