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

chronic lymphocytic leukaemia, AZD8055, rapamycin, mTOR kinase inhibition, B cell receptor signalling, chemokine signalling, lymphocyte migration.

Holroyd, Ailsa ; The Kay Kendall Leukaemia Fund (KENDALL) ; Michie, Alison M.

University:University of Glasgow

Department:Institute of Cancer Sciences

关键词: chronic lymphocytic leukaemia, AZD8055, rapamycin, mTOR kinase inhibition, B cell receptor signalling, chemokine signalling, lymphocyte migration.;   

Others  :  http://theses.gla.ac.uk/73049/1/2019HolroydPhD.pdf

来源: University of Glasgow

【 摘 要 】

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.