Evaluating MRI biomarkers of tumour hypoxia

Abstract

Tumour hypoxia is associated with resistance to radiotherapy and chemotherapy, and represents a major challenge in the treatment of head and neck squamous cell carcinoma (HNSCC). Non-invasive imaging methods to repeatedly and rapidly quantify the degree and spatial distribution of hypoxia would offer clinical benefit. This thesis focusses on the evaluation of oxygen-enhanced magnetic resonance imaging (OE-MRI) for mapping and quantifying hypoxia in HNSCC xenografts in vivo. OE-MRI relies on the quantification of changes in the longitudinal MRI relaxation rate R1, induced by excess paramagnetic oxygen molecules dissolved in blood plasma and interstitial fluid with inhalation of oxygen. A refined OE-MRI protocol was first developed, designed to incorporate susceptibility MRI in the same imaging session, thereby providing measurements of tumour R1 and R2 during air and 100% O2 breathing, and fractional blood volume (fBV) using ultrasmall superparamagnetic iron oxide particles. MRI biomarkers were validated through comparison with image-aligned tissue sections stained for the hypoxia marker pimonidazole, and the perfusion marker Hoechst 33342. Susceptibility MRI revealed that hyperoxia-induced DR2*O2-air inversely correlated with pimonidazole-derived hypoxic fraction, and fBV positively correlated with Hoechst 33342 uptake. Parcellation of the voxelwise DR2*O2-air identified voxels non-responsive to hyperoxia that may inform on cycling hypoxia. OE-MRI showed that both tumour sub-volumes refractory to hyperoxia induced changes in R1 (OxyR), and perfused OxyR (pOxyR) were associated with an extensive and heterogeneous distribution of hypoxia across the HNSCC xenografts. Both OxyR positively correlated with pimonidazole-derived hypoxic fraction, suggesting that binerisation of hyperoxia-induced DR1 data with a perfusion mask may not be necessary in strongly hypoxic tumours such as HNSCC. Finally, the potential utility of OE-MRI for monitoring tumour response to the hypoxia-alleviating drug atovaquone was investigated. OE-MRI can identify and quantify hypoxia in HNSCC and could provide an easily translatable imaging tool for patient stratification and treatment management.