Initial testing (stage 1) of AZD6244 (ARRY-142886) by the pediatric preclinical testing program

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

Research output: Contribution to journalArticle

50 Citations (Scopus)

Abstract

Background: AZD6244 (ARRY-142886) is a potent small molecule inhibitor of MEK1/2 that is in phase 2 clinical development. Procedures: AZD6244 was tested against the Pediatric Preclinical Testing Program (PPTP) in vitro panel (1 nM-10 μM). In vivo AZD6244 was tested at a dose of 100 mg/kg administered orally twice daily 5 days per week for 6 weeks. Subsequently, AZD6244 was evaluated against two juvenile pilocytic astrocytoma (JPA) xenografts using once and twice daily dosing schedules. Phosphorylation of ERK1/2 was used as a surrogate for in vivo inhibition of MEK1/2 was determined by immunoblotting. Results: At the highest concentration used in vitro (10 μM) AZD6244 only inhibited growth by 50% in 5 of the 23 cell lines. Against the in vivo tumor panels, AZD6244 induced significant differences in EFS distribution in 10 of 37 (27%) solid tumor models and 0 of 6 acute lymphoblastic leukemia (ALL) models. There were no objective responses. Pharmacodynamic studies indicated at this dose and schedule AZD6244 completely inhibited ERK1/2 phosphorylation. AZD6244 was evaluated against two JPA xenografts, BT-35 (wild-type BRAF) and BT-40 (mutant [V600E] BRAF). BT-40 xenografts were highly sensitive to AZD6244, whereas BT-35 xenografts progressed on AZD6244 treatment. Conclusions: At the dose and schedule of administration used, AZD6244 as a single agent had limited in vitro and in vivo activity against the PPTP tumor panels despite inhibition of MEK1/2 activity. However, AZD6244 was highly active against BT-40 JPA xenografts that harbor constitutively activated BRAF, causing complete regressions. Pediatr Blood Cancer.

Original languageEnglish (US)
Pages (from-to)668-677
Number of pages10
JournalPediatric Blood and Cancer
Volume55
Issue number4
DOIs
StatePublished - Oct 1 2010
Externally publishedYes

Fingerprint

Pediatrics
Heterografts
Astrocytoma
Appointments and Schedules
AZD 6244
Neoplasms
Phosphorylation
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Immunoblotting
Cell Line
Growth

Keywords

  • AZD6244
  • Developmental therapeutics
  • Preclinical testing

ASJC Scopus subject areas

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

Cite this

Initial testing (stage 1) of AZD6244 (ARRY-142886) by the pediatric preclinical testing program. / Kolb, E. Anders; Gorlick, Richard; Houghton, Peter J; Morton, Christopher L.; Neale, Geoffrey; Keir, Stephen T.; Carol, Hernan; Lock, Richard; Phelps, Doris; Kang, Min H.; Reynolds, C. Patrick; Maris, John M.; Billups, Catherine; Smith, Malcolm A.

In: Pediatric Blood and Cancer, Vol. 55, No. 4, 01.10.2010, p. 668-677.

Research output: Contribution to journalArticle

Kolb, EA, Gorlick, R, Houghton, PJ, Morton, CL, Neale, G, Keir, ST, Carol, H, Lock, R, Phelps, D, Kang, MH, Reynolds, CP, Maris, JM, Billups, C & Smith, MA 2010, 'Initial testing (stage 1) of AZD6244 (ARRY-142886) by the pediatric preclinical testing program', Pediatric Blood and Cancer, vol. 55, no. 4, pp. 668-677. https://doi.org/10.1002/pbc.22576
Kolb, E. Anders ; Gorlick, Richard ; Houghton, Peter J ; Morton, Christopher L. ; Neale, Geoffrey ; Keir, Stephen T. ; Carol, Hernan ; Lock, Richard ; Phelps, Doris ; Kang, Min H. ; Reynolds, C. Patrick ; Maris, John M. ; Billups, Catherine ; Smith, Malcolm A. / Initial testing (stage 1) of AZD6244 (ARRY-142886) by the pediatric preclinical testing program. In: Pediatric Blood and Cancer. 2010 ; Vol. 55, No. 4. pp. 668-677.
@article{ad19ba724198413999c198fed11d935d,
title = "Initial testing (stage 1) of AZD6244 (ARRY-142886) by the pediatric preclinical testing program",
abstract = "Background: AZD6244 (ARRY-142886) is a potent small molecule inhibitor of MEK1/2 that is in phase 2 clinical development. Procedures: AZD6244 was tested against the Pediatric Preclinical Testing Program (PPTP) in vitro panel (1 nM-10 μM). In vivo AZD6244 was tested at a dose of 100 mg/kg administered orally twice daily 5 days per week for 6 weeks. Subsequently, AZD6244 was evaluated against two juvenile pilocytic astrocytoma (JPA) xenografts using once and twice daily dosing schedules. Phosphorylation of ERK1/2 was used as a surrogate for in vivo inhibition of MEK1/2 was determined by immunoblotting. Results: At the highest concentration used in vitro (10 μM) AZD6244 only inhibited growth by 50{\%} in 5 of the 23 cell lines. Against the in vivo tumor panels, AZD6244 induced significant differences in EFS distribution in 10 of 37 (27{\%}) solid tumor models and 0 of 6 acute lymphoblastic leukemia (ALL) models. There were no objective responses. Pharmacodynamic studies indicated at this dose and schedule AZD6244 completely inhibited ERK1/2 phosphorylation. AZD6244 was evaluated against two JPA xenografts, BT-35 (wild-type BRAF) and BT-40 (mutant [V600E] BRAF). BT-40 xenografts were highly sensitive to AZD6244, whereas BT-35 xenografts progressed on AZD6244 treatment. Conclusions: At the dose and schedule of administration used, AZD6244 as a single agent had limited in vitro and in vivo activity against the PPTP tumor panels despite inhibition of MEK1/2 activity. However, AZD6244 was highly active against BT-40 JPA xenografts that harbor constitutively activated BRAF, causing complete regressions. Pediatr Blood Cancer.",
keywords = "AZD6244, Developmental therapeutics, Preclinical testing",
author = "Kolb, {E. Anders} and Richard Gorlick and Houghton, {Peter J} and Morton, {Christopher L.} and Geoffrey Neale and Keir, {Stephen T.} and Hernan Carol and Richard Lock and Doris Phelps and Kang, {Min H.} and Reynolds, {C. Patrick} and Maris, {John M.} and Catherine Billups and Smith, {Malcolm A.}",
year = "2010",
month = "10",
day = "1",
doi = "10.1002/pbc.22576",
language = "English (US)",
volume = "55",
pages = "668--677",
journal = "Pediatric Blood and Cancer",
issn = "1545-5009",
publisher = "Wiley-Liss Inc.",
number = "4",

