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

Abstract

PURPOSE:

The purpose of this study was to characterize imaging biomarkers for the potential benefit of hypoxia-inducible factor-1 (HIF-1)α inhibition (by PX-12) during 5-fluorouracil (5-FU) chemotherapy in the treatment of colorectal cancer (CRC).

PROCEDURES:

Therapy response to 5-FU ± PX-12 was assessed with baseline [(18)F]fluoromisonidazole ([(18)F]FMISO) and longitudinal 2-deoxy-2-[(18)F]fluoro-D-glucose ([(18)F]FDG) positron emission computed tomography (μPET/CT) in CRC xenograft model (n = 36) during breathing of a hypoxic (10 % O2) or normoxic (21 % O2) atmosphere. Ex vivo, immunohistochemistry was performed.

RESULTS:

Baseline [(18)F]FMISO uptake and relative tumor volume (RTV) 2 days after 5-FU or 5-FU + PX-12 administration correlated significantly (p ≤ 0.01). Under hypoxic breathing conditions, [(18)F]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, [(18)F]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.

CONCLUSION:

Baseline [(18)F]FMISO μPET may predict the beneficial effect of HIF-1α inhibition during 5-FU chemotherapy in CRC.

• Authors: Sven De Bruycker, Christel Vangestel, Tim Van den Wyngaert, Leonie Wyffels, An Wouters, Patrick Pauwels, Steven Staelens, Sigrid Stroobants
• Journal: Molecular imaging and biology (Mol Imaging Biol) Vol. 18 Issue 4 Pg. 606-16 (08 2016) ISSN: 1860-2002 [Electronic] United States
• PMID: 26728163 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Biomarkers, Tumor
• Fluorine Radioisotopes
• Hypoxia-Inducible Factor 1, alpha Subunit
• fluoromisonidazole
• Misonidazole
• Fluorouracil

Topics

• Animals
• Biomarkers, Tumor (metabolism)
• Cell Line, Tumor
• Colorectal Neoplasms (diagnostic imaging, drug therapy)
• Female
• Fluorine Radioisotopes
• Fluorouracil (therapeutic use)
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (antagonists & inhibitors, metabolism)
• Immunohistochemistry
• Mice, Nude
• Misonidazole (analogs & derivatives, chemistry)
• Positron-Emission Tomography (methods)
• Reproducibility of Results
• Xenograft Model Antitumor Assays