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Initial testing (stage 1) of the mTOR kinase inhibitor AZD8055 by the pediatric preclinical testing program
Author(s) -
Houghton Peter J.,
Gorlick Richard,
Kolb E. Anders,
Lock Richard,
Carol Hernan,
Morton Christopher L.,
Keir Stephen T.,
Reynolds C. Patrick,
Kang Min H.,
Phelps Doris,
Maris John M.,
Billups Catherine,
Smith Malcolm A.
Publication year - 2012
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.22935
Subject(s) - mtorc1 , mtorc2 , in vivo , medicine , protein kinase b , pi3k/akt/mtor pathway , pharmacology , kinase , ic50 , in vitro , phosphorylation , biology , signal transduction , biochemistry , microbiology and biotechnology
Background AZD8055 is a small molecule ATP‐competitive inhibitor of the serine/threonine kinase mTOR that regulates cap‐dependent translation through the mTORC1 complex and Akt activation through the mTORC2 complex. Procedures AZD8055 was tested against the PPTP in vitro panel at concentrations ranging from 1.0 nM to 10 µM and against the PPTP in vivo panels at a dose of 20 mg/kg administered orally daily × 7 for 4 weeks.Results In vitro the median relative IC 50 for AZD8055 against the PPTP cell lines was 24.7 nM. Relative I/O values >0% (consistent with a cytostatic effect) were observed in 8 cell lines and 15 cell lines showed Relative I/O values ranging from −4.7 to −92.2% (consistent with varying degrees of cytotoxic activity). In vivo AZD8055 induced significant differences in EFS distribution compared to controls in 23 of 36 (64%) evaluable solid tumor xenografts, and 1 of 6 evaluable ALL xenografts. Intermediate activity for the time to event activity measure (EFS T/C >2) was observed in 5 of 32 (16%) solid tumor xenografts evaluable. The best response was stable disease. PD2 (progressive disease with growth delay) was observed in 20 of 36 (55.6%) evaluable solid tumor xenografts. AZD8055 significantly inhibited 4E‐BP1, S6, and Akt phosphorylation following day 1 and day 4 dosing, but suppression of mTORC1 or mTORC2 signaling did not predict tumor sensitivity.Conclusions AZD8055 demonstrated broad activity in vitro, but at the dose and schedule studied demonstrated limited activity in vivo against the PPTP solid tumor and ALL panels. Pediatr Blood Cancer 2012; 58: 191–199. © 2011 Wiley Periodicals, Inc.