Ovarian cancer has the highest mortality among gynecological cancers. The 5-year survival rate is no better than 37%. Approximately 27,000 new cases are diagnosed each year in the United States and approximately 15,000 women die annually from this disease. Further, in spite of many advances in medical research, neither the survival rate nor the treatment for ovarian cancer has changed significantly for 30 years. Surgical tumor reduction followed by platinum-based chemotherapy remains the mainstay of therapy in the management of advanced ovarian cancers. Unfortunately, relapse of ovarian cancer contributing to poor prognosis often is attributable to the development of drug resistance resulting in therapeutic failure. Therefore, there is an urgent need to identify novel diagnostic, prognostic, and therapeutic agents for ovarian cancer.

The majority of ovarian cancers arise from the single layer of cells investing the ovary called the ovarian surface epithelium (OSE). However, the reasons for the propensity of cancer development in OSE are poorly understood, although about 10% of ovarian cancers are associated with an inherited predisposition and are characterized by an increased incidence and earlier onset of disease. Epidemiological studies suggest that, besides race and familial history, events associated with repeated wounding in the OSE such as repeated ovulation, may result in aberrant OSE growth contributing to ovarian cancer.

A number of genetic abnormalities have been identified in ovarian cancer, although no single genetic alteration is common to all ovarian cancers. We have identified a genetic abnormality associated with hereditary ovarian cancer. That is, normal OSE from women at risk for ovarian cancer demonstrate premature shortening at the ends of their chromosomes, in the regions referred to as the telomeres. Such premature telomeric shortening causes chromosomal instability and has been shown to lead to cellular aging or death. Occasionally, cells with critically shortened telomeres survive due to the re-activation of an enzyme called telomerase that maintains telomeric length and allows cells to progress toward malignant transformation. Over 90% of all tumors, including ovarian tumors, examined to date express telomerase activity. It appears, then, that increased telomeric instability maintained by telomerase may contribute to the malignant transformation of OSE and that telomerase represents a potentially important anticancer target.

Since little is currently known about the mechanisms that regulate telomerase activity, we developed an ovarian culture model system in which telomerase activity can be controlled in both normal and cancerous ovarian cells. The goal of this research project is to use our ovarian-telomerase model system to determine the molecular mechanisms that regulate telomerase activity in ovarian cancer. Three approaches will be employed. First, we will determine the relative contribution of the PI3K/Akt molecular pathway to mediate external cellular stimuli to elicit elevated telomerase activity. Second, we will determine if additional and/or redundant molecular pathways (the most likely alternate pathway is called the jnk pathway) also can mediated the translation of external cellular stimuli to evoke telomerase activity. Third, we hope to exploit mechanisms that abrogate telomerase activity that, when used in conjunction with conventional platinum regimes, would lead to increased chromosomal instability, thereby increasing and improving chemotherapeutic treatment efficacy and clinical outcome. It is our long-term goal to evaluate the effectiveness of telomerase as a potential anticancer target in ovarian cancer as well as a prognostic indicator of therapeutic outcome and to design novel or improved therapeutic modalities specifically targeted to ovarian cancer. This, in turn, will allow women with or at high risk of developing ovarian cancer to make more informed decisions concerning their health options and perhaps reduce the mortality of an insipid disease that kills thousands of women annually.