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Abstract

There is a clinical need for noninvasive biomarkers of tumor hypoxia for prognostic and predictive studies, radiotherapy planning, and therapy monitoring. Oxygen-enhanced MRI (OE-MRI) is an emerging imaging technique for quantifying the spatial distribution and extent of tumor oxygen delivery in vivo. In OE-MRI, the longitudinal relaxation rate of protons (ΔR1) changes in proportion to the concentration of molecular oxygen dissolved in plasma or interstitial tissue fluid. Therefore, well-oxygenated tissues show positive ΔR1. We hypothesized that the fraction of tumor tissue refractory to oxygen challenge (lack of positive ΔR1, termed "Oxy-R fraction") would be a robust biomarker of hypoxia in models with varying vascular and hypoxic features. Here, we demonstrate that OE-MRI signals are accurate, precise, and sensitive to changes in tumor pO2 in highly vascular 786-0 renal cancer xenografts. Furthermore, we show that Oxy-R fraction can quantify the hypoxic fraction in multiple models with differing hypoxic and vascular phenotypes, when used in combination with measurements of tumor perfusion. Finally, Oxy-R fraction can detect dynamic changes in hypoxia induced by the vasomodulator agent hydralazine. In contrast, more conventional biomarkers of hypoxia (derived from blood oxygenation-level dependent MRI and dynamic contrast-enhanced MRI) did not relate to tumor hypoxia consistently. Our results show that the Oxy-R fraction accurately quantifies tumor hypoxia noninvasively and is immediately translatable to the clinic. 

Author information

O'Connor JP1, Boult JK2, Jamin Y2, Babur M3, Finegan KG3, Williams KJ4, Little RA5, Jackson A5, Parker GJ5, Reynolds AR6, Waterton JC5, Robinson SP2.

1Institute of Cancer Sciences, University of Manchester, Manchester, United Kingdom. Centre for Imaging Sciences, University of Manchester, Manchester, United Kingdom. Department of Radiology, Christie NHS Foundation Trust, Manchester, United Kingdom. james.o'connor@manchester.ac.uk.

2Division of Radiotherapy and Imaging, The Institute of Cancer Research, London, United Kingdom.

3Manchester Pharmacy School, University of Manchester, Manchester, United Kingdom.

4Institute of Cancer Sciences, University of Manchester, Manchester, United Kingdom. Manchester Pharmacy School, University of Manchester, Manchester, United Kingdom.

5Centre for Imaging Sciences, University of Manchester, Manchester, United Kingdom.

6Tumour Biology Team, Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom.