Abstract 1030: Use of 18F-FDG-PET as a biomarker to demonstrate activity of the novel AKT inhibitor AZD5363 in a xenograft model
Authors: Bales Juliana , Ricketts Sally-Ann , Halliday Jane , Parmar Arvind , Keen Heather , Parker Gareth , Gingles Neill , Dudley Phillippa , Davies Barry 
Published: June 2012

Abstract
Introduction: The PI3K/Akt/PTEN network is the most frequently de-regulated pathway in human cancer. The protein kinase Akt, a key node on this pathway, has been shown to drive proliferation and survival of tumour cells, and also plays a key role in glucose metabolism. Therefore, it is hypothesized that Akt inhibition can be assessed using 18F-flurodeoxyglucose (18F-FDG) positron emission tomography (PET).
The aim of this study was to determine tumour uptake of 18F-FDG 4 hours after an acute dose of AZD5363 or vehicle using a range of doses in the U87-MG xenograft model, the overall goal being to correlate 18F-FDG changes with tumour pharmacodynamics in the absence of any systemic glucose changes.
Materials & Methods: AZD5363 was administered orally at 75, 130, 200 and 300mg/kg. Prior to dosing blood glucose concentration was measured and mice were dosed with either vehicle or AZD5363 4 hours prior to imaging. 18F-FDG was administered as an i.v. bolus under anaesthesia; followed by a 45-minute wash-out period and a 20 minute PET scan. Mice were then sacrificed and blood samples taken for pharmacokinetic (PK) analysis and blood glucose concentration. Tumours were removed and snap frozen for pharmacodynamic analysis and background tissues taken for biodistribution analysis. Image analysis was carried out using Inveon Reconstruction Workplace (IRW) software. Biodistribution data were derived from gamma counting. Decay correction and uptake values were calculated using Microsoft Excel and statistical analysis performed using Graph Pad Prism.
Results: Mean tumour volumes were not statistically different amongst the five groups. There was significantly decreased 18F-FDG uptake (p&lt;0.05) in the tumour in all of the AZD5363 treated groups as a group average compared to vehicle; maxSUV = 4.06 ± 0.41 (SEM) in the vehicle; 3.42 ± 0.23; 3.16 ± 0.16; 3.12 ± 0.18 and 2.66 ± 0.06 (SEM) in the 75, 130, 200 and 300mg/kg groups respectively. There was a significant increase in blood glucose concentration at only the higher doses of 200 and 300mg/kg compared to the vehicle group post-dose (p&lt; 0.05). There was significantly increased 18F-FDG uptake in the blood, lung and liver from biodistribution data at the 300mg/kg treated dose compared to vehicle (p&lt;0.05). Ex-vivo tumour biomarker analyses demonstrated dose-dependent inhibition of PRAS40, GSK3β and S6 phosphorylation in response to AZD5363. Furthermore, AZD5363 resulted in dose-dependent inhibition of tumour growth in this xenograft model.
Conclusions: AZD5363 significantly reduced tumour 18F-FDG uptake at all four doses investigated in U87-MG human glioma xenografts 4 hours after drug administration. This correlated with inhibition of AKT substrate and downstream biomarker phosphorylation in the tumours and was seen at doses that did not cause systemic blood glucose changes. Therefore, 18F-FDG PET has potential as a biomarker for AZD5363 activity in the clinic.
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 1030. doi:10.1158/1538-7445.AM2011-1030