| Initial testing (stage 1) of AZD6244 (ARRY-142886) by the Pediatric Preclinical Testing Program. | |
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MedLine Citation:
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PMID: 20806365 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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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Authors:
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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 |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural |
Journal Detail:
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Title: Pediatric blood & cancer Volume: 55 ISSN: 1545-5017 ISO Abbreviation: Pediatr Blood Cancer Publication Date: 2010 Oct |
Date Detail:
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Created Date: 2010-08-31 Completed Date: 2010-09-27 Revised Date: 2012-05-07 |
Medline Journal Info:
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Nlm Unique ID: 101186624 Medline TA: Pediatr Blood Cancer Country: United States |
Other Details:
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Languages: eng Pagination: 668-77 Citation Subset: IM |
Copyright Information:
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Copyright 2010 Wiley-Liss, Inc. |
Affiliation:
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A.I. duPont Hospital for Children, Nemours Center for Childhood Cancer Research, Wilmington, DE 19803, USA. eakolb@nemours.org |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Benzimidazoles / therapeutic use* Child Drug Screening Assays, Antitumor Female Humans Mice Mice, Inbred BALB C Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors* Mutation Neoplasms / drug therapy* Proto-Oncogene Proteins B-raf / genetics Xenograft Model Antitumor Assays |
| Grant Support | |
ID/Acronym/Agency:
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CA108786/CA/NCI NIH HHS; CA21765/CA/NCI NIH HHS; N01 CM042216/CM/NCI NIH HHS; N01-CM-42216/CM/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/AZD 6244; 0/Benzimidazoles; EC 2.7.11.1/Proto-Oncogene Proteins B-raf; EC 2.7.12.2/Mitogen-Activated Protein Kinase Kinases |
| Comments/Corrections | |
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