Professor Joseph Slupsky B.Sc., Ph.D.

B cell receptor (BCR) signalling plays an important role in the pathogenesis of chronic lymphocytic leukaemia (CLL) and other B cell lymphomas. The signalling pathway activated by BCR engagement drives expansion of the malignant cells in these diseases and/or promotes their survival. We are working to understand the elements of this pathway that become activated by engagement of the BCR with the purpose of identifying patients likely to benefit from certain therapies, or expoiting them as potential therapeutic targets. Our recent work identified the src-family kinase LCK as an important mediator of proximal signalling in CLL cells. We are now investigating this molecule further in relation to its value as a therapeutic target and as a potential biomarker.

We have discovered that one of the signature proteins highly expressed by CLL cells is protein kinase CβII (PKCβII), a protein that is essential for the development of this disease. In this project, which is a collaboration with Dr. Nagesh Kalakona (Liverpool) and Dr. Alison Michie (Glasgow), we are investigating the mechanism regulating this high expression, and focussing on the factors controlling transcription of the gene coding for PKCβII, PRKCB1. The mechanism that controls PKCβII may also control high expression of other proteins that give CLL cells their unique cancerous behaviour. Therefore, our research may give insight into the basic pathology of this incurable disease, and perhaps open new therapeutic options for its treatment.

The development of resistance to chemotherapies is an important problem in cancers. In leukaemia a particularly exciting new agent, called ibrutinib, is now approved for the treatment of chronic lymphocytic leukaemia (CLL) and mantle cell lymphoma (MCL). Potentially, this drug could also be useful for the treatment of acute myeloid leukaemia (AML). However, resistance of leukaemic cells to ibrutinb has been observed and the mechanism of how this occurs is poorly understood. A principal target of ibrutinib in the malignant cells of CLL is a protein called Bruton's tyrosine kinase (BTK). In this proposal we will examine the function of BTK in CLL and AML cells using a technique known as kinome profiling. This technique involves analysis of the adaptations that occur in leukaemia cells in order to accommodate the events that contribute to their malignant behaviour, and is particularly useful in understanding how cancer cells become resistant to chemotherapies that target specific proteins, such as ibrutinib and BTK. This research is being performed in collaboration with Professors Ian Prior and David MacEwan and will guide the development of new therapies designed to overcome ibrutinib resistance in leukaemia.