Ovarian cancer is the second most common malignancy of the female genital tract in the United States. According to the American Cancer Society, there will be almost 25,400 new cases of ovarian cancer in 1998. Although ovarian cancer accounts for only 4' of cancers in women, it is the leading cause of death from gynecologic cancer in the United States, with an estimated 14,500 deaths in 1998. Despite recent advances in treatment, the 5-year survival rate remains low, related to the lack of an effective screening tool and our inability to detect the disease early. Consequently, over 70' of cases are diagnosed after the cancer has already spread beyond the ovary. For women with Stage III epithelial ovarian cancer (spread to the upper abdomen or abdominal lymph nodes), which is the most common stage, the 5-year survival rate is no higher than 20', and for Stage IV disease (spread to the liver or beyond the abdominal cavity), 5-year survival rate is less than 5'. On the other hand, for women with Stage I ovarian cancer [confined to the ovary(ies)], the 5-year survival rate is 80'-90'. Clearly, early detection and prevention are critical issues. The overall goals of this grant proposal are (1) to develop innovative strategies for prevention of ovarian cancer through the identification of molecular markers and mechanisms associated with the prevention of ovarian cancer and (2) to assemble a multidisciplinary research team that will become a world leader in the field of ovarian cancer prevention. This research program is developed around the concept of achieving success through the integration of clinical and laboratory studies. In Project 1, we propose to conduct a study in female rhesus monkeys to explore the underlying biologic mechanisms of oral contraceptives (OCP), 4-HPR (a synthetic vitamin A), or a combination. In Project 2, we propose to conduct a study of the efficacy of OCP and 4-HPR to induce similar changes in women at low and high risk for ovarian cancer. Women undergoing removal of their ovaries for nonmalignant diseases or as prophylaxis (prevention) of ovarian cancer will be eligible for the study. In both the animal and the human studies, biopsies from the ovaries will be obtained for the study of molecular changes and to characterize areas of altered fluorescence. In Project 3, we will (1) explore mechanisms underlying the chemopreventive activity of OCP and 4-HPR, individually and in combination; (2) identify relevant biomarkers for the activity of these agents by studying differential gene expression; and (3) evaluate the sensitivity and specificity of optical spectroscopy for detecting apoptotic and transformed cells. Two Core Components (Administration and Histopathology) will provide the infrastructure and expertise required for the successful integration of these translational studies. In summary, a variety of approaches to the prevention of ovarian cancer employing studies of ovarian cell lines and tissues from animals and both normal and high-risk women translates into a comprehensive prevention strategy.

Project 1: Program Project Award

Chemoprevention of Ovarian Cancer: Modulation of Biomarkers in Primates Using Fenretinide (4-HPR) and Oral Contraceptives

Principal Investigator: Molly Brewer

Project 1: Public Abstract

Epidemiologic and experimental studies suggest that oral contraceptives (OCP) and a synthetic form of vitamin A called N-(4-hydroxyphenyl) fenretinide (4-HPR) may reduce the risk of ovarian cancer, but mechanisms of action of these agents remain unknown. Several studies have correlated the risk of ovarian cancer with frequency of ovulation. OCP suppress ovulation, but the decrease in risk of developing ovarian cancer is not directly proportional to the number of menstrual cycles suppressed. This suggests that other mechanisms might also contribute to the chemopreventive effect. A recent study in primates indicates that treatment with oral contraceptives or with progestins can increase apoptosis (cell death) in ovarian surface epithelial cells. Apoptosis is considered a defense mechanism of the organism against cancerous cells. Our group has found that transforming growth factor-beta (TGFb) induces apoptosis in abnormal ovarian cells. Consequently, TGFb may provide a surveillance mechanism for eliminating emerging malignant cells. At the present time, there is no animal model for ovarian cancer chemoprevention or ovarian cancer, and the purpose of this proposal is the development of the Rhesus monkey to serve as a model for cancer in humans. One of the advantages of such a closely related animal model will be that testing not possible in humans can be done in monkeys to learn how drugs prevent ovarian cancer. Understanding how these drugs work will aid in the understanding of how ovarian cancer can be prevented and also give clues to how it develops. The primate is very close genetically to the human and is the only mammal that has menstrual cycles like a woman. These close similarities will allow us to take knowledge learned in monkeys and apply these same principles to women. The purpose of this project is to develop an animal model to test the activity of OCP and 4-HPR in Rhesus monkey ovaries, which will promote further understanding of how these drugs prevent cancer and will help us develop better methods to prevent ovarian cancer in women.

