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

Publication ,  Journal Article
Houghton, PJ; Gorlick, R; Kolb, EA; Lock, R; Carol, H; Morton, CL; Keir, ST; Reynolds, CP; Kang, MH; Phelps, D; Maris, JM; Billups, C; Smith, MA
Published in: Pediatr Blood Cancer
February 2012

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 x 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.

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Published In

Pediatr Blood Cancer

DOI

EISSN

1545-5017

Publication Date

February 2012

Volume

58

Issue

2

Start / End Page

191 / 199

Location

United States

Related Subject Headings

  • Tumor Cells, Cultured
  • TOR Serine-Threonine Kinases
  • Survival Rate
  • Oncology & Carcinogenesis
  • Neoplasms, Experimental
  • Morpholines
  • Mice, SCID
  • Mice, Inbred NOD
  • Mice, Inbred BALB C
  • Mice
 

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Houghton, P. J., Gorlick, R., Kolb, E. A., Lock, R., Carol, H., Morton, C. L., … Smith, M. A. (2012). Initial testing (stage 1) of the mTOR kinase inhibitor AZD8055 by the pediatric preclinical testing program. Pediatr Blood Cancer, 58(2), 191–199. https://doi.org/10.1002/pbc.22935
Houghton, Peter J., Richard Gorlick, E Anders Kolb, Richard Lock, Hernan Carol, Christopher L. Morton, Stephen T. Keir, et al. “Initial testing (stage 1) of the mTOR kinase inhibitor AZD8055 by the pediatric preclinical testing program.Pediatr Blood Cancer 58, no. 2 (February 2012): 191–99. https://doi.org/10.1002/pbc.22935.
Houghton PJ, Gorlick R, Kolb EA, Lock R, Carol H, Morton CL, et al. Initial testing (stage 1) of the mTOR kinase inhibitor AZD8055 by the pediatric preclinical testing program. Pediatr Blood Cancer. 2012 Feb;58(2):191–9.
Houghton, Peter J., et al. “Initial testing (stage 1) of the mTOR kinase inhibitor AZD8055 by the pediatric preclinical testing program.Pediatr Blood Cancer, vol. 58, no. 2, Feb. 2012, pp. 191–99. Pubmed, doi:10.1002/pbc.22935.
Houghton PJ, Gorlick R, Kolb EA, Lock R, Carol H, Morton CL, Keir ST, Reynolds CP, Kang MH, Phelps D, Maris JM, Billups C, Smith MA. Initial testing (stage 1) of the mTOR kinase inhibitor AZD8055 by the pediatric preclinical testing program. Pediatr Blood Cancer. 2012 Feb;58(2):191–199.
Journal cover image

Published In

Pediatr Blood Cancer

DOI

EISSN

1545-5017

Publication Date

February 2012

Volume

58

Issue

2

Start / End Page

191 / 199

Location

United States

Related Subject Headings

  • Tumor Cells, Cultured
  • TOR Serine-Threonine Kinases
  • Survival Rate
  • Oncology & Carcinogenesis
  • Neoplasms, Experimental
  • Morpholines
  • Mice, SCID
  • Mice, Inbred NOD
  • Mice, Inbred BALB C
  • Mice