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Title: Targeting IKKε/TBK1 for the treatment of diffuse large B-cell lymphoma
Author: Carr, Matthew D.
ISNI:       0000 0004 7964 0835
Awarding Body: University of Leicester
Current Institution: University of Leicester
Date of Award: 2019
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Diffuse large B-cell lymphoma (DLBCL) is the most common of the non-Hodgkin lymphomas. Current treatment with conventional chemotherapy results in an overall 5-year survival rate of between 50-60%, and it is recognised that there are two major subtypes; germinal centre (GC) and activated B-cell (ABC). ABC DLBCL has a poor prognosis, highlighting a need for new treatments. IKKε and TBK1 are homologous kinases which function in innate immunity by regulating both the anti-viral response and the NF-κB pathway. IKKε and TBK1 may therefore represent attractive targets to repress NF-κB signalling in DLBCL. There was an association between TBK1 mRNA level and overall survival in DLBCL, and staining of primary DLBCL revealed that ~66% of cases expressed either TBK1 or IKKε at the protein level with association towards the non-GC DLBCL subtype. IKKε/TBK1 inhibitors were used to screen a panel of DLBCL cell lines. Sensitive DLBCL cell lines represented the ABC DLBCL subtype and showed expression of phosphorylated STAT3. ABC DLBCL are thought to rely on constitutive activation of the NF-κB pathway. Treatment of an ABC DLBCL cell line with DMX3433- a dual IKKε/TBK1 inhibitor abrogated phosphorylation of P65 and STAT3. Additionally, DMX3433 treatment significantly reduced secreted levels of IL-10, CLL3 and CCL4. Addition of IL-10 to the culture medium restored STAT3 phosphorylation. This suggests a model in which IKKε/TBK1 inhibition represses NF-κB driven IL-10 transcription to suppress JAK2/STAT3 signalling. Finally, two of four patient derived xenograft (PDX) DLBCL models were sensitive to IKKε/TBK1 inhibition. Treated PDX models show a reduction in levels of phosphorylated STAT3 and NF-κB and immune related signalling at the transcriptional level. It is proposed that targeting IKKε/TBK1 can disrupt NF-κB and STAT3 signalling, and therefore these kinases may be a novel therapeutic avenue in DLBCL especially the ABC subtype with high expression of phosphorylated STAT3.
Supervisor: Perrior, Trevor ; Chapman, Katie Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available