title: Imatinib and Dasatinib Inhibit Hemangiosarcoma and Implicate PDGFR-β and Src in Tumor Growth.
abstract: Hemangiosarcoma, a natural model of human angiosarcoma, is an aggressive vascular tumor diagnosed commonly in dogs. The documented expression of several receptor tyrosine kinases (RTKs) by these tumors makes them attractive targets for therapeutic intervention using tyrosine kinase inhibitors (TKIs). However, we possess limited knowledge of the effects of TKIs on hemangiosarcoma as well as other soft tissue sarcomas. We report here on the use of the TKIs imatinib and dasatinib in canine hemangiosarcoma and their effects on platelet-derived growth factor receptor β (PDGFR-β) and Src inhibition. Both TKIs reduced cell viability, but dasatinib was markedly more potent in this regard, mediating cytotoxic effects orders of magnitude greater than imatinib. Dasatinib also inhibited the phosphorylation of the shared PDGFR-β target at a concentration approximately 1000 times less than that needed by imatinib and effectively blocked Src phosphorylation. Both inhibitors augmented the response to doxorubicin, suggesting that clinical responses likely will be improved using both drugs in combination; however, dasatinib was significantly (P < .05) more effective in this context. Despite the higher concentrations needed in cell-based assays, imatinib significantly inhibited tumor growth (P < .05) in a tumor xenograft model, highlighting that disruption of PDGFR-β/PDGF signaling may be important in targeting the angiogenic nature of these tumors. Treatment of a dog with spontaneously occurring hemangiosarcoma established that clinically achievable doses of dasatinib may be realized in dogs and provides a means to investigate the effect of TKIs on soft tissue sarcomas in a large animal model.
authors.affiliation: Veterinary Clinical Sciences, University of Minnesota, St Paul, MN ; Masonic Cancer Center, University of Minnesota, Minneapolis, MN.
authors.forename: Erin B
authors.initials: EB
authors.lastname: Dickerson
authors.forename: Kevin
authors.initials: K
authors.lastname: Marley
authors.forename: Wade
authors.initials: W
authors.lastname: Edris
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Tyner
authors.forename: Vidya
authors.initials: V
authors.lastname: Schalk
authors.forename: Valerie
authors.initials: V
authors.lastname: Macdonald
authors.forename: Marc
authors.initials: M
authors.lastname: Loriaux
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Druker
authors.forename: Stuart C
authors.initials: SC
authors.lastname: Helfand
references.citation: J Biol Chem. 1999 Mar 19;274(12):8335-43
references.pmid: 10075741
references.citation: J Clin Oncol. 2010 Mar 1;28(7):1247-53
references.pmid: 20124181
references.citation: Cancer Res. 2001 Nov 15;61(22):8118-21
references.pmid: 11719439
references.citation: Eur J Cancer. 2004 Apr;40(6):858-80
references.pmid: 15120042
references.citation: Cancer Invest. 2000;18(8):781-92
references.pmid: 11107448
references.citation: Development. 1999 Jun;126(14):3047-55
references.pmid: 10375497
references.citation: Hum Pathol. 2000 Feb;31(2):185-92
references.pmid: 10685632
references.citation: J Clin Invest. 2003 Oct;112(8):1142-51
references.pmid: 14561699
references.citation: Lab Invest. 2004 May;84(5):562-72
references.pmid: 15064773
references.citation: N Engl J Med. 2005 Aug 18;353(7):701-11
references.pmid: 16107623
references.citation: Science. 1998 Jan 23;279(5350):577-80
references.pmid: 9438854
references.citation: Virchows Arch. 2010 Feb;456(2):153-66
references.pmid: 19396640
references.citation: J Clin Invest. 2003 May;111(9):1287-95
