The NF-kB pathway promotes survival of cancer cells. My research in ovarian cancer began with characterizing the activation state and biological relevance of NF-kB in this disease. The NF-kB family of transcription factors is ubiquitously expressed. NF-kB signaling has been implicated in ovarian cancer, but the significance and mechanism of NF-kB signaling in ovarian cancer is unknown. There is precedent to propose that NF-kB is a critical signaling mechanism in cancer. I initially hypothesized that the NF-kB pathway is over-activated in ovarian cancers with more aggressive behavior. The NF-kB pathway was implicated in ovarian cancer proliferation and cytokine secretion in vitro, and contributed to chemoresistance of ovarian cancer cell lines. I therefore sought to determine the expression patterns and prognostic associations of NF-kB pathway proteins in primary ovarian cancer tissues. I demonstrated that overexpression of the NF-kB subunit p50 at diagnosis conveyed poor outcome in these patients. The biological relevance of NF-kB in ovarian cancer was established in my laboratory. Having demonstrated the coordinate presence of NF-kB machinery in ovarian cancers, I sought to modulate its activity. Inhibitors of NF-kB (IkBs) are tagged for degradation through the proteasome upon specific inducible phosphorylation by IkB kinases (IKKs). Therefore, targeted inhibition of IKKs could isolate NF-kB as a mechanism for ovarian cancer pathogenesis. A subset of ovarian cancer cell lines was affected by inhibition of IKKb in properties of growth, adhesion, invasion and cytokine secretion. I developed a gene expression signature of IKKb signaling in ovarian cancer using both pharmacologic and genetic manipulation of IKKb. This signature gave insight into the results of NF-kB in ovarian cancer, based on known functions of the ovarian cancer-specific target genes, and allowed me to probe established ovarian cancer databases in order to estimate the relative impact of NF-kB signaling on the survival of women with ovarian cancer. Higher NF-kB activity conveyed a worse outcome, suggesting that modulation of IKKb might benefit patients whose tumors showed elevated target gene expression. A key discovery from this work was the tissue specificity of NF-kB signaling. The 9-gene signature experimentally defined in ovarian cancer was completely different from the 11 genes I previously identified in multiple myeloma. The overall goal of this project is to dissect the molecular structure of NF-kB signaling in ovarian cancer, with the intent to develop biomarkers of dependence on NF-kB, and novel points of therapeutic intervention. In FY 2013 we published a study identifying IKKepsilon as instrumental in the metastasis and invasion of ovarian cancer. We also completed two shRNA library screens, one in combination with an inhibitor of IKKbeta, and another in combination with shRNA against IKKepsilon. These studies identified novel interactions between the NF-kB pathway in ovarian cancer. In combination with IKKbeta, we found caspase 8 to be cooperative in protecting the cells from necroptosis. In combination with IKKepsilon, we discovered that CHEK1 protected the cells from catastrophic DNA damage by stalling the cell cycle driven by IKKepsilon. From a therapeutic standpoint, we previously completed a phase 2 clinical trial using the SMAC mimetic birinapant in women with relapsed and refractory ovarian cancer. There were no clinical responses. Therefore, through the NCI Major Opportunities, we completed a matrix drug screen testing 2000 compounds in combination with birinapant, in order to identify synergistic combinations to move to the clinic. We identified drug classes that met the criteria for synergy, and are in the process of testing these in mouse models.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Investigator-Initiated Intramural Research Projects (ZIA)
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Zhang, Jialing; Chen, Tony; Yang, Xinping et al. (2018) Attenuated TRAF3 Fosters Activation of Alternative NF-?B and Reduced Expression of Antiviral Interferon, TP53, and RB to Promote HPV-Positive Head and Neck Cancers. Cancer Res 78:4613-4626
House, Carrie D; Grajales, Valentina; Ozaki, Michelle et al. (2018) I??? cooperates with either MEK or non-canonical NF-kB driving growth of triple-negative breast cancer cells in different contexts. BMC Cancer 18:595
Green, Daniel S; Nunes, Ana T; David-Ocampo, Virginia et al. (2018) A Phase 1 trial of autologous monocytes stimulated ex vivo with Sylatron® (Peginterferon alfa-2b) and Actimmune® (Interferon gamma-1b) for intra-peritoneal administration in recurrent ovarian cancer. J Transl Med 16:196
Pongas, Georgios; Kim, Marianne K; Min, Dong J et al. (2017) BRD4 facilitates DNA damage response and represses CBX5/Heterochromatin protein 1 (HP1). Oncotarget 8:51402-51415
House, Carrie D; Jordan, Elizabeth; Hernandez, Lidia et al. (2017) NF?B Promotes Ovarian Tumorigenesis via Classical Pathways That Support Proliferative Cancer Cells and Alternative Pathways That Support ALDH+ Cancer Stem-like Cells. Cancer Res 77:6927-6940
Zeligs, Kristen P; Neuman, Monica K; Annunziata, Christina M (2016) Molecular Pathways: The Balance between Cancer and the Immune System Challenges the Therapeutic Specificity of Targeting Nuclear Factor-?B Signaling for Cancer Treatment. Clin Cancer Res 22:4302-8
Kim, M; Hernandez, L; Annunziata, C M (2016) Caspase 8 expression may determine the survival of women with ovarian cancer. Cell Death Dis 7:e2045
Kim, Marianne K; Caplen, Natasha; Chakka, Sirisha et al. (2016) Identification of therapeutic targets applicable to clinical strategies in ovarian cancer. BMC Cancer 16:678
Hernandez, Lidia; Kim, Marianne K; Lyle, L Tiffany et al. (2016) Characterization of ovarian cancer cell lines as in vivo models for preclinical studies. Gynecol Oncol 142:332-40
Kim, Marianne K; James, Jana; Annunziata, Christina M (2015) Topotecan synergizes with CHEK1 (CHK1) inhibitor to induce apoptosis in ovarian cancer cells. BMC Cancer 15:196

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