Cancer of the ovary remains a significant public health problem. It is the fourth leading cause of cancer deaths among women in this country and causes 140,000 deaths annually in women worldwide. Unfortunately, despite intensive research efforts over the past decade directed toward improved detection and treatment of ovarian cancer, the long-term survival of women with ovarian cancer has only improved modestly. Progress in the fight against ovarian cancer has been hampered by a number of factors, including late diagnosis, the lack of highly curative chemotherapy, and the lack of a valid animal model for the disease.

We believe that the development of effective chemopreventive agents for ovarian cancer represents our best hope for decreasing ovarian cancer mortality in the future. Based on our studies in primates and in the laboratory, we are convinced that the well-known protective effect of oral contraceptives against ovarian cancer is due in large part to the biologic effects of the progestin component of the oral contraceptive on the ovary. We have found that progestins stimulate the removal of cells from the surface of the ovary, making it likely that cells that have incurred genetic damage will be eliminated rather than develop into cancer. A number of other agents also hold promise for preventing ovarian cancer, including the retinoids. Ultimately, it is our goal to develop a preventive strategy using the best chemopreventive agents, either alone or in combination, to achieve maximum protection against ovarian cancer.

The lack of a valid ovarian cancer animal model is the biggest obstacle to progress in the development of pharmacologic agents to prevent ovarian cancer in women. To develop pharmacologic preventive strategies for ovarian cancer in a timely fashion, animal models that closely mimic ovarian cancer are desperately needed. Human prevention trials are costly requiring large numbers of subjects and many years to complete. Development of an animal model for ovarian cancer prevention research would represent a significant breakthrough and potentially open the door toward the expedited evaluation of numerous agents. Ideally, this would lead to the rapid identification of a select number of agents that have the greatest potential for ovarian cancer prevention and that then can be evaluated in human prevention trials.

We believe that the domestic hen (chicken) has great potential as an animal model for studying the chemoprevention of ovarian cancer. The domestic hen is the only animal with a high incidence of spontaneous ovarian cancer, ranging from 13 to 40 percent between 4 and 6 years of life. No investigators have taken advantage of the chicken to study ovarian cancer. The chicken ovarian cancer model is therefore untapped and yet to be validated. As part of the chemoprevention grant awarded to us by the Department of Defense in 1998, we have been performing a 2-year chemoprevention trial in the chicken designed to test the hypothesis that the hormone progestin confers preventive effects against ovarian cancer. Two thousand 2-year-old hens have been randomized to either untreated control groups or groups treated with progestin. We will compare the time of onset and number of ovarian cancers that develop in each group.

By the completion of the prevention trial, we expect to accumulate over 200 hundred chicken ovarian cancers. In addition, we will gather valuable data regarding the natural history of ovarian cancer in the chicken. This invaluable resource will afford us the opportunity to study chicken ovarian cancers in great detail, thereby critically evaluating the chicken ovarian cancer animal model and determining its relevance to human ovarian cancer research. The aim of the current proposal will be to increase our understanding of the molecular biology of chicken ovarian cancers and to draw parallels between chicken and human ovarian cancers. In addition, we hope to develop a classification for chicken ovarian cancers based on their appearance under the microscope. This is critically needed to facilitate use of this animal model for ovarian cancer research. We hope to identify similarities between chicken and human ovarian cancers, providing strong support of the chicken as an animal model for ovarian cancer research.

Hopefully, our efforts in developing the chicken ovarian cancer model will help to overcome a major obstacle in ovarian cancer prevention research and open the door to the rapid development of effective preventives for ovarian cancer.