Incorporating advanced imaging into the treatment of brain tumours

This thesis centres around how we can better understand brain tumours through imaging and in so doing improve our treatment of them. It focuses on glioblastoma (GBM)- the most aggressive primary brain tumour. During my candidature, I explored how imaging can help us discover new treatment strategies, understand treatment resistance and how imaging could indeed become the treatment; a branch of medicine now called theranostics.Chapter one reviews the current state of the art in brain tumour imaging covering computed tomography (CT), structural magnetic resonance imaging (MRI) and then outlines the available positron emission tomography (PET) tracers used in brain tumours. This chapter highlights the pros and cons of these current approaches which lead into my rationale, research aims and hypotheses for my project.Having outlined the shortcomings of MRI and CT imaging in chapter one; chapter two (Advanced imaging in a clinical trial setting for glioblastoma) presents the imaging platform that was designed using F-DOPA with the aim to better visualise GBM tumours in patients. I went on to outline the potential benefit of valproate (a radiosensitiser and histone deacetylase inhibitor) in human cell line experiments. I used the imaging as a platform to test the efficacy of sodium valproate in a clinical trial of adjuvant treatment in patients with glioblastoma.There is a building evidence base suggesting that hypoxia (low oxygen levels) within GBM tumours are a major contributor to treatment resistance. Chapter three (VPA, hypoxia and treatment resistance in glioblastoma) deals with the issue of tumour hypoxia which arose as a significant issue out of our clinical study of glioblastoma and the effect of valproate. Importantly it correlates hypoxia with an adverse tumour micro-environment and the effect on treatment resistance and mutation.2,3For the development of new treatments for GBM; Chapter four turned to tissue culture models of GBM. There was a need to develop a rapid throughput method of screening with radiotherapy. To develop this research a critical piece of research equipment – a mobile laboratory irradiator was developed to study the effects of radiation on brain tumour cell lines in vitro.During my candidature, evidence from my collaborators had shown that Ephrin type-A receptor 2 (EphA2), a receptor tyrosine kinase, was overexpressed in GBM tumours making it a potential theranostic target for treatment of patients.4 With the mobile laboratory irradiator established chapter four takes this possible EphA2 theranostic antibody into the radiobiology lab and examines the possibility of direct effects of this antibody on killing GBM cell lines.Chapter five (Advanced Imaging and Theranostics) takes this further and reviews the state of the art with regard to PET tracers and introduces the concept of theranostics. The paper extends the discussion by outlining the potential for this technology in drug development.Finally, chapter six (Conclusion and Future Directions) presents the final thesis discussion, bringing together the chapters in light of the current literature, the limitations of my studies and their future directions. It concludes with imaging becoming therapy - the development of theranostics in brain tumours.There are therefore a number of strands involved in this PhD as it spans the spectrum from laboratory cell culture work to a human clinical trial. The common hypothesis underlying is that improving the assessment of brain tumours with advanced imaging can give us insights into treatment resistance and significantly improve the way we treat patients in the future.