Project 2: Program Project Award

Chemoprevention of Ovarian Cancer: Modulation of Biomarkers in Women at Low and High Risk for Ovarian Cancer Using Fenretinide (4-HPR) and Oral Contraceptives

Principal Investigator: David Gershenson

Project 2: Public Abstract

Epidemiologic and experimental studies suggest that oral contraceptives (OCP) and a synthetic form of vitamin A called N-(4-hydroxyphenyl) retinamide (4-HPR) may reduce the risk of ovarian cancer, but mechanisms of action of these agents remain unknown. Several studies have correlated the risk of ovarian cancer with frequency of ovulation. OCP suppress ovulation, but the decrease in risk of developing ovarian cancer is not directly proportional to the number of menstrual cycles suppressed. This suggests that other mechanisms might also contribute to chemopreventive effects. A recent study in primates indicates that treatment with oral contraceptives or with progestins can increase apoptosis (cell death) in ovarian surface epithelial cells. Apoptosis is considered a defense mechanism of the organism against cancerous cells. Our group has found that transforming growth factor-beta (TGFb) induces apoptosis in abnormal ovarian cells. Consequently, TGFb may provide a surveillance mechanism for eliminating emerging malignant cells in cooperation with 4-HPR and OCP. The purpose of this project is to test the potential activity of OCP and 4-HPR for the prevention of ovarian cancer among women at low and high risk for ovarian cancer. We will explore the underlying mechanisms of the preventive activity of these compounds, and we will identify potential molecular markers that can be used as markers of their efficacy to prevent cancer to be used in the design of future studies. Women at low risk for ovarian cancer will be selected among women undergoing elective bilateral salpingo-oophorectomy (BSO) for benign conditions (low-risk women trial). Women at high risk for ovarian cancer (based on family history) will be selected among women undergoing elective BSO for prophylaxis of ovarian cancer (high-risk women trial). Eighty-one low-risk and 81 high-risk women will be recruited and assigned to receive OCP, 4-HPR, or placebo for 6 weeks before undergoing BSO. A high-risk woman will be defined as a woman with 10' or higher probability of having a BRCA1/BRCA2 mutation based on family history. Low-risk women will be identified at Lyndon B. Johnson and Hermann Hospitals in Houston, Texas. High-risk women will be identified at the University of Texas M.D. Anderson Cancer Center and Baylor College of Medicine in Houston, Texas, the Southwestern Medical School in Dallas, Texas, and the Northwestern Medical Center in Chicago, Illinois. Women assigned to 4-HPR will receive 200 mg per day for 6 weeks with a 3-day drug holiday and women assigned to the OCP arm will receive Ortho-Novum 1/35. This study will provide information on the mechanism of action of these drugs and their potential use in future studies.

Project 3: Program Project Award

Chemoprevention of Ovarian Cancer: Molecular Mechanisms and Markers

Principal Investigator: Robert Bast, Jr.

Project 3: Public Abstract

Clinical and laboratory studies suggest that oral contraceptives and derivatives of vitamin A may help to prevent ovarian cancer. Oral contraceptives may act, in part, by decreasing the number of times a woman ovulates, thus reducing the amount of wear and tear on the ovarian surface cells. By decreasing the number of times that ovarian surface cells divide, the number of genetic mistakes may be reduced. In addition, both oral contraceptives and vitamin A derivatives may drive both normal and abnormal cells on the ovarian surface to self-destruct. This process may purge the ovarian surface of genetically damaged cells and reduce the chance that a single cell could sustain sufficient genetic damage to give rise to a cancer.

