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. We performed a global RNAi sensitization screen in combination with a small molecule IKKb inhibitor looking for interactions that enhanced toxicity. Our screen identified caspase 8. A similar screen in lymphoma, performed by our collaborators, found IKKa. Therefore, I hypothesize that caspase 8 is more active in ovarian cancer, in contrast to B cell lymphomas.I validated the cooperativity of IKKb and caspase 8 using a sub-lethal concentration of IKKb inhibitor with caspase 8 shRNA. I began to examine the context of caspase 8 function in ovarian cancer. First, I asked whether caspase 8 enzymatic activity was required for synergy with IKKb. A peptide inhibitor of caspase 8 cleavage activity did not affect ovarian cancer cell viability in the presence of IKKb inhibitor, indicating that this function of caspase 8 was not necessary for its cooperation with IKKb. This finding suggests that caspase 8 plays a different function to activate NF-kB in ovarian cancer.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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National Cancer Institute Division of Basic Sciences
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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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