title: Phase I evaluation of STA-1474, a prodrug of the novel HSP90 inhibitor ganetespib, in dogs with spontaneous cancer.
abstract: BACKGROUND
  The novel water soluble compound STA-1474 is metabolized to ganetespib (formerly STA-9090), a potent HSP90 inhibitor previously shown to kill canine tumor cell lines in vitro and inhibit tumor growth in the setting of murine xenografts. The purpose of the following study was to extend these observations and investigate the safety and efficacy of STA-1474 in dogs with spontaneous tumors.
  
  
  RESULTS
  This was a Phase 1 trial in which dogs with spontaneous tumors received STA-1474 under one of three different dosing schemes. Pharmacokinetics, toxicities, biomarker changes, and tumor responses were assessed. Twenty-five dogs with a variety of cancers were enrolled. Toxicities were primarily gastrointestinal in nature consisting of diarrhea, vomiting, inappetence and lethargy. Upregulation of HSP70 protein expression was noted in both tumor specimens and PBMCs within 7 hours following drug administration. Measurable objective responses were observed in dogs with malignant mast cell disease (n = 3), osteosarcoma (n = 1), melanoma (n = 1) and thyroid carcinoma (n = 1), for a response rate of 24% (6/25). Stable disease (>10 weeks) was seen in 3 dogs, for a resultant overall biological activity of 36% (9/25).
  
  
  CONCLUSIONS
  This study provides evidence that STA-1474 exhibits biologic activity in a relevant large animal model of cancer. Given the similarities of canine and human cancers with respect to tumor biology and HSP90 activation, it is likely that STA-1474 and ganetespib will demonstrate comparable anti-cancer activity in human patients.
authors.affiliation: Department of Veterinary Biosciences, The Ohio State University, Columbus, Ohio, United States of America. london.20@osu.edu
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: London
authors.forename: Misty D
authors.initials: MD
authors.lastname: Bear
authors.forename: Jennifer
authors.initials: J
authors.lastname: McCleese
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Foley
authors.forename: Reji
authors.initials: R
authors.lastname: Paalangara
authors.forename: Takayo
authors.initials: T
authors.lastname: Inoue
authors.forename: Weiwen
authors.initials: W
authors.lastname: Ying
authors.forename: James
authors.initials: J
authors.lastname: Barsoum
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D007211:Indoles; D008297:Male; D009369:Neoplasms / Q000188:drug therapy / Q000662:veterinary*; D011355:Prodrugs / Q000627:therapeutic use*; D053719:Tandem Mass Spectrometry; D014230:Triazoles / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity
chemical_list: D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; D007211:Indoles; D011355:Prodrugs; C533237:STA 9090; D014230:Triazoles; C545221:STA-1474
references.citation: Int J Biol Macromol. 2009 Oct 1;45(3):310-4
references.pmid: 19576239
references.citation: Am J Pathol. 2010 Jan;176(1):393-401
references.pmid: 19948822
references.citation: Vet Clin North Am Small Anim Pract. 2003 May;33(3):491-516, vi
references.pmid: 12852233
references.citation: Cancer Res. 2008 Feb 15;68(4):1188-97
references.pmid: 18281495
references.citation: Biochem Cell Biol. 2005 Dec;83(6):703-10
references.pmid: 16333321
references.citation: Nature. 2003 Sep 25;425(6956):407-10
references.pmid: 14508491
references.citation: Ann N Y Acad Sci. 2007 Oct;1113:202-16
references.pmid: 17513464
references.citation: J Biol Chem. 2008 Jul 4;283(27):18473-7
references.pmid: 18442971
references.citation: Jpn J Cancer Res. 1996 Sep;87(9):908-15
references.pmid: 8878452
references.citation: Blood. 2010 Nov 25;116(22):4591-9
references.pmid: 20651072
references.citation: Nat Rev Cancer. 2005 Oct;5(10):761-72
references.pmid: 16175177
references.citation: Exp Biol Med (Maywood). 2003 Feb;228(2):111-33
references.pmid: 12563018
references.citation: Nat Biotechnol. 2006 Nov;24(11):1307
references.pmid: 17093460
references.citation: J Urol. 2007 Oct;178(4 Pt 1):1528-32
references.pmid: 17707057
references.citation: J Clin Invest. 2009 Mar;119(3):454-64
references.pmid: 19229106
references.citation: Cancer Cell. 2008 Sep 9;14(3):250-62
references.pmid: 18772114
references.citation: Cancer Res. 2006 Nov 15;66(22):10967-75
references.pmid: 17108135
references.citation: Clin Cancer Res. 2003 Jul;9(7):2755-68
references.pmid: 12855656
references.citation: Expert Opin Emerg Drugs. 2005 Feb;10(1):137-49
references.pmid: 15757409
references.citation: Oncotarget. 2010 Jul;1(3):185-97
references.pmid: 21037799
references.citation: Biochem J. 2008 Mar 15;410(3):439-53
references.pmid: 18290764
references.citation: Vet Comp Oncol. 2004 Dec;2(4):195-213
references.pmid: 19379294
references.citation: J Cancer Res Clin Oncol. 2008 Mar;134(3):281-97
references.pmid: 17965883
references.citation: Clin Cancer Res. 2007 Nov 1;13(21):6459-68
references.pmid: 17975158
references.citation: Biomarkers. 2010 Feb;15(1):31-8
references.pmid: 19747088
references.citation: Oncotarget. 2011 Mar;2(3):209-21
references.pmid: 21444945
references.citation: Clin Cancer Res. 2007 Mar 15;13(6):1625-9
references.pmid: 17363512
references.citation: BMC Genomics. 2009 Dec 23;10:625
references.pmid: 20028558
references.citation: Cancer Res. 2007 Dec 15;67(24):11942-50
references.pmid: 18089825
references.citation: Expert Opin Investig Drugs. 2009 Jun;18(6):861-8
references.pmid: 19466875
references.citation: Sci STKE. 2001 Jul 31;2001(93):re1
references.pmid: 11752668
references.citation: Nat Rev Cancer. 2010 Aug;10(8):537-49
references.pmid: 20651736
references.citation: Anticancer Res. 2007 Jan-Feb;27(1A):155-64
references.pmid: 17352227
references.citation: Med Pediatr Oncol. 2001 Jul;37(1):1-3
references.pmid: 11466715
references.citation: Exp Hematol. 2008 Oct;36(10):1266-77
references.pmid: 18657349
references.citation: Endocr Relat Cancer. 2006 Dec;13 Suppl 1:S125-35
references.pmid: 17259553
references.citation: Int J Cancer. 2009 Dec 15;125(12):2792-801
references.pmid: 19544563
references.citation: Br J Haematol. 2008 May;141(4):483-93
references.pmid: 18373709