Targeting aberrant kinase activity in myeloid leukaemias

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.

Revisiting Irish poetic modernisms

This thesis discusses Irish Modernist poetry written between 1905 and 1970, specifically the poetry of Joseph Campbell (1879-1944), Thomas MacGreevy (1893-1967), Denis Devlin (1908-1959) and Brian Coffey (1905-1995). All four poets have been largely neglected in criticism until a growth of interest encouraged by Michael Smith and Trevor Joyce’s New Writers’ Press during the 1970s. J.C.C. Mays, Stan Smith, Susan Schreibman, Terence Brown, Patricia Coughlan and Alex Davis published subsequent critical support during the ‘80s and ‘90s. My research aims to highlight poetry previously omitted from the canon of Irish literature, those with connections to British or continental European literary movements as well as poetry by women writers and writers from the North. Part of this exploration of Irish Poetic Modernisms involves an investigation of intersections between poetic modernisms and Irish war poetry and of depictions of Irish masculinity in the poetry of Devlin and Coffey. My discussion of Campbell’s poetry focuses on links between the early regional modernism of his poetry and later Irish modernist poetry, including his participation in the Ulster Literary Theatre, with the Literary Revival community in Dublin and his association with the proto-Imagist movement in London. My examination of connections between Irish war poetry and Irish modernism allows me to discuss the writing of several underrecognized Irish poets who are contemporaries and near contemporaries of the main subjects of my thesis. Thomas MacGreevy’s poetry is the most clear case study of the links between Irish modernist poetry and poetry about Ireland’s participation in the Great War. MacGreevy’s writing reveals his multiple allegiances: he both elegizes and challenges the increasing cultural inhibitions of Free State Ireland. Denis Devlin’s poetic portrayals of Ireland reveal his rejection both of the Literary Revival’s fascination with Celticism and of Dublin’s literary community while upholding tradition poetic gender roles. My research explores representations of masculinity and Irish politics, including heroic masculine imagery, in the long poems of Devlin and Coffey. My discussion of Brian Coffey considers the importance of the figure of the “poet as maker” to his writing and his relationship with Ireland during his long writing career. I also consider his role as the editor and executor of Devlin’s literary estate and the impact that had on both the latter’s posthumous reputation and Coffey’s later writing.