Ovarian cancer is the fourth most common form of cancer in females in the United States. It accounts for 4' of the total number of cancer cases and 25' of cases occurring in the female genital tract. Because of its low rate of cure, however, it is responsible for 5' of all cancer deaths in women and approximately half of deaths due to cancers of the female genital tract. Treatment of ovarian cancers when they are confined to the ovary is very effective, with a cure rate approaching 90'. Unfortunately, most patients are diagnosed when cancer cells spread to other organs in the body, and they are very difficult to treat. Most of them will die within 5 years. Therefore, research efforts that are directed at reducing incidence of and mortality from ovarian cancer are of paramount importance. This program project consists of four research projects that all target these common goals. Project 1 will study genetic changes in those ovarian cancer cells confined to the ovary. This will help us to identify a protein secreted by the cancer cells into the bloodstream, and we can use this protein as a marker for early diagnosis of the disease. Project 2 will characterize a novel enzyme (Protease M), evaluate its potential to be used as an early diagnostic marker for ovarian cancer, and identify its substrates, which may be used in the development of a drug to kill the Protease M-producing ovarian cancer cells. Project 3 will study the effect of hormones on the growth of normal ovarian cells, evaluate whether they contribute to ovarian cancer development, and identify early markers associated with hormone-induced ovarian cancer. Project 4 will use some lipids called lysophosphlipids (LPA) to develop a highly sensitive and specific marker for the early detection of ovarian cancer and to evaluate whether the enzyme that can digest them can be used to counteract the tumor-inducing effect of LPA, which may prevent tumor initiation and development. The integrated activities of the four projects and investigators will provide a comprehensive study of the etiology and early genetic changes during ovarian carcinogenesis. Outcomes from these multidisciplinary projects will provide insight into primary prevention, early diagnosis, and treatment of ovarian cancer.

Project 1: Program Project Award

Early Genetic Changes in Human Epithelial Ovarian Tumors

Principal Investigator: Samuel C. Mok

Project 1: Public Abstract

Ovarian cancer is the leading cause of death from gynecologic malignancies in the United States. It usually strikes women between the ages of 40 to 70 and kills 14,500 a year. The symptoms are usually very mild and similar to those of other medical problems, so more than 75 percent of ovarian cancers are not diagnosed until after the disease has spread beyond the ovaries. If we can detect the cancer cells when they are still confined in the ovary, the cure rate of the disease will be more than 90 percent. Recent studies on prophylactic ovaries from high-risk individuals showed the presence of very small foci of cancer cells, suggesting that they may create an identifiable milieu from which ovarian cancer will mostly likely arise. We therefore propose to use a novel technique to retrieve these cancer cells from the normal-looking ovary and study the genetic components of these cancer cells in order to identify genes that are up-regulated or expressed exclusively by these cells. We will also evaluate which gene products can be secreted by the cancer cells into the bloodstream. These gene products are particularly useful, since we may detect them even before the cancer cells spread beyond the ovary and can therefore be used as markers for early diagnosis of the disease.

Project 2: Program Project Award

A Potential Serum Marker for Ovarian Cancer

Principal Investigator: Shu-Wing Ng

Project 2: Public Abstract

For ovarian cancer, early detection is the most important determining factor for patient survival, which ranges from a 90' 5-year survival rate for women with early detected disease to a disappointing 20' survival rate for most patients diagnosed in the later stages of disease. Unfortunately, there is still no satisfactory screening marker for the early stages of ovarian cancer, which is often without any symptoms. Prostate-specific antigen (PSA) is a screening marker widely used in the blood tests for early detection of prostate cancer and for monitoring prostate patients after therapy. We have isolated a new protein that is very similar to PSA and is at a very high level in the ovarian cancer cells of early stages. This protein, named protease M, is a protease, an enzyme that breaks down other proteins. By using specific antibody, we have been able to detect protease M secreted by the growing cancer cells. High levels of protease M in the early stages of ovarian cancer suggest that up-regulation of protease M is an early event during the development of cancer, and the ability to detect the secreted protease by cancer cells suggests that this protease has a high potential of being an important screening marker for early detection of ovarian cancer. In this proposal, we will examine and confirm the levels of protease M in a larger number of ovarian cancer tissues obtained from patients at different stages of disease. We will also find out the role of protease M in the development of ovarian cancer by finding out the target protein of protease M. And finally, we will look for the most specific and sensitive method to detect protease M in the blood of ovarian cancer patients, which is very important for the development of a powerful screening test for the early detection of ovarian cancer. Taken together, this study will help us understand how ovarian cancer is developed and design a simple, sensitive, and specific screening test for early detection of ovarian cancer, which is very important for increasing the survival chance of ovarian cancer patients.

