Elucidating the role of mTOR kinase in chronic lymphocytic leukaemia cell migration

Holroyd, Ailsa (2019) Elucidating the role of mTOR kinase in chronic lymphocytic leukaemia cell migration. PhD thesis, University of Glasgow.

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Abstract

Chronic lymphocytic leukaemia is a mature B cell neoplasm which, despite recent focused research attention, remains incurable. It is the commonest leukaemia in the Western world and affects around 3,500 patients per annum in the UK and with the median age of those diagnosed at around 70 years it poses a specific challenge in disease management with standard chemoimmunotherapy being potentially too toxic for many patients. Treatments targeting the B cell receptor (BCR)-mediated signals including ibrutinib and idelalisib which target BTK and PI3K respectively, have pronounced clinical effects with improvement in progression-free and overall survival for significant patient numbers and are becoming more widely available. However, issues of disease resistance mutations and clonal evolution leave scope for novel targets of BCR and related signalling pathways. My hypothesis is that the serine/threonine protein kinase mechanistic target of rapamycin (mTOR) signalling which is located downstream of BTK and PI3K and downstream of BCR signalling offers a promising therapeutic target in CLL and may complement existing therapies that have proven clinical efficacy. Furthermore, dual mTORC1/2 inhibition offers a potential mechanism for overcoming the negative feedback loop which internally regulates mTOR kinase thus may offer potential for an improvement on the mTORC1 inhibitors already tested in clinical trial.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Keywords: chronic lymphocytic leukaemia, AZD8055, rapamycin, mTOR kinase inhibition, B cell receptor signalling, chemokine signalling, lymphocyte migration.
Colleges/Schools: College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences > Paul O'Gorman Leukemia Research Centre
Funder's Name: The Kay Kendall Leukaemia Fund (KENDALL)
Supervisor's Name: Michie, Dr. Alison M.
Date of Award: 2019
Depositing User: Dr Ailsa K Holroyd
Unique ID: glathesis:2019-73049
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 11 Jun 2019 10:41
Last Modified: 11 Jun 2019 10:43
URI: http://theses.gla.ac.uk/id/eprint/73049

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