The non-Hodgkin lymphomas (NHL) are a heterogeneous group of malignant diseases which account for >13,000 new cancer diagnoses and 4900 deaths in the UK annually. Therefore, identification of novel druggable targets is of clear clinical importance.
Glycogen synthase kinase (GSK)-3 regulates many cellular processes including cell proliferation, and cell differentiation. GSK3 protein levels are higher in NHL cells in comparison to healthy lymphocytes, while pharmacological inhibition of GSK3 leads to apoptosis of lymphoma cells, but not unstimulated mature B or T lymphocytes, suggestive of a GSK3 activity-dependent pathology. Following a Phase 1/2 investigation demonstrating safety and potential efficacy of a GSK3 inhibitor (9-ING-41) in some patients with refractory cancers, further studies are required to determine whether aberrant activity within the GSK3 pathway is a cause or consequence of malignancy, and to identify biomarkers of diagnostic and therapeutic utility.
This project will investigate the mechanism underpinning the efficacy of GSK3 inhibition in lymphoma cell death, and the association between dysregulated GSK3 and lymphomagenesis.
Specifically, it will determine:
1) Is GSK3 specific activity higher in lymphoma, in accordance with reported increases in gene expression, relative to control B- and T-cells? If so, how does this affect phosphorylation of substrates of GSK3?
2) Could tools that classify lymphoma cells by GSK3 pathway status have clinical utility in diagnosis or to monitor treatment outcomes?
3) Why does 9-ING-41 (a GSK3 inhibitor) reduce B- and T-cell proliferation and enhance apoptosis in lymphoma cells but not non-cancerous immune cells?
Applicants to complete the Application form and email to [Email Address Removed] along with a CV and 2 academic references by Monday 22nd March 2021.
First class honours degree, and/or a Masters degree in a relevant discipline. (Non-clinical applicants)
MBChB (clinical applicants)
English language requirements
IELTS minimum overall score of 6.5
Reading 5.5, Listening 5.5, Speaking 5.5 Writing 6.0