Development and validation of preclinical mouse model for serous ovarian cancer

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CAPR has established and characterized in-depth a genetically engineered mouse model of serous epithelial ovarian carcinoma. The loxP/Cre system is used to perturb the Rb, p53 and/or the Brca1/Brca2 pathways specifically in the ovarian epithelium. Currently, different induction systems are being tested to determine the most optimal design of serous ovarian cancer model applicable both for mining the basic biology of tumorigenesis in cancer type and subsequently for preclinical drug evaluation:1)Adeno-Cre infection into the bursa of the ovary by survival surgery at 6 weeks of age. 2)Genetic induction using a tamoxifen-inducible MisIIR-CreER system.3)Orthotopic transplantation of primary ovarian epithelial cells or ovarian tumor cells into the bursa of syngeneic mice.Our data showed that the combined deletion of Brca1, p53 and the Rb pathway components using adenoviral induction leads to metastatic ovarian cancer with ascites by 10 months post-induction. The impact of genetic mutations and combinations thereof on the onset and progression of the disease is currently being analyzed. Prospective studies are designed to track biomarkers and improve imaging strategies that could be clinically translated and applied for early disease detection. Tumor samples will be subject to cross species omic analyses of human and mouse cancers to identify common molecular signatures that could provide new druggable targets for cancer therapeutics. In the second phase of this project, all three tumor induction approaches will be compared for their applicability for the production of large cohorts for preclinical efficacy determination. As a pilot experiment, the Research and Model Development team of CAPR induced a large cohort of animals featuring several combination of genetic events (pRb inactivation, p53 inactivation and somatically induced mutagenesis, BRCA1/2 inactivation). The induction had been performed via intra-bursa administration of adenovirally transduced Cre recombinase. This cohort of approximately 800 animals developed various stages of ovarian malignancy allowing CAPR scientists to undergo in-depth patho-histologic investigation of resulting tumors, as well as to collect blood, ascites and cancerous vs. benign tissue samples for molecular analyses and establishing primary cell cultures. These data are currently being analyzed by modern bioinformatics/systems biology approaches by the CCR Bioinformatics Core or in collaboration with Drs. Kohn's and Annunziata's clinical groups. A comparative evaluation is under way as well with the similar data sets obtained by Mark Simpson's lab in a collection of human SEOC clinical samples. As a key scientific output of these efforts, in collaboration with Dr. Van Dyke's previous lab at the University of North Carolina, a manuscript had been published in Cancer Research, describing this specific genetic approach to model the metastatic serous ovarian cancer and molecular observations related to SEOC tumor progression and histopathologic attributes. To apply the model in preclinical workflows, CAPR is in an advanced stage of negotiations with a prospective Big Pharma partner who anticipates to employ the SEC model in a preclinical evaluation project for Company's proprietary selective proteasome inhibitor compound.