Epithelial ovarian cancer is the most common cause of death from gynecological malignancies in the United States. Unfortunately, the vast majority of women with ovarian cancer are diagnosed with advanced disease at which time curative treatment options are limited if tumors do not respond to initial surgery and combination chemotherapy. Furthermore, symptoms such as abdominal pain, bloating, and shortness of breath can be severe due to carcinomatosis or widespread tumor dissemination in the peritoneal cavity and accumulation of ascites that is commonly seen with late stage and recurrent ovarian cancer. The poor prognosis observed for ovarian cancers is in part due to less effective therapy for late stage tumors, but also to the lack of successful methods of screening and detection of early stage disease. More importantly, the precise etiology of ovarian cancer development and progression is still not fully understood.

It is well known that NF-kappaB signaling plays an important role in a number of malignancies including ovarian cancer. In addition, it is becoming increasingly apparent that the host response from immune cells to developing tumors is critical to metastatic spread and thus to clinical prognosis. Tumor-promoting immune cells implicated in the process of ovarian cancer metastases are peritoneal macrophages. Therefore, the proposed research is designed to investigate the contribution of NF-kappaB signaling in ovarian tumor and host peritoneal macrophages to ovarian cancer progression. Our group is in a unique position to carry out the proposed studies as we have developed a powerful transgenic mouse that enable us to readout NF-kappaB activity in live animals as well as in specific cell types. We will mimic the clinical development of ovarian tumors by injecting cancer cells into the peritoneum of experimental animals. An advantage of the proposed tumor cell lines is that they are the same genetic background as the mice, thus allowing us to investigate the immune response as tumors grow and spread. The novel NF-kappaB reporter mice will enable us to monitor NF-kappaB responses in the host peritoneal macrophages. In reciprocal experiments, tumor cells labeled with the NF-kappaB reporter injected into wild-type mice will enable us to monitor NF-kappaB response in tumors. In addition, we will evaluate NF-kappaB activity in response to novel NF-kappaB inhibitors derived from natural products thymoquinone and curcumin. These NF-kappaB inhibitors hold promise as anti-tumor agents for the treatment of ovarian cancer, but the effects on the host-tumor microenvironment are poorly understood. The mouse model system will be applied to test the efficacy and relative sensitivity of ovarian tumors and host peritoneal macrophages to NF-kappaB inhibitors in combination with cisplatin in a preclinical setting as important groundwork for future clinical trials.

The proposed work is highly innovative as we are applying a novel transgenic model system to the study of ovarian cancer metastasis in relation to NF-kappaB activation in both tumor and host cells. Our experimental strategy will also test a chemotherapeutic agent, FK228, to determine if the drug is effective in vivo. Together, these preclinical studies will provide the basis for a future clinical trial of FK228 and possibly other drugs that are being developed to target NF-kappaB.