Fig 1.
A single dose of AZD8835 (12.5mg/kg) reduces 18F-FDG uptake and pPRAS40 expression 2 hours after dosing in the BT474C model.
A) tumour 18F-FDG uptake following AZD8835 dosing (individual animal data). *p<0.05. B) Immunohistochemistry pPRAS40 data following AZD8835 dosing (mean ± SEM) a) = representative image at x20 magnification; b) = overlay of image anaylsis:; +#p<0.05 vs vehicle. C) ELISA pPRAS40 data following AZD8835 dosing (mean± SEM). *p<0.05.
Table 1.
18F-FDG uptake in the BT474C xenograft model in background tissues following dosing with AZD8835 (12.5mg/kg) or vehicle.
*p<0.05 vs vehicle.
Fig 2.
Pharmacodynamic knockdown of PI3K pathway activity using 18F-FDG PET is observed 2 hours after dosing in the BT474C model at 12.5, 25 and 50mg/kg.
Tumour 18F-FDG uptake following AZD8835 dosing (individual animal data). (vehicle n = 8; AZD8835 3mg/kg n = 9; AZD8835 6mg/kg n = 9; AZD8835 12.5mg/kg n = 7; AZD8835 25mg/kg n = 8; AZD8835 50mg/kg n = 4). Representative images demonstrate the decrease in 18F-FDG uptake at the highest dose of 50mg/kg compared to vehicle.
Table 2.
18F-FDG uptake in the BT474C xenograft model in background tissues following dosing with AZD8835 (3,6,12.5, 25 and 50mg/kg) or vehicle.
*p<0.05 vs vehicle.
Fig 3.
Pharmacokinetic and Meso Scale Discovery Assay (MSD) data demonstrate a good dose response effect following AZD8835 administration.
A) Plasma pharmacokinetic analysis following AZD8835 dosing. Vehicle treated animals showed no circulating AZD8835; AZD8835 3mg/kg n = 9; AZD8835 6mg/kg; AZD8835 12.5mg/kg n = 7; AZD8835 25mg/kg n = 8; AZD8835 50mg/kg n = 4. B) MSD assay to assess AKT phosphorylation. Data is expressed as the % of phosphorylated AKT to total AKT. Vehicle n = 8; AZD8835 3mg/kg n = 9; AZD8835 6mg/kg n = 9; AZD8835 12.5mg/kg n = 7; AZD8835 25mg/kg n = 8; AZD8835 50mg/kg n = 4
Fig 4.
Pharmacodynamic ELISA and immunohistochemistry (IHC) PRAS40 data demonstrate a good dose response effect following AZD8835 administration.
A) Plasma pharmacodynamic ELISA analysis following AZD8835 dosing. Data is expressed as the volume of phosphorylated AKT to total AKT expressed as a %. Vehicle n = 8; AZD8835 3mg/kg n = 9; AZD8835 6mg/kg; AZD8835 12.5mg/kg n = 7; AZD8835 25mg/kg n = 8; AZD8835 50mg/kg n = 4. B) IHC pharmacodynamic analysis following AZD8835. Vehicle n = 8; AZD8835 3mg/kg n = 9; AZD8835 6mg/kg n = 9; AZD8835 12.5mg/kg n = 7; AZD8835 25mg/kg n = 8; AZD8835 50mg/kg n = 4
Fig 5.
Blood glucose pharmacodynamic data demonstrates a dose response effect following AZD8835 administration with no significant change in glucose homeostasis.
A) Blood glucose concentration before and after dosing with AZD8835/vehicle. Data is expressed as the individual animal data. Vehicle n = 8; AZD8835 3mg/kg n = 9; AZD8835 6mg/kg; AZD8835 12.5mg/kg n = 7; AZD8835 25mg/kg n = 8; AZD8835 50mg/kg n = 4. B) The change in blood glucose concentration following AZD8835/ vehicle dosing. Data is expressed as the mean and individual animal data. Vehicle n = 8; AZD8835 3mg/kg n = 9; AZD8835 6mg/kg n = 9; AZD8835 12.5mg/kg n = 7; AZD8835 25mg/kg n = 8; AZD8835 50mg/kg n = 4.