Inhibition of Toll Like Receptor pathways as a potential therapeutic strategy for Chronic Lymphocytic Leukaemia
Supervisors: Dr Andrea Pepper, Prof Chris Pepper, Dr Sandra Sacre
Project Description: Applications are invited for a 3.5-year PhD studentship to join a new Leukaemia Research group at BSMS on the University of Sussex Campus. The group is led by Professor Chris Pepper and Dr Andrea Pepper (née Buggins) who have recently joined BSMS from successful CLL research groups based at Cardiff University and King’s College London respectively.
Chronic lymphocytic leukaemia (CLL) is a common B-cell malignancy that follows a remarkably diverse clinical course. It is characterised by an accumulation of mature B-lymphocytes in the peripheral blood, bone marrow (BM) and secondary lymphoid organs such as the lymph nodes (LN). We have recently shown that LN-CLL cells manifest a distinct phenotype to those in the PB and demonstrate an enhanced capacity for T-cell activation and immunological synapse formation1. Data from our novel in-vitro circulation model2 implies that, within a patient, a small but aggressive subset of CLL cells with a distinct phenotype (identical to that manifest by CLL cells in the LN) are inherently more capable of migrating and are primed for pro-survival and proliferation interaction with T-cells.
Most previous investigations into CLL have focussed on signalling through the B-cell receptor (BCR). However, we have data that strongly supports a role for Toll Like Receptor signalling, particularly in cells which possess a LN-CLL phenotype. Therefore, we are collaborating with Dr Sandra Sacre, who has an expertise in TLR signalling, and the aim of this studentship is to study and dissect the role of TLR signalling in primary CLL cells using activating and inhibitory oligonucleotides3 as well as naturally occurring CgG-rich autologous serum from patients. We also plan to investigate whether inhibition of TLR signalling has the potential to synergise with new drugs currently being used for the treatment of CLL. These drugs, targeting Bruton Tyrosine Kinase (BTK) and phosphatidylinositide 3-kinase delta (PI-3Kd) induce a striking tissue redistribution elicited by inhibiting CLL cell lymphoid tissue homing. However, despite extremely positive effects these agents are not curative and some patients remain refractory or relapse following initial response. Therefore, investigations into the potential for therapeutic synergy by targeting multiple signalling pathways are both a timely and relevant.
The project will involve extensive and complex tissue culture techniques including use of our novel circulation system. In addition, the student will acquire analytical skills as well as experience in tumour modelling, molecular biology and flow cytometry. We fully anticipate that this studentship will yield important new insights resulting in high impact papers. It will therefore provide an excellent opportunity for the right candidate to gain critical skills and experience that will provide a springboard into the next stage of their career. Committed candidates with a particular interest in translational oncology are particularly encouraged to apply.
Funding Notes: Applications for this 3.5-year Chowen funded PhD studentship are invited from candidates with a Master’s degree (or equivalent) in biological, cancer sciences or a related discipline. As a minimum, you should hold, or expect to obtain, a first or upper second class undergraduate degree or equivalent, in an appropriate subject from a recognised academic institution.
This studentship is only open to UK and EU citizens.
Please apply via University of Brighton application portal, and include a personal statement and CV.
Informal enquiries should be directed to Dr Andrea Pepper (email@example.com) or Prof. Chris Pepper (firstname.lastname@example.org).
Phenotype and immune function of lymph node and peripheral blood CLL cells are linked to transendothelial migration. Pasikowska M, Walsby E, Apollonio B, Cuthill K, Phillips E, Coulter E, Longhi MS, Ma Y, Yallop D, Barber LD, Patten P, Fegan C, Ramsay AG, Pepper C and Buggins* AG. Blood. 2016 Jul 28;128(4):563-73.
Development and characterization of a physiologically relevant model of lymphocyte migration in chronic lymphocytic leukemia. Walsby E, Buggins* A, Devereux S, Jones C, Pratt G, Brennan P, Fegan C, Pepper C. Blood. 2014 Jun 5;123(23):3607-17
Oligodeoxynucleotide inhibition of Toll-like receptors 3, 7, 8, and 9 suppresses cytokine production in a human rheumatoid arthritis model. Sacre S, Lo A, Gregory B, Stephens M, Chamberlain G, Stott P, Brennan F. Eur J Immunol. 2016 Mar;46(3):772-81
*A Buggins is now A. Pepper
Application deadline: Friday 30 June 2017
On application, please enter the following text in the ‘Research Proposal’ field: Supervisor defined project, followed by the project title.