Characterisation and Treatment of Pan-Human Epidermal Receptor Tyrosine Kinase Inhibitor-Induced Gastrointestinal Toxicity

Abstract

The format of my thesis is as follows: two literature reviews, three research chapters, a general discussion, references and appendices. During my candidature, I made a significant effort to publish my research findings. Each chapter is presented in its original publication format, with the exception of spelling changes to keep consistent English spelling, and the references which are listed in the final chapter. This may result in slight repetition between chapters arising from the same study. My thesis has two distinct themes relating to the pathobiology of gastrointestinal toxicity second to targeted cancer treatment. The first theme aims to characterise gastrointestinal toxicity induced by dacomitinib, a pan-human epidermal receptor (HER) tyrosine kinase inhibitor (TKI) associated with high levels of diarrhoea. This theme gives rise to the first four chapters. Chapter 1 was an invited review introducing dacomitinib, highlighting the increasing incidence of gastrointestinal toxicity seen with second generation small molecule HER-TKIs and incorporating basic information required for understanding of subsequent chapters. Chapter 2 is a detailed literature review proposing chloride secretion as a mechanistic hypothesis for development of HER TKI-induced diarrhoea. Chapter 3 is my first original research chapter, which characterised dacomitinib-induced gastrointestinal toxicity in a novel rat model. Chapter 4, my second original research chapter, advances on this characterisation, and introduces crofelemer, a chloride channel blocker as a therapeutic intervention for the prevention of dacomitinib-induced diarrhoea. During my candidature, I had the opportunity to work with Assistant Professor Tom Carney from the Institute of Molecular and Cell Biology (IMCB), Biopolis, Singapore. This collaboration comprises Chapter 5, the second theme of this thesis. This chapter attempted to address the need for an innovative model for the study of gastrointestinal toxicity, investigating transgenic zebrafish reporter lines as a novel model for the study of chemotherapy and targeted therapy-induced gastrointestinal toxicity. Parts of this thesis were funded by Pfizer Pharmaceuticals under an unrestricted investigator-initiated grant (Reference #WI175212). The report I generated for this grant, which partly formed the basis of the publications presented in Chapters 3 and 4, is included as an appendix in this thesis.