Stem Cell-based Platform for Targeted Enzyme/Prodrug Therapy of Recurrent Ovarian Cancer

Project Summary: Ovarian cancer (OC) is associated with the highest mortality rate of all gynecologic malignancies in the United States. The low rate of survival is mainly due to two factors: 1) the advanced stage of the disease at diagnosis, and 2) the inadequate efficacy of available therapeutic options, especially for recurrent metastatic disease. The standard-of-care for patients with primary OC includes debulking surgery (removal of ovaries and visible intraperitoneal tumors) followed by chemotherapy with platinum-based drugs (e.g., cisplatin) and paclitaxel (PTX). However, approximately 90% of patients after suboptimal resection and 70% of patients after optimal cytoreduction will experience relapse within 18-24 months. Unfortunately, there is no effective standard-of-care for recurrent patients who return to the clinic with drug-resistant metastatic disease. As a result, their survival rate is very low. The objective of this research is ?to develop a non-surgical, targeted, and clinically translatable stem cell-based platform that can overcome drug resistance in recurrent and metastatic ovarian cancer?. The success of the developed stem cell-based platform will be measured by not only demonstrating the eradication of metastasis and inhibition of relapse, but also providing long-term survival benefits. To achieve this objective, we genetically engineered and isolated a unique adipose-derived stem cell (ASC) clone that overexpresses secretory human carboxylesterase 2 for targeted enzyme/prodrug therapy of cancer, and nanoluciferase for quantification of response to therapy and evaluation of cancer relapse. Using bioluminescent imaging (BLI) complemented with magnetic resonance imaging (MRI) and immunohistochemistry, we demonstrated that the engineered ASCs migrate and localize at both ovarian tumor stroma and necrotic regions. Our published data also show that the engineered ASCs are able to target and kill the drug-resistant OC cells that are rich in cancer stem-like cells (CSCs), overexpress MDR-1/ABCG2 drug efflux pumps, and have high ALDH enzyme activity. Statistical analyses of tumor burden and survival rates showed that administration of the engineered ASCs in combination with the prodrug irinotecan provided complete tumor response and survival benefits in 80% of treated mice. To transform this ASC-based technology into a platform with a broad application in targeted therapy of recurrent OC, we will use epithelial OC cells that are obtained from patients who have received various treatment modalities but have returned to the clinic with drug-resistant disease. The biodistribution and tumor tropism of the engineered ASCs will be determined by BLI, MRI, and immunohistochemistry. The tumor response to therapy, inhibition of cancer relapse, and long-term survival benefits will be determined in immunocompromised mice. Tumor tissues from non-responsive groups will be collected and characterized at molecular, cellular and genomic levels to understand the mechanisms underlying their escape and to help develop corrective measures. Adverse effects during treatment and toxicity to healthy tissues will be studied by histopathology & hematology.