Initial Testing (Stage 1) of the Akt Inhibitor GSK690693 by the Pediatric Preclinical Testing Program

Background GSK690693 is a small molecule ATP competitive inhibitor of the pro survival kinase Akt Since Akt regulates multiple downstream targets including transcription factors, glycogen synthase 3 the pro apoptotic protein Bid is well as MDM2 and mTORC1, it was tested against the in vitro and in vivo panels of the Pediatric Preclinical Testing Program (PPTP) Procedures GSK690693 was tested in vitro at concentrations from 1 nM to 10 mu M and against the in vivo panel of xenografts at a dose of 30 mg/kg daily x 5 for 6 consecutive weeks Three measures of in vivo antitumor activity were used (1) an objective response measure modeled after the clinical setting (2) a treated to control (TIC) tumor volume measure and (3) a time to event measure based on the median event free survival (EFS) of treated and control animals for each xenograft Results GSK690693 inhibited cell growth in vitro with IC50 values between 6 5 nM and >10 mu M In vivo GSK690693 significantly increased EFS in 11 of 34 (32%) solid tumor xenografts most notably in all 6 osteosarcoma models but not in any of the 8 ALL xenografts tested No objective responses were observed and only one solid tumor met EFS TIC criteria for intermediate activity Conclusions GSK690693 demonstrated broad activity in vitro, how ever our results against both the solid tumor and ALL PPTP in vivo panels demonstrate that, as single agent at the dose and schedule used GSK690693 has only modest antitumor activity Pediatr Blood Cancer 2010 55 1329-1337 (C) 2010 Wiley Liss Inc