CAPR is establishing 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 and Brca2 pathways specifically in the ovaries (Fig. 1). 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. Preliminary 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. At present, the Research and Development team of CAPR handles a large cohort of animals featuring a correct combination of genetic events induced via intra-bursa administration of adenovirally transduced Cre. Based of prior observations, it is projected that this experimental group of mice will start developing ovarian malignancies around December 2010, thus allowing CAPR scientists to undergo in-depth patho-histologic investigation of resulting tumors, as well as to collect blood and tissue samples for molecular analyses and establishing primary cell cultures. In parallel, in collaboration with Dr. Van Dyke's lab at the University of North Carolina, a manuscript is in preparation, describing selected genetic approach to model serous ovarian cancer and gathered earlier observations related to tumor induction and histologic attributes.
| Szabova, Ludmila; Bupp, Sujata; Kamal, Muhaymin et al. (2014) Pathway-specific engineered mouse allograft models functionally recapitulate human serous epithelial ovarian cancer. PLoS One 9:e95649 |
| Szabova, Ludmila; Yin, Chaoying; Bupp, Sujata et al. (2012) Perturbation of Rb, p53, and Brca1 or Brca2 cooperate in inducing metastatic serous epithelial ovarian cancer. Cancer Res 72:4141-53 |
| Serber, Daniel W; Rogala, Allison; Makarem, Maisam et al. (2012) The BRG1 chromatin remodeler protects against ovarian cysts, uterine tumors, and mammary tumors in a lineage-specific manner. PLoS One 7:e31346 |
| Walrath, Jessica C; Hawes, Jessica J; Van Dyke, Terry et al. (2010) Genetically engineered mouse models in cancer research. Adv Cancer Res 106:113-64 |
