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Characterization of the nuclear factor kappa B pathway in endometrial and ovarian cancer and identification of therapeutic mechanisms
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Date
2021-04-05
Authors
Noonan, Anne M.
Journal Title
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Publisher
University College Cork
Published Version
Abstract
Endometrial and ovarian cancers are difficult cancers to screen for, and morbidity and mortality from advanced and metastatic disease is significant. Previous work performed by our group demonstrated a role for NFκB signaling in ovarian cancer. NFκB signaling has been shown to be associated with poor prognosis in many cancers and is associated with invasiveness, metastasis, chemoresistance, cancer stem cell maintenance and immune evasion. We first undertook an assessment of the NFκB pathway in endometrial cancer cell lines and found similar aberration to that seen in high grade serous ovarian cancer. Direct inhibition of NFκB signaling has proven challenging in the clinical setting due to profound toxicity from NFκB inhibitors. Following a series of drug screens in the endometrial and ovarian cancer cell lines, we concluded that the best method to intercept the NFκB pathway was by manipulation of apoptosis signaling using the SMAC mimetic birinapant which inhibited both classical NFκB signaling, in addition to inducing apoptosis by degrading cellular inhibitors of apoptosis proteins (cIAPs). Only one endometrial cell line, ARK-1, was sensitive to cell death with birinapant, thus attention was focused on the more sensitive high grade serous ovarian cancer cell lines to generate pre-clinical data for a clinical trial with birinapant. We then undertook a phase II trial of birinapant in platinum resistant and refractory epithelial ovarian cancer. The trial did not confirm efficacy of single agent birinapant in this population, but important pharmacodynamic data was generated to better understand the mechanism of action of birinapant. Birinapant showed consistent target suppression of cIAP1 in vivo, favourable pharmacokinetics, strong penetration of birinapant in tumours and could be safely administered at doses that completely suppress cIAP1. However, since inhibition of cIAPs was insufficient to result in clinical efficacy of birinapant, attention was focused on combining birinapant with other apoptosis stimuli to trigger the intrinsic and extrinsic apoptosis cascades. Docetaxel, which is clinically active in ovarian cancer, has been shown to induce Bcl-2 phosphorylation which results in decreased binding of Bcl-2 to Bax, which in turn decreases the Bcl-2/Bax ratio, allowing Bax-mediated apoptosis. Caspase-8 is at the intersection of the intrinsic and extrinsic apoptosis pathways as cleavage of caspase-8 activates BID and mitochondrial outer membrane permeabilization. Since birinapant activates caspase-8, we hypothesized that the combination of birinapant and docetaxel would activate both intrinsic and extrinsic apoptosis pathways and result in increased tumour cell death. Cooperativity of birinapant and docetaxel was seen in CaOV3 cell line. In vivo toxicity studies in mice xenograft models also confirmed that treatment with birinapant and docetaxel resulted in increased tumour shrinkage and increased survival compared to either birinapant or docetaxel alone. Thus, our preclinical work exploring the mechanism of action of the combination of birinapant and docetaxel demonstrates synergy and provides support to explore this combination in a clinical trial as a therapeutic option for patients with advanced ovarian cancer.
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Keywords
NFkappaB , Apoptosis , Birinapant , Ovarian cancer , Endometrial cancer , Docetaxel
Citation
Noonan, A. M. 2021. Characterization of the nuclear factor kappa B pathway in endometrial and ovarian cancer and identification of therapeutic mechanisms. PhD Thesis, University College Cork.
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Copyright
© 2021, Anne Mary Noonan.