Ovarian cancer is a leading cause of death among American women, with over 27,000 new cases and 15,000 deaths in 2000. Eighty percent to 85' of ovarian neoplasms arise from the otherwise inconspicuous tissue that covers the outer aspect of the ovary, the so-called ovarian surface epithelium (OSE). Current data also indicate that over 50' of women affected with OSE cancer die annually in the United States. Obtaining better insight on the mechanisms involved in the development and progression of OSE cancer and on the identification of molecular targets for therapeutic intervention is thus highly relevant. The importance of basic and translational inroads into this insipid disease was recognized by the University of South Florida and the H. Lee Moffitt Cancer Center and Research Institute that in 1996 supported the creation an Ovarian Epithelial Cancer Pathobiology Program to investigate the genetic, hormonal, and growth factor regulation of OSE cancer.

OSE cancer may result from the dysregulated or unchecked growth of native OSE cells. Accumulation of OSE cells and tumor progression may also result from a defect in the suicidal machinery (so-called programmed cell death or apoptosis) of these cells. The studies proposed in this Program Project are programmatically centered around the hypothesis that elucidating the pathways and signals involved in tumor cell growth and survival will ensure a better insight into ovarian epithelial carcinogenesis and pave the way for novel and targeted therapeutic intervention. Elucidation of growth, survival, and apoptotic pathways and transduction signals and characterization of a biological compound that, by activating apoptotic pathways, may be therapeutically relevant are the goals of the overall Program Project.

Already the Principal Investigators of this Program Project and their collaborators have made exciting and potentially important observations. The Akt2 oncogene has been recognized as a key molecule in ovarian epithelial cancer and its cellular signaling pathway identified as a potential target for therapeutic intervention. Telomerase, a molecule that is important in maintenance of chromosomal integrity and longevity, has been found to correlate with enhanced OSE cancer cell survival. Preliminary data indicate that vitamin D suppresses cell growth by inducing apoptosis and cell growth arrest in sensitive OSE cancer cell lines and that alterations in vitamin D receptors are found in malignant but not benign or borderline OSE neoplasms. These findings are exciting in view of the reported inverse relationship between sun exposure and the incidence of a number of cancers such as breast and prostate carcinomas. Ascorbyl stearate (a vitamin C derivative) has been found to induce apoptosis in OSE cancer cell lines overexpressing the oncogene Akt2 and the receptor to insulin-like growth factor.

Using a multidisciplinary and complementary approach and the support of two cores, the goal of this Program Project is to utilize cutting-edge biological and molecular strategies to dissect and characterize those molecular mechanisms already identified as potentially relevant in OSE cell growth, survival, and apoptosis. The four research components of the Program Project will investigate the (1) role of Akt2 oncogene in OSE cancer (Cheng), (2) anti-apoptotic role of telomerase in OSE cancer (Kruk), (3) resistance of OSE cancer cells to vitamin D-induced apoptosis and cell cycle arrest (Bai), and (4) apoptotic and anti-proliferative roles of ascorbyl stearate in OSE cancer cells (Coppola, Idea grant).

Ultimately, this research should lead to a better comprehension of OSE carcinogenesis and pave the way for targeted therapeutic intervention in the most lethal gynecologic malignancy today.