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

28 Citations (Scopus)

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

Fingerprint

Phosphotransferases
Pediatrics
Heterografts
Neoplasms
Cell Line
TOR Serine-Threonine Kinases
S 6
Cytostatic Agents
(5-(2,4-bis((3S)-3-methylmorpholin-4-yl)pyrido(2,3-d)pyrimidin-7-yl)-2-methoxyphenyl)methanol
Appointments and Schedules
Adenosine Triphosphate
Phosphorylation
N-propyl-4-phenyl-1,2,3,6-tetrahydropyridine
Growth
In Vitro Techniques
TOR complex 2
mechanistic target of rapamycin complex 1

Keywords

  • Developmental therapeutics
  • MTOR inhibitor
  • Preclinical testing

ASJC Scopus subject areas

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

Cite this

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. Pediatric Blood and Cancer, 58(2), 191-199. https://doi.org/10.1002/pbc.22935

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

In: Pediatric Blood and Cancer, Vol. 58, No. 2, 02.2012, p. 191-199.

Research output: Contribution to journalArticle

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 2012, 'Initial testing (stage 1) of the mTOR kinase inhibitor AZD8055 by the pediatric preclinical testing program', Pediatric Blood and Cancer, vol. 58, no. 2, pp. 191-199. https://doi.org/10.1002/pbc.22935
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. / Initial testing (stage 1) of the mTOR kinase inhibitor AZD8055 by the pediatric preclinical testing program. In: Pediatric Blood and Cancer. 2012 ; Vol. 58, No. 2. pp. 191-199.
@article{c7872ce548524afa918893c8ef19eb29,
title = "Initial testing (stage 1) of the mTOR kinase inhibitor AZD8055 by the pediatric preclinical testing program",
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.",
keywords = "Developmental therapeutics, MTOR inhibitor, Preclinical testing",
author = "Houghton, {Peter J.} and Richard Gorlick and Kolb, {E. Anders} and Richard Lock and Hernan Carol and Morton, {Christopher L.} and Keir, {Stephen T.} and Reynolds, {C. Patrick} and Kang, {Min H.} and Doris Phelps and Maris, {John M.} and Catherine Billups and Smith, {Malcolm A.}",
year = "2012",
month = "2",
doi = "10.1002/pbc.22935",
language = "English (US)",
volume = "58",
pages = "191--199",
journal = "Pediatric Blood and Cancer",
issn = "1545-5009",
publisher = "Wiley-Liss Inc.",
number = "2",

}

TY - JOUR

T1 - Initial testing (stage 1) of the mTOR kinase inhibitor AZD8055 by the pediatric preclinical testing program

AU - Houghton, Peter J.

AU - Gorlick, Richard

AU - Kolb, E. Anders

AU - Lock, Richard

AU - Carol, Hernan

AU - Morton, Christopher L.

AU - Keir, Stephen T.

AU - Reynolds, C. Patrick

AU - Kang, Min H.

AU - Phelps, Doris

AU - Maris, John M.

AU - Billups, Catherine

AU - Smith, Malcolm A.

PY - 2012/2

Y1 - 2012/2

N2 - 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.

AB - 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.

KW - Developmental therapeutics

KW - MTOR inhibitor

KW - Preclinical testing

UR - http://www.scopus.com/inward/record.url?scp=83455253885&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=83455253885&partnerID=8YFLogxK

U2 - 10.1002/pbc.22935

DO - 10.1002/pbc.22935

M3 - Article

C2 - 21337679

AN - SCOPUS:83455253885

VL - 58

SP - 191

EP - 199

JO - Pediatric Blood and Cancer

JF - Pediatric Blood and Cancer

SN - 1545-5009

IS - 2

ER -