Baseline [18F]FMISO μPET as a Predictive Biomarker for Response to HIF-1α Inhibition Combined with 5-FU Chemotherapy in a Human Colorectal Cancer Xenograft Model

The purpose of this study was to characterize imaging biomarkers for the potential benefit of hypoxia-inducible factor-1 (HIF-1)alpha inhibition (by PX-12) during 5-fluorouracil (5-FU) chemotherapy in the treatment of colorectal cancer (CRC). Therapy response to 5-FU +/- PX-12 was assessed with baseline [F-18]fluoromisonidazole ([F-18]FMISO) and longitudinal 2-deoxy-2-[F-18]fluoro-d-glucose ([F-18]FDG) positron emission computed tomography (mu PET/CT) in CRC xenograft model (n = 36) during breathing of a hypoxic (10 % O-2) or normoxic (21 % O-2) atmosphere. Ex vivo, immunohistochemistry was performed. Baseline [F-18]FMISO uptake and relative tumor volume (RTV) 2 days after 5-FU or 5-FU + PX-12 administration correlated significantly (p a parts per thousand currency signaEuro parts per thousand 0.01). Under hypoxic breathing conditions, [F-18]FDG uptake (-53.1 +/- 8.4 %) and Ki67 expression (-16 %) decreased and RTV stagnated in the 5-FU + PX-12 treatment group, but not in 5-FU alone-treated tumors. Under normoxic breathing, [F-18]FDG uptake (-23.5 +/- 15.2 % and -72.8 +/- 7.1 %) and Ki67 expression (-5 % and -19 %) decreased and RTV stagnated in both the 5-FU and the combination treatment group, respectively. Baseline [F-18]FMISO mu PET may predict the beneficial effect of HIF-1 alpha inhibition during 5-FU chemotherapy in CRC.