Initial testing (stage 1) of the mTOR kinase inhibitor AZD8055 by the pediatric preclinical testing program

Peter J. Houghton, Richard Gorlick, E. Anders Kolb, Richard Lock, Hernan Carol, Christopher L. Morton, Stephen T. Keir, C. Patrick Reynolds, Min H. Kang, Doris Phelps, John M. Maris, Catherine Billups, Malcolm A. Smith

Research output: Contribution to journalArticle

29 Scopus citations

Abstract

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 1.0nM to 10μM and against the PPTP in vivo panels at a dose of 20mg/kg administered orally daily×7 for 4 weeks. Results: In vitro the median relative IC 50 for AZD8055 against the PPTP cell lines was 24.7nM. 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.

Original languageEnglish (US)
Pages (from-to)191-199
Number of pages9
JournalPediatric Blood and Cancer
Volume58
Issue number2
DOIs
StatePublished - Feb 2012

Keywords

  • Developmental therapeutics
  • MTOR inhibitor
  • Preclinical testing

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Hematology
  • Oncology

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    Houghton, P. J., Gorlick, R., Kolb, E. A., Lock, R., Carol, H., Morton, C. L., Keir, S. T., Reynolds, C. P., Kang, M. H., Phelps, D., Maris, J. M., Billups, C., & Smith, M. A. (2012). Initial testing (stage 1) of the mTOR kinase inhibitor AZD8055 by the pediatric preclinical testing program. Pediatric Blood and Cancer, 58(2), 191-199. https://doi.org/10.1002/pbc.22935