Pharmacologic opportunities for the chemoprevention of ovarian cancer.

CS18-03

Epithelial ovarian cancer is a highly lethal malignancy. It is the fourth leading cause of cancer deaths among women in the United States and causes 140,000 deaths annually in women worldwide. Despite intensive research efforts over the past decade directed towards improved detection and treatment of ovarian cancer, the long-term survival of women with ovarian cancer has only improved modestly. Progress in the fight against ovarian cancer has been hampered by a number of factors, including late diagnosis, the molecular heterogeneity of tumors, the absence of highly curative chemotherapy, and the lack of a valid animal model for the disease.

There is immense potential to decrease ovarian cancer incidence and mortality through chemoprevention. A potent ovarian cancer preventive agent already exists in the estrogen-progestin combination pill (OCP), suggesting that pharmacologic chemoprevention of ovarian cancer is possible. Routine use of the OCP confers a remarkable 30-50% reduction in the risk of developing subsequent epithelial ovarian cancer. Our research strategy has been driven by the notion that a better understanding of the biologic mechanism(s) underlying the ovarian cancer protective effect of the OCP could open the door to a highly effective pharmacologic strategy for the prevention of ovarian cancer.

Based on our research findings, we believe that we have discovered a major biologic mechanism underlying the ovarian cancer preventive effects the OCP. Specifically, we have discovered in primates that the progestin component of the OCP is functioning as a classic chemopreventive agent, by activating potent chemopreventive molecular events in the ovarian epithelium such as apoptosis and TGF-\#946; signaling. These two molecular events have been strongly implicated in cancer prevention in vivo, and are believed to underlie the protective effects of other well-known chemopreventive agents. In addition, we have performed a trial in chickens, which demonstrated a protective effect of progestins against the development of reproductive tract tumors. Our laboratory and animal research findings are supported by human data demonstrating that progestin-potent OCPs confer twice the ovarian cancer protective effect as OCPs containing weak progestins, and that a progestin-only contraceptive significantly lowers ovarian cancer risk. These animal and human data strongly support the notion that progestins are effective preventive agents for ovarian cancer and suggest that a regimen that has enhanced chemopreventive biologic potency in the ovarian epithelium will be more effective than a lower potency regimen for ovarian cancer prevention.

Our findings open the door both toward development of progestins for ovarian cancer prevention, as well as to development of other (non-progestin) compounds that have biologic effects similar to progestins as candidate ovarian cancer preventive agents. Among other agents, a growing body of epidemiologic and laboratory evidence suggests that several agents may confer ovarian cancer prevention and induce apoptosis in ovarian epithelial cells, including Non-Steroidal Anti-inflammatory Agents (NSAIDs), Vitamin D, and Omega-3 fatty acids.

The ideal preventive agent for ovarian cancer may comprise a combination of agents that act in an additive or synergistic fashion to maximally activate molecular pathways that inhibit carcinogenesis in the ovarian epithelium, thereby maximizing ovarian cancer prevention while minimizing side effects. In this regard, we have gathered laboratory evidence demonstrating that NSAIDs synergistically enhance the biologic effects of progestins in the ovary. Using a primary culture of normal human ovarian surface epithelial cells (NOE), a transformed line of human ovarian surface epithelial cells (H10-118V), two human ovarian epithelial cancer cell lines (OVCAR-3 and OVCAR-5) and a human colon cancer cell line with a well-characterized response to NSAIDs (HT-29), we evaluated the apoptotic effects of progestins and NSAIDs alone and in combination. Both progestins and NSAIDs inhibited growth and induced apoptosis in a dose-dependent fashion. At doses of NSAIDs or progestins that independently caused minimal adverse effects on cell viability (less than 30% loss), the combination showed a synergistic reduction in cell viability (70-95% loss). Apoptosis in cells treated with the NSAID/Progestin combination was associated with a 10-fold increase in caspase-3 activation, significantly greater than treatment with either agent alone. Our results suggest it may be possible to combine progestins and NSAIDs to achieve ovarian cancer prevention at lower doses of each than are required for single administration, thereby lessening the risk of side effects posed by these agents, while still maintaining chemopreventive potency.