The focus of our current research involves the development of mouse models for human diseases, specifically ovarian cancer. Ovarian cancer can be effectively treated if detected early, but it is generally diagnosed after it has metastasized. This seriously impacts the survival rate of patients, and has limited our knowledge of the early genetic changes that induce ovarian cancer. Presently, there are no developed experimental systems that recapitulate genetic changes that occur during ovarian carcinoma initiation or simulate the complex interactions between ovarian surface epithelial and stromal cells. We are developing mouse ovarian organ culture systems in which genetic alterations can be introduced into ovarian surface epithelial cells in order to simulate the early stages of ovarian cancer biogenesis. These models will aid in a better understanding of the changes in the normal ovarian surface epithelium and elucidate the molecular events that promote ovarian cancer progression.
Another aspect of ovarian cancer that is poorly understood is the complexity of genetic alterations and their roles in ovarian cancer progression and the development of drug resistance. We have developed a system in which defined multiple genetic lesions can be introduced into mouse ovarian surface epithelial cells, a cell type that is believed to be the precursor for ovarian carcinoma. This system is based on avian RCAS virus delivery to cells that are programmed to express the avian TVA receptor under the control of a tissue-specific promoter. Various candidate genes that are thought to play a role in ovarian cancer can be introduced simultaneously or sequentially into mouse ovarian surface epithelial cells. We have used this system to determine the functional contributions of individual pathways that are necessary for cell proliferation and tumor maintenance, as well as to test the molecular mechanisms of tumor resistance to pathway-targeted therapy. It is expected that knowledge from the molecular biology of ovarian cancer will be translated into improvements in early diagnosis and the development of tumor therapy tailored to the causative genetic events in human ovarian cancers.
Our laboratory is developing mouse ovarian cancer models with defined genetic alterations in order to elucidate the molecular events responsible for ovarian cancer initiation, progression and metastasis. Such information will be helpful in developing diagnostic tools for early ovarian cancer detection and identifying specific biochemical pathways that can be therapeutically targeted.
Center for Cancer Research 