references.pmid: 12727920
references.citation: Res Vet Sci. 2006 Aug;81(1):76-86
references.pmid: 16256156
references.citation: Clin Cancer Res. 2008 Jul 1;14(13):4284-91
references.pmid: 18594011
references.citation: Top Companion Anim Med. 2009 Aug;24(3):106-12
references.pmid: 19732728
references.citation: Am J Surg Pathol. 2002 Apr;26(4):486-92
references.pmid: 11914627
references.citation: J Surg Oncol. 2008 Mar 15;97(4):321-9
references.pmid: 18286475
references.citation: Int J Cancer. 1998 Apr 13;76(2):223-7
references.pmid: 9537584
references.citation: Blood. 2007 Dec 1;110(12):4055-63
references.pmid: 17720881
references.citation: Neoplasia. 2004 Mar-Apr;6(2):106-16
references.pmid: 15140399
references.citation: Histopathology. 1990 May;16(5):455-60
references.pmid: 2163355
references.citation: Oncogene. 1996 Apr 18;12(8):1697-705
references.pmid: 8622890
references.citation: Am J Pathol. 2000 Mar;156(3):791-5
references.pmid: 10702394
references.citation: Science. 2003 Jan 31;299(5607):708-10
references.pmid: 12522257
references.citation: Cancer Res. 2012 May 15;72(10):2501-11
references.pmid: 22461510
references.citation: Bone. 2011 Sep;49(3):356-67
references.pmid: 21621658
references.citation: Nat Rev Cancer. 2008 Feb;8(2):147-56
references.pmid: 18202698
references.citation: J Clin Oncol. 2008 Feb 1;26(4):620-5
references.pmid: 18235121
references.citation: Physiol Rev. 1999 Oct;79(4):1283-316
references.pmid: 10508235
references.citation: Vet Comp Oncol. 2012 Sep;10(3):214-22
references.pmid: 22487216
references.citation: BMC Cancer. 2009 Oct 14;9:363
references.pmid: 19825192
references.citation: Cancer Cell. 2004 Sep;6(3):209-14
references.pmid: 15380511
references.citation: Xenobiotica. 2007 May;37(5):503-13
references.pmid: 17523053
references.citation: BMC Cancer. 2010 Nov 09;10:619
references.pmid: 21062482
references.citation: Proc Natl Acad Sci U S A. 2008 Apr 8;105(14):5507-12
references.pmid: 18367669
references.citation: PLoS One. 2009 May 20;4(5):e5549
references.pmid: 19461996
references.citation: J Clin Oncol. 2003 May 15;21(10):1952-60
references.pmid: 12743148
references.citation: Am J Pathol. 2007 Jan;170(1):366-76
references.pmid: 17200208
references.citation: CA Cancer J Clin. 2010 Sep-Oct;60(5):277-300
references.pmid: 20610543
references.citation: Cancer Res. 2004 Apr 15;64(8):2725-33
references.pmid: 15087386
references.citation: Exp Hematol. 2007 Oct;35(10):1510-21
references.pmid: 17681669
references.citation: Pediatr Blood Cancer. 2013 Aug;60(8):1313-9
references.pmid: 23526721
references.citation: Oncogene. 2008 Feb 7;27(7):957-65
references.pmid: 17653080
references.citation: J Natl Compr Canc Netw. 2010 Jun;8(6):630-74
references.pmid: 20581298
references.citation: J Clin Oncol. 2008 Feb 1;26(4):626-32
references.pmid: 18235122
references.citation: J Vet Intern Med. 2008 Jul-Aug;22(4):985-8
references.pmid: 18564222
references.citation: Oncogene. 1995 Feb 16;10(4):739-49
references.pmid: 7862451
references.citation: J Pathol. 2009 Mar;217(4):469-82
references.pmid: 19148905
references.citation: Clin Cancer Res. 2002 Nov;8(11):3584-91
references.pmid: 12429650
references.citation: Cancer Biol Ther. 2009 Apr;8(8):696-703
references.pmid: 19276677
references.citation: Curr Opin Cell Biol. 1997 Apr;9(2):187-92
references.pmid: 9069259
references.citation: Cancer Cell. 2006 Jul;10(1):65-75
references.pmid: 16843266
references.citation: Nat Rev Cancer. 2005 Jul;5(7):505-15
references.pmid: 16069815
references.citation: J Med Chem. 2004 Dec 30;47(27):6658-61
references.pmid: 15615512
references.citation: J Pharmacol Exp Ther. 2000 Oct;295(1):139-45
references.pmid: 10991971