Abstract 4767: Preclinical mouse model of recurrent epithelial ovarian cancer.
Authors: Park Jaemin , Huang Zhiqing , Berchuck Andrew , Murphy Susan 
Published: August 2014

Abstract
Purpose: Most women diagnosed with advanced stage serous epithelial ovarian cancer exhibit a complete clinical response to surgical debulking and platinum-based chemotherapy. Remission can last months to years, with residual cancer cells eventually re-emerging to cause relapse. The identity and nature of these cells is unclear, except that they are believed to be slow growing or dormant during remission, and may consist of a chemoresistant population of cancer stem cells. We previously identified therapeutic agents that more effectively target slow growing ovarian cancer cells and have hypothesized that targeting of slow growing residual cancer cells during remission would delay or prevent disease recurrence. Our objective here was to develop an in vivo ovarian cancer xenograft model of recurrent disease to provide a platform for testing this hypothesis in a preclinical setting.
Procedures: We used a lentiviral system to transduce ovarian cancer cells (carboplatin-sensitive CAOV2 cells and five SV40-immortalized cell lines either from primary ovarian cancer tissues or ascites, iPOC) with the pGreenFire Lenti-reporter construct (co-expresses GFP and firefly luciferase, SBI System Biosciences). The GFP positive cells were selected by flow cytometry and expanded in culture. Cells (3.5X10ˆ5 per mouse) were injected IP into 6-7-week female Ncr-nu/nu mice. The mice were monitored every 2 days using an IVIS Imaging System to detect appearance of luciferase-expressing tumors following IP injection of luciferin. Tumors were treated with IP carboplatin (40, 60 or 80 mg/kg) at 2-, 3- or 4-day intervals for a total of five cycles. Tumor response was monitored twice weekly using the IVIS Imaging System. Results:Tumor formation was evident by live imaging at 4-5 days post cell injection. Carboplatin treatment was optimized for dose and schedule to maximize response while preserving health since the ultimate aim is to enable testing of novel drugs during disease remission. We determined that treatment with four cycles of 80 mg/kg IP carboplatin at four-day intervals was optimal for producing near complete reduction in tumor volume while maintaining robust health of the mice. Surprisingly, tumor formation was also detected within 4-5 days in mice injected with iPOC cells, although the tumors were overall much smaller than those formed from CAOV2 cells (p = 0.0003). Ninety percent of the mice developed tumors following iPOC injection. iPOC-derived tumors appeared more sensitive to carboplatin than CAOV2 xenograft tumors .
Conclusions: We have developed and optimized a xenograft mouse model of epithelial ovarian cancer that mimics treatment response and recurrence of human disease. We are now implementing this model to test novel drugs in the preclinical consolidation setting against slow growing tumor cells that we hypothesize are responsible for disease recurrence.
Citation Format: Jaemin Park, Zhiqing Huang, Andrew Berchuck, Susan Murphy. Preclinical mouse model of recurrent epithelial ovarian cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4767. doi:10.1158/1538-7445.AM2013-4767