Project 3: Program Project Award

Hormones as Etiological Factors of Ovarian Carcinogenesis

Principal Investigator: Shuk-mei Ho

Project 3: Public Abstract

Ovarian cancer (OC) is the highest-ranking cause of death from gynecological cancers among American women. While the etiology of OC remains elusive, epidemiological observations have implicated ovarian steroids and/or gonadotropins, particularly when present at abnormal levels during and after menopause, as probable risk factors of OC. In a preliminary study, we discovered that exposure to abnormally high levels of estrogens and/or gonadotropins stimulate normal human ovarian epithelial (HOSE) cell growth whereas progesterone and an adrenal androgen, DHEA, inhibit HOSE cell proliferation. Hence, we hypothesize that the changing hormonal milieu during or following menopause may put women at risk of developing OC. In this proposal, we will use a newly developed in vitro transformation assay to directly assess the oncogenic potentials of these hormones and determine if they have enhancement or inhibitory interaction on ovarian carcinogenesis. Results from these studies may permit the development of new hormone/anti-hormone-based strategies for OC prevention or intervention.

Project 4: Program Project Award

Development of a Highly Sensitive and Specific Method for the Early Detection of and a Strategy for the Early Intervention of Ovarian Cancer

Principal Investigator: Yan Xu

Project 4: Public Abstract

For women, ovarian cancer is second only to lung cancer in terms of oncologic mortality. This year 25,400 women will be diagnosed with ovarian cancer and more than two-thirds of them will present in advanced stages, when the cancer is widespread. Currently, surgery and chemotherapy are only partially effective to treat late stage diseases. Advanced stage diagnoses and ineffective treatments result in a high mortality rate for ovarian cancer patients. Out of the 25,400 women diagnosed with ovarian cancer this year, 14,500 of them will have died from the disease in 3-5 years. Moreover, most of these women will endure multiple surgical and chemotherapeutic treatments, with their associated serious side effects. However, ovarian cancer is a curable disease if it is detected early. Over 90' percent of patients with Stage I ovarian cancer (when tumors are confined to the ovaries) will be disease-free 5 years after the initial surgery. Unfortunately, patients with early stage ovarian cancers often show no symptoms, or display symptoms mistaken for other benign diseases. Therefore, the key issues in reducing the death rate in patients with ovarian cancer are to find an effective way to detect this disease at an early stage, comparable to the pap smear test for cervical cancer and the mammography test for breast cancer, and to prevent tumors from further development. A molecule (such as a protein, carbohydrate, lipid, or gene) that is associated with a certain disease (such as cancer), may be used as a marker to detect that disease. For the past two decades, more than 20 different molecules have been examined for their value in detecting ovarian cancer. Unfortunately, these markers, including CA 125 (which is the most widely used marker for ovarian cancer), can only detect a small percentage of Stage I cancers. Multiple-marker tests have been shown to have markedly improved sensitivity, but unsatisfactory specificity. Therefore, there is an urgent need to develop a more effective method for the early detection or prevention of the development of ovarian cancer, allowing early intervention.

Ovarian tumors are often associated with the production of a large volume of ascitic fluids. These fluids are not only a painful burden to patients, but they also provide a growth environment for tumor cells. We have identified such a factor, called lysophosphatidic acid, or LPA, a lipid molecule in ascites from patients with ovarian cancer. Importantly, normal ovarian surface cells do not respond to LPA in a growth-promoting manner. More recently, we reported that LPA is elevated in the plasma of patients with all stages of ovarian cancer. In particular, the elevation is detected in 9 of 10 patients with Stage I ovarian cancer (JAMA 280, 719-723, 1998). As an ovarian cancer marker, LPA has a sensitivity of 95' and specificity 89', which is greatly improved over the current tests available. LPA is distinct from other current available markers for ovarian cancer in three aspects: (1) It detects early stage ovarian cancer at a higher rate. (2) While the function for other markers are largely unknown, LPA stimulates the growth of ovarian cancer cells. Therefore, LPA may serve a dual function: it may represent a marker for early detection and a useful target for the prevention or therapy of ovarian cancer. (3) It is a lipid molecule, while others are either protein or carbohydrate molecules. Our studies of LPA as a potential diagnostic test are preliminary and must be evaluated by a large, longitudinal study. In addition, for ovarian cancer (which has a relatively low prevalence), higher sensitivity and specificity will be necessary for the test to have a real impact on the detection and screening of ovarian cancer. In addition, due to the lipid nature of LPA, it is very difficult to produce a specific antibody that can be used to detect LPA. The detection method that we used involves many steps and is rather cumbersome. To overcome these problems, we will improve our previous work to develop a highly sensitive and specific test for the early detection of ovarian cancer. A new method to analyze LPA will be developed in this study. We will also develop an early intervention strategy for ovarian cancer by reducing LPA levels through actions of phosphatidic acid phosphatase (PAP). PAP is an enzyme that cuts a piece off the LPA molecule to make LPA unable to stimulate the growth of ovarian cancer cells. This work could have a strong impact on advancing the early detection and intervention of ovarian cancer and therefore may improve the overall survival rate of patients with this disease.