The NF-kB family of gene transcription factors is expressed in many tissue types, but has been studied most extensively in the context of the immune system and related cancers. Aberrant NF-kB signaling also has been identified in tumors of epithelial origin including breast, colon, lung and ovarian carcinomas. A systematic approach discovered IKKe, a cellular enzyme involved in triggering NF-kB signaling, as an oncogene in breast cancer. Research studies suggested the importance of these proteins in the propagation of ovarian cancer, but the significance and the mechanism of NF-kB signaling in ovarian cancer are unknown.

Our clinical focus in ovarian cancer inspired me to explore the NF-kB pathway in this malignancy at a scientific level. The stimulus for NF-kB signaling in cancer cells may be intrinsic or extrinsic to the cell. In certain cases, the cells may acquire individual genetic abnormalities of NF-kB regulators, thereby providing an intrinsic mechanism of cell-autonomous NF-kB activity. This type of mechanism was identified in breast cancer, lymphoma and myeloma. A second mechanism of NF-kB activation in ovarian cancer could be provided by signals from cells in the environment surrounding the tumor. Inflammatory proteins, growth factors, and adhesion molecules have been associated with NF-kB activation in several tissue types. Our lab defined and characterized the molecular mechanisms and the biological relevance of NF-kB activity in ovarian cancer. We proposed that NF-kB signaling defines a subset of ovarian cancer susceptible to therapeutic targeting of this pathway. Specific interruption of the pathway will isolate NF-kB as a mechanism for the growth and survival of ovarian cancer cells.

Our initial experiments identified a subset of ovarian cancer cell lines that are dependent on NF-kB signaling for growth and survival. A detailed understanding of the individual NF-kB components involved in ovarian cancer identified patients who may benefit from NF-kB blockade, and provided specific guidance to the development of future therapeutic agents or combinations. Our laboratory was interested in developing rational combinations of targeted therapies for ovarian malignancies. Combination therapy has been a mainstay of cancer treatment. Therapy targeted at sequential points in a biochemical pathway critical for cell survival has the potential to effectively eliminate the cancer cell. We employed novel high-throughput screening techniques to identify critical interactions with the NF-kB pathway that are important for the growth and survival of ovarian cancers.