Abstract
Abstract Introduction: mTOR is a a sensor of mitogen, energy and nutrient levels and a central controller of cell growth. mTOR is present in two multi-protein complexes: mTORC1, rapamycin sensitive and containing raptor, and mTORC2, rapamycin-insensitive. AZD8055 is a small molecule ATP competitive inhibitor of mTOR kinase, thus inhibiting both mTORC1 and mTORC2. This results in a greater reduction of mTORC1 substrates pS6 on Ser235/236 and p4EBP1 on T37/46 compared to rapamycin. AZD8055 also reduces the mTORC2 substrate pAKT on Ser473. The PI3K-AKT-mTOR pathway is involved in glucose uptake/metabolism. 18F-Flurodeoxyglucose (18F-FDG) is a biomarker for glucose metabolism detectable by positron emission tomography (PET). It is used in clinical oncology for tumor diagnosis and is currently under evaluation for therapy monitoring. The aim of this study was to assess the impact of a single and 4 daily dosing of AZD8055 on 18F-FDG uptake in U87-MG human glioma xenografts implanted subcutaneously in nude mice. Methods: AZD8055 was administered orally at a dose of 20 mg/kg qd for 1 or 4 days. Animals received either vehicle or AZD8055 1 hour prior to imaging. Mice were anaesthetised and then injected with approximately 15 MBq 18F-FDG i.v. via the tail vein. Forty-five minutes later, mice underwent PET scanning (20 minute scan, 3D histogramming and OSEM2D reconstruction) followed by biodistribution analysis. Image analysis was carried out using Inveon Research Workplace (IRW) software. Biodistribution data were derived from gamma counting. Results: Plasma drug concentrations were not modified significantly by anesthesia and the imaging procedure. In the vehicle and AZD8055-treated groups, tumor volumes were comparable after single dose, but differed significantly following 4 days of treatment due to drug effect. Image analysis of 18F-FDG uptake after single and multiple doses showed that there was a significant difference (p<0.05) in meanSUV, maxSUV and the percentage of injected dose per gram of tissue (%ID/g) between vehicle and drug treated tumors. Biodistribution analysis showed that the average 18F-FDG %ID/g in vehicle-treated tumors was significantly higher than in AZD8055-treated tumors (p<0.05). The changes in glucose uptake after 1 and 4 administrations were consistent with the pharmacodynamic effects of AZD8055 on pS6 and pAKT biomarkers in U87-MG tumors collected at the same time-points. Conclusions: AZD8055 reduces significantly 18F-FDG uptake in U87-MG human glioma xenografts, as early as 1 hour after a single dose. This data suggests that 18F-FDG uptake could be used as an early sign of metabolic response to AZD8055. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A225.
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