This grant will explore the factors that contribute to the elimination of ovarian surface cells, studying the role of a natural growth inhibitor, transforming growth factor beta (TGFb) and its interaction with vitamin A derivatives and the hormones that are contained in oral contraceptives (estrogen and progestin). Portions of ovaries will be grown outside the body and treated with each of these factors, individually and in combination. Effects on the production of TGFb, the self-destruction of ovarian surface cells and the activation or deactivation of different genes will be studied.

The ability of normal ovarian cells, dying ovarian cells, and ovarian cancer cells to absorb and scatter light will be measured in an attempt to develop a method for detection of abnormal cells on the surface of the ovary and the inner surface of the abdominal wall in women at risk for developing ovarian cancer. Use of laser light may permit monitoring of the use of drugs to prevent ovarian cancer and may detect ovarian cancer at an early interval when it can be more readily cured.

Core A: Program Project Award

Administration

Principal Investigator: David Gershenson

Core A: Public Abstract

The responsibilities of the Administrative Core include provision of leadership and general administration of all activities related to this grant. The Core Director, Dr. David Gershenson, will direct all projects and cores. He will be assisted by the Core Co-Director, Dr. Gordon Mills. Dr. Gershenson will chair an Executive Committee composed of all Project and Core Directors and administrative staff. The Executive Committee will meet on a monthly basis to review the scientific and fiscal status and progress of grant activities, to identify any problems or barriers, and to assure that all goals are met within realistic time and budget constraints. The Administrative Coordinator, Ms. Aileen Maloney, will work closely with Dr. Gershenson and the Co-Director to schedule all meetings of investigators and to ensure optimal communications with both internal and external investigators. The Core Director will hold weekly meetings with administrative personnel. All investigators within the program will meet monthly to review research activities. In addition, two 1-day research retreats will be convened annually to review research progress. An Internal Scientific Advisory Committee consisting of Waun Ki Hong, M.D., Mien-Chi Hung, Ph.D., and James Abbruzzese, M.D., will attend research meetings quarterly and research retreats twice annually to evaluate progress. The specific responsibilities of the Administrative Core are (1) to convene all necessary meetings; (2) to evaluate and track the direction and progress of each project and core in order to regulate cooperative efforts and to keep the scope of research focused; (3) to ensure communications between investigators, including both internal communications (with investigators at M.D. Anderson Cancer Center) and external communications (with investigators at collaborating institutions); (4) to coordinate quality control and quality assurance; (5) to maintain fiscal control; (6) to prepare required reports and publications, including abstracts, manuscripts, and audiovisual materials; (7) to provide academic support with editorial services; and (8) to organize two research retreats annually.

Core B: Program Project Award

Histopathology Core

Principal Investigator: Michael Deavers

Core B: Public Abstract

The purpose of the Histopathology Core is to provide central and uniform histopathologic (processing of tissue specimens to produce thin sections on glass slides for microscopic examination), immunohistochemical (special staining of tissue specimens using antibodies developed to mark specific products or parts of cells), in situ hybridization (special staining of a slide to identity specific nucleic acid in cells), and TUNEL assay (a special test used to evaluate apoptosis or genetically driven cell death) support to the projects in this proposal. Histopathology, immunohistochemistry, in situ hybridization, and evaluation of apoptosis have a central role in the design of these projects. Overall, there will be 1,060 specimens processed for histomorphologic interpretation, 10,600 immunohistochemical stains performed and evaluated, 1,060 in situ hybridizations done and analyzed, and 1,060 TUNEL assays carried out and quantified. The Histopathology Core, in using one central lab for this large workload, will promote uniformity of results by controlling variables associated with specimen handling and with the technical performance and interpretation of these tests. The laboratory facilities, equipment, and personnel are available to successfully complete these tasks.