MR Imaging of Hypoxia

Hypoxia is critical in determining therapeutic response and promoting genomic instability in tumours, thereby acting as a potential driver of the complex genetic heterogeneity observed in human cancers. Both hypoxia inducible factor (HIF)-dependent and HIF-independent mechanisms are activated in response to hypoxic stress and these stimulate the growth, maintenance and spread of tumours via various pathways, including up-regulation of vascular endothelial growth factor and promotion of angiogenesis.

Hypoxia has been demonstrated in all solid tumours and is a critical factor in determining both therapy response and tumour progression. Mapping tumour oxygen tension and hypoxia can have significant impact on patient management be that through selecting appropriate treatments or monitoring response. Hypoxia can be measured in a number of ways. :

Biopsy and histological sampling have the drawbacks of being invasive and not providing comprehensive tissue coverage. Imaging approaches are attractive in that they are non-invasive, enable multiple measurements and allow whole tumour mapping.

Oxygen-enhanced magnetic resonance imaging (OE-MRI) is a promising technique for quantifying tissue oxygenation status and tumour hypoxia, which has been developed as a cancer biomarker in Manchester. This work builds on our development of pulmonary OE-MRI, pre-clinical studies of hypoxia in treatment response, and development of histopathological and genetic assays of tumour biology. OE-MRI exploits the fact that oxygen is paramagnetic when dissolved in blood plasma and tissue fluid, thereby affecting the MRI signal by increasing the longitudinal relaxation rate of water protons. This phenomenon is linearly dependent on the partial pressure of oxygen in plasma. Recent improvements in MR scanner hardware and methods have enabled application of OE-MRI to explore oxygen delivery from the lungs, via the blood stream to healthy tissues and to tumours. As the method simply uses medical oxygen and standard MR equipment, with no investigational tracers or devices, it is readily translatable from animal models to humans. Manchester has pioneered much of this research.

OE-MRI is now believed to induce MR signal increases in normoxic tissue and reductions in signal in hypoxic tissue. OE-MRI is, therefore, highly promising for identifying tumour regions that are normoxic or hypoxic, as demonstrated in a recent clinical study of glioblastoma multiforme (GBM) with pre-clinical validation. These mechanisms are different to the blood oxygenation level dependent (BOLD) signal, which is sensitive to oxygen carriage by haemoglobin molecules by altering tissue transverse relaxation rate.

Quantitative OE-MRI measures of tissue oxygenation status and tumour hypoxia require further development, including rigorous pre-clinical validation, implementation in new anatomical locations and assessment of test-retest reproducibility in clinical studies. What is as yet unknown is how OE-MRI relates to other measures of hypoxia, for example, positron emission tomography (PET) using established radiotracers and whether there are subtleties in the “hypoxia” revealed by these methods that would determine subsequent use as clinical biomarkers of treatment response.

Pre-clinical studies will be used to investigate oxygen-enhanced signal change in models of glioma, breast and lung cancer. In these studies, MR measures will be compared to histological measures of hypoxia, vessel density and perfusion, micro-CT measures of vessel geometry and positron emission tomography (PET) measures of hypoxia (18F-FAZA). Collaboration with Cambridge colleagues will investigate how OE-MRI relates to hyperpolarised imaging of lactate and pyruvate and novel hypoxia-biomarkers based on photoacoustic imaging.

In order to assess the potential of OE-MRI as a biomarker of response, we will image tumours at baseline and at several time points following radiotherapy. Imaging parameters will be compared with histology and an exploratory endpoint will determine whether baseline and early changes in imaging parameters relate to tumour growth. A specific focus will be in lung, to evaluate whether OE-MRI is informative of changes in lung function that occur as a consequence of radiation-induced inflammation.

Professor Kaye Williams

Head of the Hypoxia and Therapeutics group in the Manchester Pharmacy School at The University of Manchester.

Dr Corinne Faivre-Finn

Leader of the Radiotherapy in Lung Cancer group in the Institute of Cancer Sciences at The University of Manchester.

Dr James O'Connor

Cancer Research UK Clinician Scientist Fellow at The University of Manchester and Honorary Consultant Radiologist at The Christie NHS Foundation Trust.