There is immense potential to decrease ovarian cancer incidence and mortality through prevention. Extensive epidemiological evidence has shown that routine use of the combination estrogen-progestin oral contraceptive pill (OCP) confers a remarkable 30-50% reduction in the risk of developing subsequent epithelial ovarian cancer. Based on our research findings, we believe the progestin component of the OCP is functioning as a chemopreventive agent by activating potent and well-known molecular signaling pathways. Human data demonstrate that progestin-potent OCPs confer twice the ovarian cancer protection as newer weak-progestin OCPs.

A strategy to increase progestin potency is to combine a progestin with a second preventive agent that is non-toxic and enhances progestin efficacy. In this regard, there is strong epidemiological and laboratory evidence in support of vitamin D for the prevention of malignancy, including ovarian cancer, making vitamin D an attractive second agent. Importantly, we have discovered that progesterone and vitamin D have synergistic inhibitory effects on cell viability in cells derived from the ovarian epithelium. This effect is shown by a marked increase in apoptosis. We have also made the novel discovery that progestin can inhibit and degrade CYP24, the enzyme that renders vitamin D inactive. By inhibiting vitamin D's degradation via inhibition of CYP24, the active form of vitamin D has a longer local biologic half life, and thus cellular effect.

Recent evidence has shown that what has been identified as ovarian cancer may in fact arise from the fallopian tube. We hypothesize that progestins and vitamin D both target the early steps of carcinogenesis in the fallopian tube epithelium and/or ovarian surface epithelium, and that the combination of progestin and vitamin D will more effectively prevent ovarian cancer than either agent administered alone. The student will have the opportunity to further develop this hypothesis by examining the inhibitory effect of vitamin D (1,25 dihydroxyvitamin D3), progesterone, and the combination in tumor-derived cells lines and in a prospective study using genetically modified mice that develop fallopian tube cancer.

1) To determine the relative efficacy of vitamin D, progesterone, and combined vitamin D and progesterone in inhibiting growth of tumor cells in culture and of tumors in mice.

2) To determine the impact of treatment with vitamin D, progesterone, or combined vitamin D and progesterone on CYP24 enzyme production in tumor cells in culture and tumors in mice.

For the in vitro studies, established tumor cell lines will be grown and treated with 1,25 dihydroxyvitamin D3 or an analog, with progesterone, and with vitamin D and progesterone combined. Total RNA and protein will be extracted for the analysis of gene expression by RT-PCR and for protein production of CYP24 and apoptosis-related molecules.

For the in vivo studies, mice that have been genetically modified to produce fallopian tube cancer will be treated with vitamin D, progesterone, or the combination, and tumor growth will be monitored. Tumors will be assessed for apoptosis by both morphologic and molecular assays. They will also be assayed for the expression of molecular markers including CYP24, Ki-67, and transforming growth factor-beta. Statistical comparisons using ANOVA will be made among treatment groups and controls.

The Rodriguez lab conducts frequent lab meetings in which the student will participate as a full member, presenting his/her experiences in the lab each week. The Department of Obstetrics & Gynecology holds weekly Grand Rounds. The American Association for Cancer Research and the Society of Gynecologic Oncologists annual meetings provide an opportunity for abstract submission and presentation of mature research findings. Depending on the progress made, the student could be eligible to participate.