The Ewing Sarcoma (EWS) family of tumors is one of the most common tumors diagnosed in children and adolescents and is characterized by a translocation involving the EWS gene. EWS tumor cells express the receptor tyrosine kinases, platelet-derived growth factor receptor (PDGFR) and c-KIT. ABT-869(Linifanib, VEGFR/PDGFR inhibitor) is a multitargeted small-molecule inhibitor that targets Fms-like tyrosine kinase-3, c-KIT, vascular endothelial growth receptors, and PDGFRs. To determine the potential therapeutic benefit of ABT-869 in EWS cells, we examined the effects of ABT-869 on EWS cell lines and xenograft mouse models.At low micromolar concentrations ABT-869 showed decreased phosphorylation of ERK 1/2 in both the TC71 and A4573 cell lines and also showed decreased phosphorylation of AKT in the A4573 cell line. Given the higher IC50 of ABT-869 in EWS compared with in AML cells, the results suggest that the drug inhibits proliferation at least in part through suppressing the activation of the PDGFß and c-Kit receptors and their downstream targets. However, these pathways do not seem to be strong drivers of EWS cell proliferation. Additional pathways or kinases, such as VEGFR, involving angiogenesis, may be alternative mechanisms by which ABT-869 inhibits EWS cells in vivo. Imatinib which also been shown to decrease autophosphorylation of c-KIT in vitro required a dose that was much higher than ABT-869. This suggests that c-KIT inhibition alone is insufficient to provide a therapeutic effect in EWS.

To examine the effects of ABT-869 in vivo, the drug was given to mice injected with EWS cells. We observed inhibition of growth of EWS tumor cells in a xenograft mouse model and prolonged survival in a metastatic mouse model of EWS. Very little toxicity was observed in mice, suggesting that this drug could be potentially used to treat patients with EWS.

In summary, the in vitro and in vivo studies show that ABT-869 inhibits proliferation of EWS cells through inhibition of PDGFRß and c-KIT pathways.  

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Reference:

ABT-869 Inhibits the Proliferation of Ewing Sarcoma Cells and Suppresses Platelet-Derived Growth Factor Receptor ß and c-KIT Signaling Pathways