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Development and Maintenance of a Preclinical Patient Derived Tumor Xenograft Model for the Investigation of Novel Anti-Cancer Therapies
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Published on: September 30, 2016

Imatinib and Dasatinib Inhibit Hemangiosarcoma and Implicate PDGFR-β and Src in Tumor Growth

Erin B Dickerson1, Kevin Marley, Wade Edris

  • 1Veterinary Clinical Sciences, University of Minnesota, St Paul, MN ; Masonic Cancer Center, University of Minnesota, Minneapolis, MN.

Translational Oncology
|April 2, 2013
PubMed

Insights

Dasatinib demonstrates superior efficacy over imatinib in canine hemangiosarcoma treatment by inhibiting key growth factors. This study suggests tyrosine kinase inhibitors (TKIs) hold promise for treating soft tissue sarcomas in dogs.

Area of Science:

  • Veterinary Oncology
  • Molecular Oncology
  • Pharmacology

Background:

  • Hemangiosarcoma in dogs serves as a natural model for human angiosarcoma.
  • Receptor tyrosine kinases (RTKs) are expressed in these tumors, making them targets for tyrosine kinase inhibitors (TKIs).
  • Limited data exists on TKI efficacy in hemangiosarcoma and other soft tissue sarcomas.

Purpose of the Study:

  • To evaluate the effects of imatinib and dasatinib on canine hemangiosarcoma.
  • To assess the inhibition of platelet-derived growth factor receptor β (PDGFR-β) and Src by these TKIs.
  • To investigate the potential of TKIs in combination with doxorubicin for enhanced therapeutic outcomes.

Main Methods:

  • In vitro assessment of TKI effects on cell viability and target phosphorylation (PDGFR-β, Src).
  • In vivo evaluation using a canine hemangiosarcoma xenograft model.
  • Clinical case study involving a dog with spontaneously occurring hemangiosarcoma treated with dasatinib.

Main Results:

  • Both imatinib and dasatinib reduced cell viability, with dasatinib showing significantly greater potency.
  • Dasatinib inhibited PDGFR-β and Src phosphorylation at much lower concentrations than imatinib.
  • Both TKIs enhanced the response to doxorubicin, with dasatinib being more effective.
  • Imatinib inhibited tumor growth in a xenograft model, suggesting PDGFR-β/PDGF pathway targeting is crucial.
  • Clinically achievable doses of dasatinib were confirmed in a canine patient.

Conclusions:

  • Dasatinib is a more potent inhibitor of canine hemangiosarcoma cell viability and key signaling pathways (PDGFR-β, Src) compared to imatinib.
  • TKIs, particularly dasatinib, show potential for combination therapy with doxorubicin in treating hemangiosarcoma.
  • Targeting PDGFR-β/PDGF signaling is a viable strategy for addressing the angiogenic nature of these tumors.
  • Canine hemangiosarcoma provides a valuable large animal model for investigating TKI efficacy in soft tissue sarcomas.

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