BAY 87–2243 is a novel small molecule inhibitor of hypoxia inducible factor-1α (HIF-1α) activity. Preclinical studies with BAY 87–2243 in a number of murine tumor models showed moderate to high tumor growth inhibition. The present study describes a non-invasive positron emission tomographic (PET) imaging method that monitors early therapeutic efficacy of this drug. To identify optimal tracer(s) for monitoring BAY 87–2243 anti-tumor activity, female nude mice were implanted on both scapulae with either 3.5×106 human non-small cell lung cancer (H460) or 2×106 human prostate cancer cells (PC3). Both are growth-inhibited by BAY 87–2243. Xenografts were grown to 200 mm3 over 10 days. Four PET tracers were assessed for uptake into tumor xenografts: 18F-FDG, 18F-FPP(RGD)2, 18F-FLT and 18F-FAZA. Tracers were injected via the tail vein. After pre-scan, BAY 87–2243 was orally administered, daily at 9mg/kg to 7 days. Tracer uptake was examined 1 and 3 day(s) after initial administration. Each treatment group for each PET tracer tested consisted of 6 tumors in 3 animals. At each imaging time point, RNA from BAY 87–2243-treated and vehicle-treated H460 tumor xenografts (3 additional animals each) was isolated. HIF target genes were quantified by Real-Time polymerase chain (RT-PCR) reaction. For both 18F-FDG and 18F-FPP(RGD)2, uptake was not significantly altered. However, 18F-FAZA tumor uptake (%ID mean/g) declined by 55–70% (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) models at both 1 and 3 days after drug administration. The decline occurred before any significant difference in tumor volume between drug- and vehicle-treated animals was observed, thus suggesting that decline in 18F-FAZA uptake reflected early changes in tumor biochemistry. A similar observation was noted for 18F-FLT in the H460 model, although the decline was less pronounced (30%; p<0.05 for all time-points). Analysis of HIF target gene expression by RT-PCR revealed that BAY 87–2243 reduced expression of the hypoxia regulated genes CA IX and ANGPTL4 by 99 % and 93 % respectively (p<0.001 for both) which corresponds with reduced 18F-FAZA uptake upon drug treatment. Reduced 18F-FLT uptake was not accompanied by reduced expression of TK1. Expression level of genes associated with glucose metabolism was heterogeneous and did not fully match with unchanged 18F-FDG uptake: GLUT-1 expression was unchanged while HK-2 decreased by 75 % (p<0.01). We detected low ITGB3 expression in untreated xenografts but were unable to detect transcripts after BAY 87–2243 treatment. This findings may explain the lack of change in 18F-FPP(RGD)2 uptake. In conclusion, our pilot studies suggest the suitability of 18F-FAZA-PET to monitor the efficacy of anti-cancer agents targeting the HIF pathway (e.g. BAY 87–2243) as an early PD marker prior to changes in tumor volume

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-147. doi:10.1158/1538-7445.AM2011-LB-147