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


METHODS
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).
Department of Radiology, Molecular Imaging Program at Stanford, Canary Center for Early Cancer Detection, Stanford University, Palo Alto, California.
Edwin
E
Chang
Department of Radiology, Molecular Imaging Program at Stanford, Canary Center for Early Cancer Detection, Stanford University, Palo Alto, California.
Hongguang
H
Liu
Bayer Pharma AG, Global Drug Discovery, Wuppertal, Germany.
Kerstin
K
Unterschemmann
Bayer Pharma AG, Global Drug Discovery, Wuppertal, Germany.
Peter
P
Ellinghaus
Department of Radiology, Molecular Imaging Program at Stanford, Canary Center for Early Cancer Detection, Stanford University, Palo Alto, California.
Shuanglong
S
Liu
Bayer Pharma AG, Global Drug Discovery, Berlin, Germany.
Volker
V
Gekeler
Department of Radiology, Molecular Imaging Program at Stanford, Canary Center for Early Cancer Detection, Stanford University, Palo Alto, California.
Zhen
Z
Cheng
Bayer Pharma AG, Global Drug Discovery, Berlin, Germany.
Dietmar
D
Berndorff
Department of Radiology, Molecular Imaging Program at Stanford, Canary Center for Early Cancer Detection, Stanford University, Palo Alto, California. sgambhir@stanford.edu.
Sanjiv S
SS
Gambhir
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D015224:Dideoxynucleosides / Q000493:pharmacokinetics; D005260:Female; D019788:Fluorodeoxyglucose F18 / Q000493:pharmacokinetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D008819:Mice, Nude; D009593:Nitroimidazoles / Q000493:pharmacokinetics*; D010069:Oxadiazoles / Q000494:pharmacology / Q000627:therapeutic use*; D049268:Positron-Emission Tomography; D011471:Prostatic Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000473:pathology; D011720:Pyrazoles / Q000494:pharmacology / Q000627:therapeutic use*; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics*; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
C000591541:1-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; D000970:Antineoplastic Agents; D015224:Dideoxynucleosides; D009593:Nitroimidazoles; D010069:Oxadiazoles; D011720:Pyrazoles; D019275:Radiopharmaceuticals; D019788:Fluorodeoxyglucose F18; C498052:fluoroazomycin arabinoside; C002854:alovudine