Targeting aberrant kinase activity in myeloid leukaemias

Kelly, Kevin R.

Targeting aberrant kinase activity in myeloid leukaemias

dc.check.embargoformat	Not applicable	en
dc.check.info	No embargo required	en
dc.check.opt-out	Not applicable	en
dc.check.reason	No embargo required	en
dc.check.type	No Embargo Required
dc.contributor.advisor	Cahill, Mary R.	en
dc.contributor.advisor	Giles, Francis J.	en
dc.contributor.advisor	Carew, Jennifer S.	en
dc.contributor.author	Kelly, Kevin R.
dc.date.accessioned	2013-08-22T14:38:47Z
dc.date.available	2013-08-22T14:38:47Z
dc.date.issued	2013
dc.date.submitted	2013
dc.description.abstract	Acute myeloid leukaemia (AML) is the most common form of acute leukaemia in adults. Its treatment has remained largely unchanged for the past 30 years. Chronic myeloid leukaemia (CML) represents a tremendous success story in the era of targeted therapy but significant challenges remain including the development of drug resistance and disease persistence due to presence of CML stem cells. The Aurora family of kinases is essential for cell cycle regulation and their aberrant expression in cancer prompted the development of small molecules that selectively inhibit their activity. Chapter 2 of this thesis outlines the efficacy and mechanism of action of alisertib, a novel inhibitor of Aurora A kinase, in preclinical models of CML. Alisertib possessed equipotent activity against CML cells expressing unmutated and mutated forms of BCR-ABL. Notably, this agent retained high activity against the T315I and E255K BCR-ABL mutations, which confer the greatest degree of resistance to standard CML therapy. Chapter 3 explores the activity of alisertib in preclinical models of AML. Alisertib disrupted cell viability, diminished clonogenic survival, induced expression of the forkhead box O3 (FOXO3a) targets p27 and BCL-2 interacting mediator (BIM), and triggered apoptosis. A link between Aurora A expression and sensitivity to ara-C was established. Chapter 4 outlines the role of the proto-oncogene serine/threonine-protein (PIM) kinases in resistance to ara-C in AML. We report that the novel small molecule PIM kinase inhibitor SGI-1776 disrupted cell viability and induced apoptosis in AML. We establish a link between ara-C resistance and PIM over-expression. Finally, chapter 5 explores how the preclinical work outlined in this thesis may be translated into clinical studies that may lead to novel therapeutic approaches for patients with refractory myeloid leukaemia.	en
dc.description.status	Not peer reviewed	en
dc.description.version	Accepted Version
dc.format.mimetype	application/pdf	en
dc.identifier.citation	Kelly, K.R. 2013. Targeting aberrant kinase activity in myeloid leukaemias. PhD Thesis, University College Cork.	en
dc.identifier.endpage	409
dc.identifier.uri	https://hdl.handle.net/10468/1230
dc.language.iso	en	en
dc.publisher	University College Cork	en
dc.rights	© 2013, Kevin Kelly	en
dc.rights.uri	http://creativecommons.org/licenses/by-nc-nd/3.0/	en
dc.subject	Leukaemia	en
dc.subject	Aurora kinases	en
dc.subject	PIM kinases	en
dc.subject	Drug resistance	en
dc.subject.lcsh	Leukemia	en
dc.subject.lcsh	Cancer--Chemotherapy	en
dc.thesis.opt-out	false	*
dc.title	Targeting aberrant kinase activity in myeloid leukaemias	en
dc.type	Doctoral thesis	en
dc.type.qualificationlevel	Doctoral	en
dc.type.qualificationname	PhD (Medicine and Health)	en
ucc.workflow.supervisor	maryr.cahill@hse.ie	*