18F-FAZA PET imaging response tracks the reoxygenation of tumors in mice upon treatment with the mitochondrial complex I inhibitor BAY 87-2243.

Abstract

PURPOSE:

We describe a noninvasive PET imaging method that monitors early therapeutic efficacy of BAY 87-2243, a novel small-molecule inhibitor of mitochondrial complex I as a function of hypoxia-inducible factor-1α (HIF1α) activity.

EXPERIMENTAL DESIGN:

Four PET tracers [(18)F-FDG, (18)F-Fpp(RGD)2, (18)F-FLT, and (18)F-FAZA] were assessed for uptake into tumor xenografts of drug-responsive (H460, PC3) or drug-resistant (786-0) carcinoma cells. Mice were treated with BAY 87-2243 or vehicle. At each point, RNA from treated and vehicle H460 tumor xenografts (n = 3 each) was isolated and analyzed for target genes.

RESULTS:

Significant changes in uptake of (18)F-FAZA, (18)F-FLT, and (18)F-Fpp(RGD)2 (P < 0.01) occurred with BAY 87-2243 treatment with (18)F-FAZA being the most prominent. (18)F-FDG uptake was unaffected. (18)F-FAZA tumor uptake declined by 55% to 70% (1.21% ± 0.10%ID/g to 0.35 ± 0.1%ID/g; n = 6, vehicle vs. treatment) in both H460 (P < 0.001) and PC3 (P < 0.05) xenografts 1 to 3 days after drug administration. (18)F-FAZA uptake in 786-0 xenografts was unaffected. Decline occurred before significant differences in tumor volume, thus suggesting (18)F-FAZA decrease reflected early changes in tumor metabolism. BAY 87-2243 reduced expression of hypoxia-regulated genes CA IX, ANGPTL4, and EGLN-3 by 99%, 93%, and 83%, respectively (P < 0.001 for all), which corresponds with reduced (18)F-FAZA uptake upon drug treatment. Heterogeneous expression of genes associated with glucose metabolism, vessel density, and proliferation was observed.

CONCLUSIONS:

Our studies suggest suitability of (18)F-FAZA-PET as an early pharmacodynamic monitor on the efficacy of anticancer agents that target the mitochondrial complex I and intratumor oxygen levels (e.g., BAY 87-2243).

• Authors: Edwin Chang, Hongguang Liu, Kerstin Unterschemmann, Peter Ellinghaus, Shuanglong Liu, Volker Gekeler, Zhen Cheng, Dietmar Berndorff, Sanjiv S Gambhir
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 21 Issue 2 Pg. 335-46 (Jan 15 2015) ISSN: 1557-3265 [Electronic] United States
• PMID: 25381339 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2014 American Association for Cancer Research.

Chemical References

• 1-cyclopropyl-4-(4-((5-methyl-3-(3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)-1H-pyrazol-1-yl)methyl)pyridin-2-yl)piperazine
• Antineoplastic Agents
• Dideoxynucleosides
• Nitroimidazoles
• Oxadiazoles
• Pyrazoles
• Radiopharmaceuticals
• Fluorodeoxyglucose F18
• fluoroazomycin arabinoside
• alovudine

Topics

• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Cell Hypoxia
• Cell Line, Tumor
• Dideoxynucleosides (pharmacokinetics)
• Female
• Fluorodeoxyglucose F18 (pharmacokinetics)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Male
• Mice, Nude
• Nitroimidazoles (pharmacokinetics)
• Oxadiazoles (pharmacology, therapeutic use)
• Positron-Emission Tomography
• Prostatic Neoplasms (diagnostic imaging, drug therapy, pathology)
• Pyrazoles (pharmacology, therapeutic use)
• Radiopharmaceuticals (pharmacokinetics)
• Tumor Burden (drug effects)
• Xenograft Model Antitumor Assays