Development of Robust Multimodal Imaging Biomarkers of the Non-viable Tumour Component for Cancer Drug Development

Abstract

This project was initiated with the objective of obtaining a magnetic resonance imaging (MRI) derived measure of the non-viable cell fraction of a tumour. The word "biomarker" pervades much of the quantitative imaging literature. There exist a variety of imaging parameters which purport to convey information about the underlying pathophysiology. These are generically labelled as "biomarkers", although a review of the literature indicates that there is little, (or often contradictory) evidence to support this assertion. Indeed, the absence of robust validation is in evidence across the broad spectrum of imaging modalities. As the development of novel chemotherapeutic agents progresses from in vitro studies performed in a Petri dish to in vivo animal experiments, treatment efficacy can be gauged by a number of methods, one of which is imaging. Translational imaging offers the opportunity of developing and validating imaging techniques in the preclinical setting, with potential for their adoption into a clinical trial. The Apparent Diffusion Coefficient (ADC) of water proton spins has emerged as a potential "biomarker" of cell death. Two studies were performed to investigate the relationship between ADC and the pathophysiologic changes occurring subsequent to radiotherapy or chemotherapy in preclinical cancer models. Dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) is purported to offer a means of quantifying the non-viable cell fraction through the pharmacokinetic parameter "ve", the extravascular extracellular space volume per unit volume of tissue. Performing a DCE-MRI experiment requires measurements of T1 before and after the administration of a contrast agent. To this end, methods development undertaken included extensive validation experiments to determine the accuracy and reproducibility of the T1 relaxation time for use in a DCE-MRI study. Validation of ADC measurements was performed through the use of a novel ice water phantom designed for a narrow bore preclinical MRI scanner. A means of determining the quantity of contrast agent within a tumour can be performed through the use of ICP-MS (Inductively Coupled Plasma Mass Spectrometry). A validation experiment was performed through the preparation of a phantom of known quantity of contrast agent and comparison against that returned from ICP-MS analysis. This thesis contends that the development of an MRI derived measure of the non-viable cell fraction does not appear viable within the framework of the present pharmacokinetic models and imaging hardware available. The literature fails to address significant confounds in the scientific method, indeed this is in evidence in the variability of observed imaging parameters.

Date of Award	31 Dec 2013
Original language	English
Awarding Institution	The University of Manchester
Supervisor	John Waterton (Supervisor), Kaye Williams (Supervisor) & James O'Connor (Supervisor)