title: Initial testing (stage 1) of the histone deacetylase inhibitor, quisinostat (JNJ-26481585), by the Pediatric Preclinical Testing Program.
abstract: BACKGROUND
  Quisinostat (JNJ-26481585) is a second-generation pyrimidyl-hydroxamic acid histone deacetylase (HDAC) inhibitor with high cellular potency towards Class I and II HDACs. Quisinostat was selected for clinical development as it showed prolonged pharmacodynamic effects in vivo and demonstrated improved single agent antitumoral efficacy compared to other analogs.
  
  
  METHODS
  Quisinostat was tested against the PPTP in vitro panel at concentrations ranging from 1.0 nM to 10 μM and was tested against the PPTP in vivo panels at a dose of 5 mg/kg (solid tumors) or 2.5 mg/kg (ALL models) administered intraperitoneally daily × 21.
  
  
  RESULTS
  In vitro quisinostat demonstrated potent cytotoxic activity, with T/C% values approaching 0% for all of the cell lines at the highest concentration tested. The median relative IC50 value for the PPTP cell lines was 2.2 nM (range <1-19 nM). quisinostat induced significant differences in EFS distribution compared to control in 21 of 33 (64%) of the evaluable solid tumor xenografts and in 4 of 8 (50%) of the evaluable ALL xenografts. An objective response was observed in 1 of 33 solid tumor xenografts while for the ALL panel, two xenografts achieved complete response (CR) or maintained CR, and a third ALL xenograft achieved stable disease.
  
  
  CONCLUSIONS
  Quisinostat demonstrated broad activity in vitro, and retarded growth in the majority of solid tumor xenografts studied. The most consistent in vivo activity signals observed were for the glioblastoma xenografts and T-cell ALL xenografts.
authors.affiliation: Children's Cancer Institute Australia for Medical Research, Randwick, NSW, Australia.
authors.forename: Hernan
authors.initials: H
authors.lastname: Carol
authors.forename: Richard
authors.initials: R
authors.lastname: Gorlick
authors.forename: E Anders
authors.initials: EA
authors.lastname: Kolb
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Morton
authors.forename: Donya Moradi
authors.initials: DM
authors.lastname: Manesh
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Keir
authors.forename: C Patrick
authors.initials: CP
authors.lastname: Reynolds
authors.forename: Min H
authors.initials: MH
authors.lastname: Kang
authors.forename: John M
authors.initials: JM
authors.lastname: Maris
authors.forename: Amy
authors.initials: A
authors.lastname: Wozniak
authors.forename: Ian
authors.initials: I
authors.lastname: Hickson
authors.forename: Dmitry
authors.initials: D
authors.lastname: Lyalin
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
authors.forename: Richard
authors.initials: R
authors.lastname: Lock
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects*; D002648:Child; D004353:Drug Evaluation, Preclinical; D005260:Female; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology; D014407:Tumor Cells, Cultured
chemical_list: D006877:Hydroxamic Acids; C541788:quisinostat
keywords: HDAC inhibitor; developmental therapeutics; preclinical testing
references.citation: J Clin Oncol. 2006 Aug 1;24(22):3678-85
references.pmid: 16877737
references.citation: Nature. 1997 Sep 25;389(6649):349-52
references.pmid: 9311776
references.citation: J Clin Oncol. 2010 Aug 1;28(22):3623-9
references.pmid: 20606092
references.citation: Oncologist. 2007 Oct;12(10):1247-52
references.pmid: 17962618
references.citation: J Biol Chem. 2009 Mar 20;284(12):7436-45
references.pmid: 19158084
references.citation: Pediatr Blood Cancer. 2011 Feb;56(2):239-49
references.pmid: 20922763
references.citation: Proc Natl Acad Sci U S A. 2000 Aug 29;97(18):10014-9
references.pmid: 10954755
references.citation: Mol Cancer Ther. 2003 Feb;2(2):151-63
references.pmid: 12589032
references.citation: Pediatr Blood Cancer. 2008 Jul;51(1):34-41
references.pmid: 18260120
references.citation: Mol Cell Biol. 2006 Nov;26(21):7913-28
references.pmid: 16940178
references.citation: Clin Cancer Res. 2009 Jun 15;15(12):3970-7
references.pmid: 19509171
references.citation: Clin Cancer Res. 2006 Jan 15;12(2):634-42
references.pmid: 16428510
references.citation: J Biol Chem. 1999 Dec 3;274(49):34940-7
references.pmid: 10574969
references.citation: J Cell Physiol. 2000 Jul;184(1):1-16
references.pmid: 10825229
references.citation: Clin Cancer Res. 2006 Jan 1;12(1):223-34
references.pmid: 16397046
references.citation: Nat Rev Cancer. 2006 Jan;6(1):38-51
references.pmid: 16397526
references.citation: Int J Biochem Cell Biol. 2009 Jan;41(1):185-98
references.pmid: 18804549
references.citation: Br J Haematol. 2010 May;149(4):529-36
references.pmid: 20331455
references.citation: Clin Cancer Res. 2011 Apr 15;17(8):2339-49
references.pmid: 21421857
references.citation: Cell Mol Life Sci. 2001 May;58(5-6):728-36
references.pmid: 11437234
references.citation: J Clin Oncol. 2007 Sep 10;25(26):4051-6
references.pmid: 17827453
references.citation: Mol Cell. 2005 May 27;18(5):601-7
references.pmid: 15916966
references.citation: Cancer Lett. 2009 Aug 8;280(2):168-76
references.pmid: 19103471
references.citation: Cell Cycle. 2010 May;9(9):1830-8
references.pmid: 20404560
references.citation: Nat Genet. 1999 Jan;21(1):103-7
references.pmid: 9916800
references.citation: Br J Haematol. 2002 Dec;119(4):965-9
references.pmid: 12472574
references.citation: Leuk Res. 2010 Feb;34(2):221-8
references.pmid: 19682743
references.citation: Int J Cancer. 2005 Sep 20;116(5):784-92
references.pmid: 15849726
references.citation: Cancer Res. 2002 Nov 1;62(21):6108-15
references.pmid: 12414635
references.citation: Blood. 2007 Jan 1;109(1):31-9
references.pmid: 16960145
references.citation: Blood. 2004 May 15;103(10):3905-14
references.pmid: 14764536
references.citation: EMBO J. 2002 Jun 3;21(11):2672-81
references.pmid: 12032080
references.citation: Pediatr Blood Cancer. 2009 Sep;53(3):505-8
references.pmid: 19418547
references.citation: Clin Cancer Res. 2013 Aug 1;19(15):4262-72
references.pmid: 23741066
references.citation: Clin Cancer Res. 2009 Nov 15;15(22):6841-51
references.pmid: 19861438
references.citation: Nature. 1998 Feb 19;391(6669):811-4
references.pmid: 9486654
references.citation: Pediatr Blood Cancer. 2007 Dec;49(7):928-40
references.pmid: 17066459
references.citation: Nat Rev Drug Discov. 2002 Apr;1(4):287-99
references.pmid: 12120280
references.citation: Pediatr Blood Cancer. 2008 Jan;50(1):37-45
references.pmid: 17420992
references.citation: Mol Pharmacol. 2004 Oct;66(4):956-63
references.pmid: 15235103
references.citation: Proc Natl Acad Sci U S A. 2005 Mar 8;102(10):3697-702
references.pmid: 15738394
references.citation: Pediatr Blood Cancer. 2009 Sep;53(3):509-12
references.pmid: 19418543