Developing non-human primate models for ovarian cancer

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Abstract Epithelial ovarian cancer is a deadly disease with no effective treatment. The cancer is typically detected at advanced stages when it is already unresponsive to therapy. Therefore, there is an immediate need to define the biology of this cancer and develop novel methods for early diagnosis and therapies. Genetically modified mice or rodents grafted with tumor cell lines are the only mammalian models available to study ovarian cancer. Mice do not spontaneously develop ovarian cancer or its precursor lesions. A significant proportion of high grade serous ovarian carcinoma develops from transformed secretory fallopian tube epithelium that implants on the outer surface of the ovaries. In mice, the ovaries are encased in the bursa and therefore are not able to truly mimic the implantation of the tumors on the human ovarian surface. Other major subtypes of ovarian cancer, clear cell and endometrioid carcinomas originate from endometriotic lesions. Endometriosis is not a disease that spontaneously occurs in mice. These differences indicate that there is a need for a higher order animal model that is more representative of the anatomy and physiology in humans. More desirable will be a model where the ovarian tumors or at least its precursor lesions occur spontaneously. In this grant application we propose that the rhesus macaque can be developed into a model that is a better mimic of the three major subsets of ovarian cancer. The rhesus anatomy and endocrine physiology is highly similar to women and endometriosis is a spontaneously occurring condition. We have identified ovarian and peritoneal neoplasia in rhesus with endometriosis suggesting the possibility that these tumors may be spontaneously occurring clear cell or endometrioid ovarian carcinomas. The goal of this proposal therefore is to develop the rhesus as a model for the major subtypes of ovarian cancer. In Aim 1, we will conduct an immunohistological survey from the proximal to distal ends of the rhesus fallopian tubes to identify precursor lesions of high grade serous tumors. In Aim 2, we will demonstrate similarities in the genome, transcriptome, and signaling pathways in endometriosis and associated peritoneal and ovarian neoplasms of rhesus with the matching lesions found in women. The results of this proposal will be used to develop a network with the Oregon, California, Southwest and Tulane National Primate Research Centers to establish the rhesus as a model for ovarian cancer. This network will be available to all researchers to study the biology of ovarian cancer as well as to test novel diagnostic and therapeutic approaches in the rhesus prior to testing in clinical trials.