Blunt, Matthew - University of Southampton

个人简介

Dr Blunt graduated with a First-class degree in Biological Sciences from the University of Reading in 2009. He completed a PhD in Immunology and Pharmacology at the University of Bath, funded by the BBSRC and Novartis. In 2013 he joined the Cancer Sciences Unit at the University of Southampton as a Postdoctoral Research Fellow in the laboratory of Dr Andrew Steele. His research focuses on novel treatment strategies in lymphoid malignancies and how the lymph node environment and B cell receptor (BCR) signaling mediate resistance to chemotherapies. Dr Blunt was awarded the prestigious Catovsky prize in 2014 by the UK CLL forum and the John Marsden Prize in 2015 by the University of Southampton for his publication on the dual mTOR/PI3K inhibitor PF-04691502 in Blood. Dr Blunt has a number of internal collaborations and works closely with Professor Freda Stevenson, Professor Graham Packham, Dr Francesco Forconi, Professor Jon Strefford and Professor Mark Cragg.

研究领域

The treatment of Chronic Lymphocytic Leukaemia (CLL) has been revolutionised in recent years by B cell receptor (BCR) small molecule kinase inhibitors such as the BTK inhibitor ibrutinib and the PI3Kδ inhibitor idelalisib. These drugs are not curative however and a proportion of patients can develop resistance for unknown reasons. Therefore there is a need to investigate how resistance to current therapies arises and to develop subsequent novel treatment strategies for these patients. CLL cells in the lymph nodes, via a multitude of different signals, are protected against both basal and drug induced apoptosis. Dr Blunt uses primary human CLL cells in combination with conditions which mimic the lymph node microenvironment in the laboratory to investigate how these signals promote drug resistance. Subsequently we can use these same conditions to evaluate novel compounds or treatment strategies which have the potential to overcome these survival signals. Recent projects include: Targeting the phosphoinositide-3 kinase (PI3K)/mTOR pathway in CLL The importance of the PI3K/mTOR signalling pathway is exemplified by the clinical efficacy and approval of the PI3Kδ inhibitor idelalisib. We have shown recently that targeting all four class I PI3K isoforms as well as mTOR induces more substantial apoptosis of CLL cells that PI3Kδ inhibition alone (Blunt et al, Blood, 2015). This indicates that other PI3K isoforms and/or other pathways leading to activation of mTOR can compensate for PI3Kδ inhibition in terms of CLL survival. IL-4 signalling in CLL IL-4 which is proposed to be secreted by T cells of CLL patients can protect CLL cells from spontaneous and drug-induced apoptosis (Steele et al, Blood, 2010). We have now shown that CLL cells treated with IL-4 can also protect CLL cells from ibrutinib and idelalisib. IL-4 induced BCR (sIgM) expression and subsequent downstream signalling and caused a reduction in chemokine receptor (CXCR4 and CXCR5) expression and subsequent migration. These effects can be reversed by pharmacological targeting of the JAK/STAT signalling pathway and may be used as a strategy to promote more durable remissions in CLL patients treated with BCR kinase inhibitors such as ibrutinib and idelalisib. Targeting the Unfolded Protein Response (UPR) The UPR serves to protect cells from the consequences of protein misfolding. Activation of the UPR following engagement of the BCR leads to upregulation of HSP family members including HSP70 and these aid in refolding misfolded proteins or facilitate their degradation via the proteasome. If the stress is resolved, the UPR signalling pathway is switched off, however, if stress persists the UPR switches to a pro-apoptotic signal in order to remove the damaged cells. We are using novel inhibitors to promote cell death via the UPR pathway in CLL cells. We have shown that targeting the UPR pathway kills CLL cells independently of genetic abnormalities such as TP53 mutation and are assessing the effectiveness of this approach in combination with other treatment modalities.

近期论文

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The dual Syk/JAK inhibitor cerdulatinib antagonises B-cell receptor and microenvironmental signaling in chronic lymphocytic leukemia - Blunt, Matthew, Koehrer, S., Dobson, R., Larrayoz, M., Wilmore, S., Hayman, A., Parnell, J., Smith, L. D., Davies, A., Johnson, P. W., Conley, P. B., Pandey, A., Strefford, J. C., Stevenson, F. K., Packham, G., Forconi, F., Coffey, G. P., Burger, J. and Steele, Andrew Published:2016Publication:Clinical Cancer ResearchPage Range:1-25doi:10.1158/1078-0432.CCR-16-1662 To BH3 profile or not to BH3 profile - Blunt, Matthew and Steele, Andrew Published:2016Publication:BloodVolume:127, (25)Page Range:3111-3112doi:10.1182/blood-2016-04-711762PMID:27340250 IL-4 enhances expression and function of surface IgM in CLL cells - Aguilar-Hernandez, Maria M., Blunt, Matthew, Dobson, Rachel, Yeomans, Alison, Thirdborough, Stephen, Larrayoz, Marta, Smith, Lindsay, Linley, Adam, Strefford, Jonathan C., Davies, Andrew, Johnson, Peter, Savelyeva, Natalia, Cragg, Mark, Forconi, Francesco, Packham, Graham, Stevenson, Freda K. and Steele, Andrew J. Published:2016Publication:BloodPage Range:1-25doi:10.1182/blood-2015-11-682906PMID:27002119 The SF3B1 inhibitor spliceostatin A (SSA) elicits apoptosis in chronic lymphocytic leukemia cells through downregulation of Mcl-1 - Larrayoz, M., Blakemore, S.J., Dobson, R.C., Blunt, M.D., Rose-Zerilli, M.J.J., Walewska, R., Duncombe, A., Oscier, D., Koide, K., Forconi, F., Packham, G., Yoshida, M., Cragg, M.S., Strefford, J.C. and Steele, A .J. Published:2015Publication:LeukemiaVolume:30Page Range:351-360doi:10.1038/leu.2015.286PMID:26488112