Abstract 329: A mouse model of epithelial ovarian cancer with defined oncogenic drivers.

Epithelial ovarian cancers (EOC) represent the gynecologic malignancy with the highest mortality rate. The Cancer Genome Atlas demonstrated a high degree of genetic heterogeneity among the papillary serous (PS) tumors, the most lethal of the EOC subtypes. Aside from almost universal mutation in TP53, there was a low prevalence of recurrent mutations in other genes, presenting a challenge to the development of targeted therapeutics against this aggressive tumor type. We are developing a mouse model of EOC by introducing defined genetic alterations to mouse ovarian surface epithelial (MOSE) cells. We had a particular interest in developing a cyclin E amplified tumor model, as CCNE1 amplification is found in 20% of human EOC tumors, making this one of the most prevalent PS EOC subtypes. We infected MOSE cells from p53-/- mice with different combinations of oncogenes encoded in retroviral vectors including CCNE1, myc and H-RAS. MOSE cells were infected with one or two oncogenes, passaged and injected into the peritoneal cavity of nude mice. Myc-HRAS caused the rapid development of hemorrhagic ascites and intraperitoneal carcinomatosis in 5 of 5 mice by day 18. HRAS alone and HRAS-CCNE1 both caused intraperitoneal and omental tumors to develop with clear ascites by day 35 in 5 of 5 mice. Myc caused bloating due to the development of frank hemoperitoneum in all 5 mice between days 101 and 150. Only 4 of the 5 mice had small volume intraperitoneal tumors. Myc-CCNE1 similarly caused bloating due to ascites in 2 mice and hemoperitoneum in 2 mice. Three of these four mice had small volume intraperitoneal tumors. One mouse has not developed any phenotype by 150 days. CCNE1 alone has not caused tumor formation in any of 5 mice by day 150. Histology of the Myc-HRAS, HRAS, HRAS-CCNE1, and Myc tumors were all consistent with high-grade undifferentiated carcinoma. Tumor cells generated in the Myc-HRAS, HRAS and HRAS-CCNE1 experiments were capable of causing intraperitoneal tumor development in immunocompetent C57BL/6 mice by day 17, 29 and 54 respectively. Taken together, our data demonstrate a reproducible mouse model for the development of high-grade epithelial ovarian carcinomas with defined genetic alterations that are capable of study in both immunodeficient and immunocompetent mice. Tumor phenotypes varied based on the combination of activated oncogenes. Citation Format: Hasmik Agadjanian, Dong-Joo Cheon, Elena Diaz, Anna Laury, Carl Miller, Beth Karlan, Sandra Orsulic, Christine Walsh. A mouse model of epithelial ovarian cancer with defined oncogenic drivers. [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 329. doi:10.1158/1538-7445.AM2013-329