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Preclinical Evaluation of Tumour Hypoxia: A Multimodal Imaging Approach for Biomarker Development
[Thesis]. Manchester, UK: The University of Manchester; 2018.
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Abstract
Background: Tumour hypoxia is a common feature of solid tumours and is associated with resistance to chemotherapy and radiotherapy (RT). Consequently hypoxia is an important therapeutic target, but translation of promising hypoxia therapies to the clinic is poor. To overcome this, robust biomarkers that track and quantify changes in tumour hypoxia are needed urgently. This thesis investigated whether the imaging modalities Fluoroazomycin arabinoside ([18F]FAZA) Positron Emission Tomography (PET) and Oxygen-Enhanced Magnetic Resonance Imaging (OE-MRI) known to detect hypoxia, could be exploited to generate functional biomarkers of intratumoural hypoxia that monitor treatment response. It was hypothesised that different imaging biomarkers could interrogate different aspects of hypoxia biology, and differentially track treatment-induced changes in intratumoural hypoxia. Approach: The ability of [18F]FAZA and OE-MRI imaging-derived hypoxic biomarkers to track treatment-induced change were evaluated in Calu-6 non-small cell lung cancer xenografts using the hypoxia-targeted drugs AQ4N and Atovaquone. These drugs have distinct mechanisms of action in reducing hypoxic cell populations; AQ4N becomes cytotoxic in hypoxia and Atovaquone reduces the oxygen consumption of cells. The ability of imaging biomarkers to detect hypoxia was confirmed by cross-validation with histopathology. To further assess the applicability of imaging derived biomarkers, [18F]FAZA PET was used to track response to fractionated RT ± AQ4N. Finally, [18F]FAZA uptake was used to evaluate if a newly developed hypoxic gene signature (specific to sarcoma) could detect hypoxia, and if [18F]FAZA PET derived biomarkers could track the treatment effect of AQ4N in human sarcoma xenografts. Results: A reduction in intratumoural hypoxia caused by AQ4N and Atovaquone could be monitored by [18F]FAZA uptake in the tumour normalised to muscle to give T:M ratios. For OE-MR, hypoxic changes in the tumour could be monitored by changes in the proton longitudinal relaxation rate (R1). T:M ratios and R1â€Â“based biomarkers of hypoxia agreed with histological measurements of hypoxia. In addition, a correlation was observed between baseline T:M ratios and change in intratumoural hypoxia induced by Atovaquone. A change in [18F]FAZA uptake and delayed tumour growth was observed in the RT+ AQ4N cohort relative to the RT alone cohort. Finally, a strong agreement between in vitro-derived gene signature hypoxia scores and in vivo PET-derived measurements of hypoxia was observed in a subset of sarcoma models. Conclusion: [18F]FAZA PET and OE-MRI imaging derived biomarkers can track and quantify treatmentâ€Â“induced changes in intratumoural hypoxia. In addition, T:M ratios may have a potential role in predicting the treatment effect of Atovaquone.