title: Initial testing (stage 1) of eribulin, a novel tubulin binding agent, by the pediatric preclinical testing program.
abstract: BACKGROUND
  Antimitotic agents are essential components for curative therapy of pediatric acute leukemias and many solid tumors. Eribulin is a novel agent that differs from both Vinca alkaloids and taxanes in its mode of binding to tubulin polymers.
  
  
  METHODS
  Eribulin was tested against the PPTP in vitro cell line panel at concentrations from 0.1 nM to 1.0 μM and against the PPTP in vivo xenograft panels at a dose of 1 mg/kg (solid tumors) or 1.5 mg/kg (ALL models) using a q4dx3 schedule repeated at Day 21.
  
  
  RESULTS
  In vitro eribulin demonstrated cytotoxic activity, with a median relative IC50 value of 0.27 nM, (range <0.1-14.8 nM). Eribulin was well tolerated in vivo, and all 43 xenograft models were considered evaluable for efficacy. Eribulin induced significant differences in event-free survival (EFS) distribution compared to control in 29 of 35 (83%) of the solid tumors and in 8 of 8 (100%) of the ALL xenografts. Objective responses were observed in 18 of 35 (51%) solid tumor xenografts. Complete responses (CR) or maintained CR were observed in panels of Wilms tumor, Ewing sarcoma, rhabdomyosarcoma, glioblastoma, and osteosarcoma xenografts. All eight ALL xenografts achieved CR or MCR.
  
  
  CONCLUSIONS
  The high level of activity observed for eribulin against the PPTP preclinical models makes this an interesting agent to consider for pediatric evaluation. The activity pattern observed for eribulin in the solid tumor panels is equal or superior to that observed previously for vincristine.
authors.affiliation: AI duPont Hospital for Children, Wilmington, Delaware 19803, USA.
authors.forename: E Anders
authors.initials: EA
authors.lastname: Kolb
authors.forename: Richard
authors.initials: R
authors.lastname: Gorlick
authors.forename: C Patrick
authors.initials: CP
authors.lastname: Reynolds
authors.forename: Min H
authors.initials: MH
authors.lastname: Kang
authors.forename: Hernan
authors.initials: H
authors.lastname: Carol
authors.forename: Richard
authors.initials: R
authors.lastname: Lock
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Keir
authors.forename: John M
authors.initials: JM
authors.lastname: Maris
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Billups
authors.forename: Christopher
authors.initials: C
authors.lastname: Desjardins
authors.forename: Raushan T
authors.initials: RT
authors.lastname: Kurmasheva
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Houghton
authors.forename: Malcolm A
authors.initials: MA
authors.lastname: Smith
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D005663:Furans / Q000494:pharmacology*; D006801:Humans; D007659:Ketones / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016513:Mice, SCID; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology; D050257:Tubulin Modulators / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays / Q000379:methods*; D000095662:Polyether Polyketides
chemical_list: D005663:Furans; D007659:Ketones; D050257:Tubulin Modulators; C490954:eribulin; D000095662:Polyether Polyketides
references.citation: Clin Cancer Res. 2009 Jun 15;15(12):4207-12
references.pmid: 19509177
references.citation: Clin Cancer Res. 2011 Nov 1;17(21):6615-22
references.pmid: 21859830
references.citation: Biochemistry. 2010 Feb 16;49(6):1331-7
references.pmid: 20030375
references.citation: Ann Pharmacother. 2012 Jun;46(6):802-11
references.pmid: 22619477
references.citation: JAMA. 1963 Mar 2;183:741-6
references.pmid: 13992692
references.citation: J Pediatr. 1964 Apr;64:534-41
references.pmid: 14136871
references.citation: Cancer Chemother Rep. 1971 Feb;55(1):67-78
references.pmid: 5287340
references.citation: Pediatr Blood Cancer. 2011 Feb;56(2):239-49
references.pmid: 20922763
references.citation: Br J Clin Pharmacol. 2013 Feb;75(2):507-15
references.pmid: 22803519
references.citation: Lancet. 2011 Mar 12;377(9769):914-23
references.pmid: 21376385
references.citation: Cancer. 1990 Feb 1;65(3):439-45
references.pmid: 2297634
references.citation: Cancer Res. 2011 Jan 15;71(2):496-505
references.pmid: 21127197
references.citation: J Clin Oncol. 1987 Jan;5(1):21-6
references.pmid: 3543236
references.citation: Mol Cancer Ther. 2005 Jul;4(7):1086-95
references.pmid: 16020666
references.citation: Cancer Res. 2001 Feb 1;61(3):1013-21
references.pmid: 11221827
references.citation: Invest New Drugs. 2012 Oct;30(5):1926-33
references.pmid: 21887501
references.citation: J Clin Oncol. 1984 Mar;2(3):152-6
references.pmid: 6366150
references.citation: Clin Cancer Res. 2009 Jun 15;15(12):4213-9
references.pmid: 19509146
references.citation: Lancet Oncol. 2011 Oct;12(11):1045-52
references.pmid: 21937277
references.citation: Blood. 2004 May 15;103(10):3905-14
references.pmid: 14764536
references.citation: Invest New Drugs. 2013 Apr;31(2):381-9
references.pmid: 22555773
references.citation: Pediatr Blood Cancer. 2009 Oct;53(4):590-3
references.pmid: 19533657
references.citation: Med Pediatr Oncol. 1987;15(2):69-77
references.pmid: 3295501
references.citation: JAMA. 1967 Oct 30;202(5):381-4
references.pmid: 4293363
references.citation: Invest New Drugs. 2007 Aug;25(4):285-95
references.pmid: 17384918
references.citation: Clin Cancer Res. 2012 Jul 15;18(14):3846-55
references.pmid: 22648270
references.citation: Mol Cancer Ther. 2007 Mar;6(3):886-97
references.pmid: 17363483
references.citation: Cancer. 2002 Jun 15;94(12):3263-8
references.pmid: 12115359
references.citation: Pediatr Blood Cancer. 2010 Jan;54(1):47-54
references.pmid: 19731320
references.citation: Pediatr Blood Cancer. 2007 Dec;49(7):928-40
references.pmid: 17066459
references.citation: Xenobiotica. 2011 Apr;41(4):320-6
references.pmid: 21162698
references.citation: J Biol Chem. 1991 Aug 25;266(24):15882-9
references.pmid: 1874739
references.citation: Lancet. 1997 Sep 27;350(9082):911-7
references.pmid: 9314869
references.citation: Cancer Chemother Pharmacol. 2012 Dec;70(6):823-32
references.pmid: 23010853
references.citation: J Clin Oncol. 2009 Jun 20;27(18):2954-61
references.pmid: 19349550
references.citation: Nat Rev Cancer. 2004 Apr;4(4):253-65
references.pmid: 15057285
references.citation: Cancer Chemother Rep. 1968 Jun;52(4):485-7
references.pmid: 5743694
references.citation: Pediatrics. 1966 Sep;38(3):465-72
references.pmid: 5950594
references.citation: Natl Cancer Inst Monogr. 1981 Apr;(56):213-20
references.pmid: 6946291