}

TY - JOUR

T1 - Initial testing (stage 1) of AZD6244 (ARRY-142886) by the pediatric preclinical testing program

AU - Kolb, E. Anders

AU - Gorlick, Richard

AU - Houghton, Peter J

AU - Morton, Christopher L.

AU - Neale, Geoffrey

AU - Keir, Stephen T.

AU - Carol, Hernan

AU - Lock, Richard

AU - Phelps, Doris

AU - Kang, Min H.

AU - Reynolds, C. Patrick

AU - Maris, John M.

AU - Billups, Catherine

AU - Smith, Malcolm A.

PY - 2010/10/1

Y1 - 2010/10/1

N2 - Background: AZD6244 (ARRY-142886) is a potent small molecule inhibitor of MEK1/2 that is in phase 2 clinical development. Procedures: AZD6244 was tested against the Pediatric Preclinical Testing Program (PPTP) in vitro panel (1 nM-10 μM). In vivo AZD6244 was tested at a dose of 100 mg/kg administered orally twice daily 5 days per week for 6 weeks. Subsequently, AZD6244 was evaluated against two juvenile pilocytic astrocytoma (JPA) xenografts using once and twice daily dosing schedules. Phosphorylation of ERK1/2 was used as a surrogate for in vivo inhibition of MEK1/2 was determined by immunoblotting. Results: At the highest concentration used in vitro (10 μM) AZD6244 only inhibited growth by 50% in 5 of the 23 cell lines. Against the in vivo tumor panels, AZD6244 induced significant differences in EFS distribution in 10 of 37 (27%) solid tumor models and 0 of 6 acute lymphoblastic leukemia (ALL) models. There were no objective responses. Pharmacodynamic studies indicated at this dose and schedule AZD6244 completely inhibited ERK1/2 phosphorylation. AZD6244 was evaluated against two JPA xenografts, BT-35 (wild-type BRAF) and BT-40 (mutant [V600E] BRAF). BT-40 xenografts were highly sensitive to AZD6244, whereas BT-35 xenografts progressed on AZD6244 treatment. Conclusions: At the dose and schedule of administration used, AZD6244 as a single agent had limited in vitro and in vivo activity against the PPTP tumor panels despite inhibition of MEK1/2 activity. However, AZD6244 was highly active against BT-40 JPA xenografts that harbor constitutively activated BRAF, causing complete regressions. Pediatr Blood Cancer.

AB - Background: AZD6244 (ARRY-142886) is a potent small molecule inhibitor of MEK1/2 that is in phase 2 clinical development. Procedures: AZD6244 was tested against the Pediatric Preclinical Testing Program (PPTP) in vitro panel (1 nM-10 μM). In vivo AZD6244 was tested at a dose of 100 mg/kg administered orally twice daily 5 days per week for 6 weeks. Subsequently, AZD6244 was evaluated against two juvenile pilocytic astrocytoma (JPA) xenografts using once and twice daily dosing schedules. Phosphorylation of ERK1/2 was used as a surrogate for in vivo inhibition of MEK1/2 was determined by immunoblotting. Results: At the highest concentration used in vitro (10 μM) AZD6244 only inhibited growth by 50% in 5 of the 23 cell lines. Against the in vivo tumor panels, AZD6244 induced significant differences in EFS distribution in 10 of 37 (27%) solid tumor models and 0 of 6 acute lymphoblastic leukemia (ALL) models. There were no objective responses. Pharmacodynamic studies indicated at this dose and schedule AZD6244 completely inhibited ERK1/2 phosphorylation. AZD6244 was evaluated against two JPA xenografts, BT-35 (wild-type BRAF) and BT-40 (mutant [V600E] BRAF). BT-40 xenografts were highly sensitive to AZD6244, whereas BT-35 xenografts progressed on AZD6244 treatment. Conclusions: At the dose and schedule of administration used, AZD6244 as a single agent had limited in vitro and in vivo activity against the PPTP tumor panels despite inhibition of MEK1/2 activity. However, AZD6244 was highly active against BT-40 JPA xenografts that harbor constitutively activated BRAF, causing complete regressions. Pediatr Blood Cancer.

KW - AZD6244

KW - Developmental therapeutics

KW - Preclinical testing

UR - http://www.scopus.com/inward/record.url?scp=77957071661&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77957071661&partnerID=8YFLogxK

U2 - 10.1002/pbc.22576

DO - 10.1002/pbc.22576

M3 - Article

VL - 55

SP - 668

EP - 677

JO - Pediatric Blood and Cancer

JF - Pediatric Blood and Cancer

SN - 1545-5009

IS - 4

ER -