Premium
Initial testing (stage 1) of the Akt inhibitor GSK690693 by the pediatric preclinical testing program
Author(s) -
Carol Hernan,
Morton Christopher L.,
Gorlick Richard,
Kolb E. Anders,
Keir Stephen T.,
Reynolds C. Patrick,
Kang Min H.,
Maris John M.,
Billups Catherine,
Smith Malcolm A.,
Houghton Peter J.,
Lock Richard B.
Publication year - 2010
Publication title -
pediatric blood and cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.116
H-Index - 105
eISSN - 1545-5017
pISSN - 1545-5009
DOI - 10.1002/pbc.22710
Subject(s) - in vivo , medicine , in vitro , protein kinase b , osteosarcoma , mtorc1 , cancer research , pharmacology , oncology , apoptosis , biology , biochemistry , microbiology and biotechnology
Abstract 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 Bad, as 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 µM, and against the in vivo panel of xenografts at a dose of 30 mg/kg daily × 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 (T/C) 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 IC 50 values between 6.5 nM and >10 µM. 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 T/C criteria for intermediate activity. Conclusions GSK690693 demonstrated broad activity in vitro, however 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. © 2010 Wiley‐Liss, Inc.