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.
  
  
  METHODS
  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.
authors.affiliation: A.I. duPont Hospital for Children, Nemours Center for Childhood Cancer Research, Wilmington, DE 19803, USA. eakolb@nemours.org
authors.forename: E Anders
authors.initials: EA
authors.lastname: Kolb
authors.forename: Richard
authors.initials: R
authors.lastname: Gorlick
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Houghton
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Morton
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Neale
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Keir
authors.forename: Hernan
authors.initials: H
authors.lastname: Carol
authors.forename: Richard
authors.initials: R
authors.lastname: Lock
authors.forename: Doris
authors.initials: D
authors.lastname: Phelps
authors.forename: Min H
authors.initials: MH
authors.lastname: Kang
authors.forename: C Patrick
authors.initials: CP
authors.lastname: Reynolds
authors.forename: John M
authors.initials: JM
authors.lastname: Maris
authors.forename: Catherine
authors.initials: C
authors.lastname: Billups
authors.forename: Malcolm A
authors.initials: MA
authors.lastname: Smith
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000627:therapeutic use*; D002648:Child; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors*; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: C517975:AZD 6244; D001562:Benzimidazoles; D048493:Proto-Oncogene Proteins B-raf; D020929:Mitogen-Activated Protein Kinase Kinases
references.citation: Cancer Res. 2008 Nov 1;68(21):8673-7
references.pmid: 18974108
references.citation: Radiother Oncol. 2009 Dec;93(3):639-44
references.pmid: 19853943
references.citation: Cancer Res. 2007 Dec 1;67(23):11300-8
references.pmid: 18056456
references.citation: J Pathol. 2009 Jun;218(2):172-81
references.pmid: 19373855
references.citation: Cancer Res. 2008 Aug 15;68(16):6803-9
references.pmid: 18701506
references.citation: Cancer Cell. 2004 Oct;6(4):313-9
references.pmid: 15488754
references.citation: Leukemia. 2005 Feb;19(2):310-2
references.pmid: 15538400
references.citation: Clin Cancer Res. 2010 Mar 1;16(5):1613-23
references.pmid: 20179232
references.citation: Blood. 2004 May 15;103(10):3905-14
references.pmid: 14764536
references.citation: Cell. 2004 Mar 19;116(6):855-67
references.pmid: 15035987
references.citation: Hematol J. 2002;3(3):157-63
references.pmid: 12111653
references.citation: Clin Cancer Res. 2006 Jan 1;12(1):223-34
references.pmid: 16397046
references.citation: Nature. 2006 Jan 19;439(7074):358-62
references.pmid: 16273091
references.citation: J Clin Invest. 2008 May;118(5):1739-49
references.pmid: 18398503
references.citation: Mol Cancer Ther. 2007 May;6(5):1620-8
references.pmid: 17483438
references.citation: Clin Cancer Res. 2008 Jan 1;14(1):230-9
references.pmid: 18172275
references.citation: BMC Cancer. 2006 Jul 05;6:177
references.pmid: 16822308
references.citation: J Clin Oncol. 2008 May 1;26(13):2139-46
references.pmid: 18390968
references.citation: Cancer Res. 2009 May 15;69(10):4286-93
references.pmid: 19401449
references.citation: Cancer Res. 1988 Aug 1;48(15):4189-95
references.pmid: 3390813
references.citation: Clin Cancer Res. 2007 Mar 1;13(5):1576-83
references.pmid: 17332304
references.citation: Eur J Cancer. 2006 Mar;42(5):646-9
references.pmid: 16434186
references.citation: Nature. 2002 Jun 27;417(6892):949-54
references.pmid: 12068308
references.citation: Proc Natl Acad Sci U S A. 2009 Dec 1;106(48):20411-6
references.pmid: 19915144
references.citation: Mol Cancer Ther. 2007 Aug;6(8):2209-19
references.pmid: 17699718
references.citation: Pediatr Blood Cancer. 2008 Jan;50(1):37-45
references.pmid: 17420992
references.citation: Clin Cancer Res. 2005 Oct 1;11(19 Pt 1):6950-8
references.pmid: 16203787
references.citation: Mol Cancer Ther. 2007 Mar;6(3):886-97
references.pmid: 17363483
references.citation: Acta Neuropathol. 2004 Dec;108(6):467-70
references.pmid: 15517309
references.citation: Pediatr Blood Cancer. 2007 Dec;49(7):928-40
references.pmid: 17066459
references.citation: Oncogene. 2009 May 21;28(20):2119-23
references.pmid: 19363522
references.citation: Oncol Rep. 2004 Dec;12(6):1269-72
references.pmid: 15547749