Authors: James P B O'Connor, Jessica KR Boult, Yann Jamin, Muhammad Babur, Katherine G Finegan, Kaye J Williams, Ross A Little, Alan Jackson, Geoff J.M. Parker, Andrew R. Reynolds, John C Waterton, and Simon P Robinson
Summary: There is a clinical need for non-invasive 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 (∆R1) changes in proportion to the concentration of molecular oxygen dissolved in plasma or interstitial tissue fluid. Therefore, well-oxygenated tissues show positive ∆RR1. We hypothesized that the fraction of tumor tissue refractory to oxygen challenge (lack of positive ∆RR1, 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 pOR2 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 non-invasively and is immediately translatable to the clinic.
Source:
Cancer Research; (12/09/15)