- Chemoprevention of Ovarian Cancer with Progestins
- Antibody Immunity to Cancer-Related Proteins as a Serologic Marker for Ovarian Cancer
For a number of years, clinicians have attempted to understand the association between oral contraceptive use and subsequent lower ovarian cancer risk. While various theories help explain the nature of this association, the actual underlying mechanism behind this protective effect of oral contraceptives largely remains unknown. If this mechanism can be elucidated, it may be possible to devise a chemopreventive strategy that is more effective than oral contraceptives while not interfering with ovulation or causing other side effects.
Significant epidemiological evidence has linked ovulation with ovarian cancer risk. Although inhibition of ovulation is presumed to underlie the protective effect of oral contraceptives, this protective effect is greater in magnitude than would be predicted on the basis of inhibition of ovulation alone. In preliminary laboratory studies, Duke University researchers funded by the Ovarian Cancer Research Program have demonstrated that the progestin component of oral contraceptives activates cancer preventive molecular pathways in the ovary, suggesting that a strong biologic effect independent of ovulation may underlie the protective effect of oral contraceptives against ovarian cancer. In a primate model comparing the combined and individual components of a common oral contraceptive product to a control, the group of monkeys that received progestin demonstrated significantly greater programmed cell death and differential regulation of transforming growth factor-beta in the ovarian surface epithelium.
Investigators now hope to determine what known regulators of programmed cell death are affected by progestin and test their hypothesis in human cell lines and domestic fowl, which have a high incidence of spontaneous ovarian cancer. The long-term plan is to conduct a clinical trial in women at high risk for ovarian cancer.
Rodriguez GC, Walmer DK, Cline M, Krigman HR, Lessey B, Whitaker R, Dodge R, and Hughes CL. 1998. Effect of progestin on the ovarian epithelium of macaques: cancer prevention through apoptosis? J. Soc. Gynecol. Investig., 5: 271-276.
Rodriguez GC, Nagarshef N, Bentley RC, Walmer DK, Cline M, Whitaker RS, Eisner P, Berchuck A, Dodge R, Adams M, and Hughes CL. 2001. Progestin induction of apoptosis in the macaque ovarian epithelium is differential regulation of transforming growth factor beta. J. Natl. Cancer Inst. In press.
Schildkraut J, Caligert B, and Rodriguez GC. 2001. The impact of progestin and estrogen potency of oral contraceptives on ovarian cancer risk. J. Natl. Cancer Inst. In press.
Present methods of ovarian cancer screening suffer from limited sensitivity and specificity. For example, ultrasound and CA-125, a serological marker of ovarian cancer, are mostly associated with advanced disease. Thus, the need for an improved ovarian cancer screening test that readily detects early-stage disease is evident. Ovarian Cancer Research Program investigators at the Virginia Mason Research Center and the University of Washington, in collaboration with the Fred Hutchinson Cancer , are trying to determine whether the presence of antibodies to specific ovarian cancer proteins is a reliable indicator of early-stage ovarian cancer. Prior work has identified three different tumor antigens that cause antibodies to be produced in the blood of women with ovarian or other cancers. These proteins are named HER2/neu, p53, and Myc. Blood from women without cancer, women with benign ovarian masses, and women with ovarian cancer are being tested to see if the presence of antibodies to these proteins distinguishes women with cancer from those without. In addition, for a blood test to be clinically useful, it should identify the vast majority of ovarian cancer cases, either alone or in conjunction with other testing methods. As a result, this study also will identify new ovarian tumor proteins that can be used in combination with HER2/neu, p53, and Myc to detect a larger proportion of ovarian cancer cases. To date, 19 proteins have been identified that in preliminary studies appear to induce antibody responses exclusively in cancer patients. In addition to their potential utility for early detection of ovarian cancer, a subset of these proteins show promise as a target for immune-based therapy of ovarian cancer such as cancer vaccines.
Stone B, Schummer M., Paley PJ, et al. 2001. MAGE F1, a novel ubiquitously expressed member of the MAGE superfamily. Gene 267(2): 173-82.