An investigation into the role of receptor tyrosine kinases in childhood Acute Lymphoblastic Leukaemia

Wilson, Shaun Robert (2014). An investigation into the role of receptor tyrosine kinases in childhood Acute Lymphoblastic Leukaemia. University of Birmingham. Ph.D.

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Abstract

Deregulation of tyrosine kinases has been implicated in Philadelphia chromosome negative Acute Lymphoblastic Leukaemia (ALL) with a higher risk of relapse. The studies in this thesis sought to identify potential receptor tyrosine kinase targets and to explore the use of tyrosine kinase inhibitors (TKIs) in childhood ALL.

Initial work describes the baseline receptor tyrosine kinase profiles of 18 primary ALLs. Alterations in the phosphorylation signals of Axl, EphA2, EphB2, FGFR2, FLT3, Mer and PDGFRβ were identified and associated with clinical and biological features.

Subsequently, 5 ALL cell lines and a panel of 20 primary samples representative of common biological features were screened for sensitivity to a library of TKIs. Significant heterogeneity in sensitivity was observed in the panel of leukaemia cells. No correlation was evident between response to TKIs and current clinical or biological stratification parameters in the primary cell panel.

Two candidate inhibitors, dovitinib and foretinib, were taken forward for further preclinical work. Potent nanomolar activity was demonstrated in cell lines and primary ALL. The combination of dovitinib or foretinib with conventional cytotoxics demonstrated significant synergy and sensitised steroid – resistant cell lines to dexamethasone. Objective responses were not identified to single agent TKI therapy in a murine primagraft model.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):