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Developing novel agents targeting the NF-κB pathway for the treatment of multiple myeloma

Varley, Melanie 2017. Developing novel agents targeting the NF-κB pathway for the treatment of multiple myeloma. PhD Thesis, Cardiff University.
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Abstract

The key aim was to characterise Nuclear factor-κB (NF-κB) inhibitors in four multiple myeloma (MM) cell lines to evaluate their use as potential therapeutic agents in this incurable haematological malignancy. The NF-κB inhibitors were characterised in terms of their effects on cytotoxicity, nuclear NF-κB activity, global gene expression changes and the survival protein Mcl-1. Using this workflow, the following inhibitors were investigated: the commercial non-specific NF-κB inhibitor BAY 11-7082; a series of first-in-class putative IKKα inhibitors (SU compounds); and a novel putative NIK inhibitor (CW15337) in MM cell lines. BAY 11-7082, CW15337 and most of the SU compounds induced dosedependent cytotoxicity in the MM cell lines. For BAY 11-7082 and CW15337, cytotoxicity was associated with dose-dependent changes in NF-κB activity, although BAY 11-7082 inhibited both the canonical and the non-canonical NF-κB pathway, whereas CW15337 specifically inhibited the non-canonical NF-κB activity. In addition, the apoptosis induced by CW15337 was accompanied by a dose-dependent decrease in Mcl-1 expression in all tested MM cell lines. In contrast, the cytotoxicity of the SU compounds did not correlate with the dose-dependent down-regulation of Mcl-1 expression or NF-κB activity, and could not be completely explained by the SU compounds IKKα, IKKβ and CDK9 inhibitory profiles. Microarray analysis indicated a large disparity between the numbers of genes differentially regulated by some of the SU compounds; the number altered and the magnitude of the changes was associated with their cytotoxicity. Therefore, it seems likely that the increased potency of some of the SU compounds was caused by off-target effects. Overall, this work supports the concept of NF-κB as a molecular target in MM and suggests that NIK inhibition may present the most promising therapeutic option for specific non-canonical NF-κB targeting in MM. However, a more detailed investigation of CW15337 across the kinome is merited.

Item Type: Thesis (PhD)
Status: Unpublished
Schools: Medicine
Date of First Compliant Deposit: 1 March 2018
Last Modified: 13 Mar 2019 02:30
URI: http://orca.cf.ac.uk/id/eprint/109394

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