American Association for Cancer Research
10780432ccr140217-sup-124977_3_supp_2679020_ncmdm3.pptx (64.81 kB)

Supplemental Figure S5 from 18F-FAZA PET Imaging Response Tracks the Reoxygenation of Tumors in Mice upon Treatment with the Mitochondrial Complex I Inhibitor BAY 87-2243

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posted on 2023-03-31, 19:02 authored by Edwin Chang, Hongguang Liu, Kerstin Unterschemmann, Peter Ellinghaus, Shuanglong Liu, Volker Gekeler, Zhen Cheng, Dietmar Berndorff, Sanjiv S. Gambhir

Supplemental Figure S5. Bar graphs showing effect of BAY 87-2243 on RT-PCR expression profiles for (A) SLC16A, (B) ITGB1, (C) IGF-2 and (D) TK-1



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 [18F-FDG, 18F-Fpp(RGD)2, 18F-FLT, and 18F-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 18F-FAZA, 18F-FLT, and 18F-Fpp(RGD)2 (P < 0.01) occurred with BAY 87-2243 treatment with 18F-FAZA being the most prominent. 18F-FDG uptake was unaffected. 18F-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. 18F-FAZA uptake in 786-0 xenografts was unaffected. Decline occurred before significant differences in tumor volume, thus suggesting 18F-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 18F-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 18F-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). Clin Cancer Res; 21(2); 335–46. ©2014 AACR.