Can PET hypoxia tracers predict radioresistance?

Objectives PET imaging of hypoxia could be useful in predicting resistance to radiotherapy, but it is not clear whether the oxygen tension (pO₂) at which cells “switch” from low to high tracer uptake match that at which they “switch” from radiation sensitive to resistant. The aim of this study was to directly compare the dependence of tracer uptake (Cu-64 complexes of ATSM and new ligands ATS, ATSE, DTS, DTSE, DTSM, and F-18-FMISO), radiosensitivity, pimonidazole binding, and HIF1-α expression on pO₂. HIF1 expression has been shown to influence overall tumor radioresponsiveness.

Methods Experiments were performed in HCT116 and MCF-7 cancer cell lines using a single hypoxia apparatus using the same method of inducing hypoxia, a consistent unit of measurement and one type of pO₂ sensor. Radiosensitivity was assessed by clonogenic assay, tracer uptake by gamma counting, pimonidazole binding by flow cytometry and HIF1-α levels by Western blotting.

Results Radioresistance started to occur below a pO₂ of 25 mmHg, with maximal resistance at 0 mmHg. Pimonidazole binding showed a sharp increase below 25 mmHg reaching a plateau at 10 mmHg. HIF1-α rapidly increased as pO₂ dropped below ~20 mm Hg reaching a maximum at a pO₂ sensor reading of -0.1 mm Hg. All tracers showed significant uptake only at pO₂ levels << 2 mm Hg.

Conclusions Radiotracer uptake increased only at extreme hypoxia, well below the pO₂ at which radioresistance became significant. Thus a considerable fraction of radioresistant, HIF1-expressing and pimonidazole-binding cells will not take up tracer because they are not hypoxic enough. New tracers are needed whose uptake/pO₂ profile better matches the radioresistance profile in order to predict radioresistance or provide a surrogate biomarker for HIF1 expression.

Research Support KCL-UCL CCIC funded by Cancer Research UK (CRUK) & EPSRC, in association with the MRC and the Department of Health (England). NIHR comprehensive Biomedical Research Centre award to Guy’s & St Thomas’ NHS Foundation Trust in partnership with KCL and King’s College Hospital NHS Foundation Trust.CRUK fellowship (KC)