Research
B cell receptor signalling in chronic lymphocytic leukaemia cells.
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.
PRKCB1 gene expression and leukaemogenesis in chronic lymphocytic leukaemia.
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.
Characterising the Bruton's tyrosine kinase signaling nexus in leukaemia
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.
Research grants
Translational Relevance of the Stimulator of Interferon Genes (STING) pathway and viral infection in Follicular Lymphoma
NORTH WEST CANCER RESEARCH INCORPORATING CLATTERBRIDGE CANCER RESEARCH (UK)
February 2023 - February 2026
Bench Fees for Razan Abdulhameed R Aldahhan 201763973
KINGDOM OF SAUDI ARABIA MINISTRY OF EDUCATION (SAUDI ARABIA)
January 2024 - January 2028
Assessing Gas6+ neutrophils in the blood of pancreatic cancer patients undergoing chemotherapy to generate evidence for targeting Gas6/AXL signalling in patients
THE CLATTERBRIDGE CANCER CENTRE NHS FOUNDATION TRUST (UK)
September 2023 - August 2025
Retrospective costing to match research agreement
VERASTEM (USA)
April 2016 - July 2021
Dissecting the biology underpinning pancreatic cancer-associated diabetes
PANCREATIC CANCER UK (UK)
September 2021 - September 2024
Bench fees to support PhD student Anil Mondru
MINISTRY OF SOCIAL JUSTICE AND EMPOWERMENT (INDIA)
February 2015 - January 2018
Kinomic reprogramming during clonal evolution and therapy resistance in chronic lymphocytic leukaemia
LEUKA (UK)
September 2018 - December 2020
Bench fees for Mariah Nawwab Abdullah
ROYAL EMBASSY OF SAUDI ARABIA CULTURAL BUREAU IN LONDON (UK)
October 2017 - September 2020
Kinome profiling and mass cytometry as tools to detect rewiring of B cell receptor signalling in the malignant cells of chronic lymphocytic leukaemia patients taking ibrutinib
NORTH WEST CANCER RESEARCH INCORPORATING CLATTERBRIDGE CANCER RESEARCH (UK)
March 2019 - September 2022
Bench Fees - Miss Alzahra Alshayeb
ROYAL EMBASSY OF SAUDI ARABIA
November 2015 - October 2019
Bench Fees - Taha Yahya T Alqahtani
ROYAL EMBASSY OF SAUDI ARABIA CULTURAL BUREAU IN LONDON (UK)
April 2017 - March 2020
Motility in lymphoma
LYMPHOMA RESEARCH TRUST
June 2014 - March 2015
Determining ibrutinib's potential to treat human leukaemias - novel uses for an exciting new Bruton's tyrosine kinase (TTK) inhibitor
NORTH WEST CANCER RESEARCH FUND
September 2014 - June 2021
PRKCB gene expression and leukaemogenesis in chronic lymphocytic leukaemia
BLOODWISE (UK)
July 2013 - March 2017
Characterising the Bruton's kinase signaling nexus in leukaemia
NORTH WEST CANCER RESEARCH INCORPORATING CLATTERBRIDGE CANCER RESEARCH (UK)
September 2015 - September 2018