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Initial testing (stage 1) of AZD6244 (ARRY-142886) by the Pediatric Preclinical Testing Program.

Publication ,  Journal Article
Kolb, EA; Gorlick, R; Houghton, PJ; Morton, CL; Neale, G; Keir, ST; Carol, H; Lock, R; Phelps, D; Kang, MH; Reynolds, CP; Maris, JM ...
Published in: Pediatr Blood Cancer
October 2010

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 microM). 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 microM) 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.

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Published In

Pediatr Blood Cancer

DOI

EISSN

1545-5017

Publication Date

October 2010

Volume

55

Issue

4

Start / End Page

668 / 677

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Proto-Oncogene Proteins B-raf
  • Oncology & Carcinogenesis
  • Neoplasms
  • Mutation
  • Mitogen-Activated Protein Kinase Kinases
  • Mice, Inbred BALB C
  • Mice
  • Humans
  • Female
 

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MLA
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Kolb, E. A., Gorlick, R., Houghton, P. J., Morton, C. L., Neale, G., Keir, S. T., … Smith, M. A. (2010). Initial testing (stage 1) of AZD6244 (ARRY-142886) by the Pediatric Preclinical Testing Program. Pediatr Blood Cancer, 55(4), 668–677. https://doi.org/10.1002/pbc.22576
Kolb, E Anders, Richard Gorlick, Peter J. Houghton, Christopher L. Morton, Geoffrey Neale, Stephen T. Keir, Hernan Carol, et al. “Initial testing (stage 1) of AZD6244 (ARRY-142886) by the Pediatric Preclinical Testing Program.Pediatr Blood Cancer 55, no. 4 (October 2010): 668–77. https://doi.org/10.1002/pbc.22576.
Kolb EA, Gorlick R, Houghton PJ, Morton CL, Neale G, Keir ST, et al. Initial testing (stage 1) of AZD6244 (ARRY-142886) by the Pediatric Preclinical Testing Program. Pediatr Blood Cancer. 2010 Oct;55(4):668–77.
Kolb, E. Anders, et al. “Initial testing (stage 1) of AZD6244 (ARRY-142886) by the Pediatric Preclinical Testing Program.Pediatr Blood Cancer, vol. 55, no. 4, Oct. 2010, pp. 668–77. Pubmed, doi:10.1002/pbc.22576.
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. Initial testing (stage 1) of AZD6244 (ARRY-142886) by the Pediatric Preclinical Testing Program. Pediatr Blood Cancer. 2010 Oct;55(4):668–677.
Journal cover image

Published In

Pediatr Blood Cancer

DOI

EISSN

1545-5017

Publication Date

October 2010

Volume

55

Issue

4

Start / End Page

668 / 677

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Proto-Oncogene Proteins B-raf
  • Oncology & Carcinogenesis
  • Neoplasms
  • Mutation
  • Mitogen-Activated Protein Kinase Kinases
  • Mice, Inbred BALB C
  • Mice
  • Humans
  • Female