Beschreibung:
<jats:title>Abstract</jats:title><jats:sec><jats:label /><jats:p>Targeting the vascular endothelial growth factor signaling axis in glioblastoma inevitably leads to tumor recurrence and a more aggressive phenotype. Therefore, other angiogenic pathways, like the angiopoietin/tunica interna endothelial cell kinase (<jats:styled-content style="fixed-case">TIE</jats:styled-content>) signaling axis, have become additional targets for therapeutic intervention. Here, we explored whether targeting the receptor tyrosine kinase <jats:styled-content style="fixed-case">TIE</jats:styled-content>‐2 using a novel, highly potent, orally available small molecule <jats:styled-content style="fixed-case">TIE</jats:styled-content>‐2 inhibitor (<jats:styled-content style="fixed-case">BAY</jats:styled-content>‐826) improves tumor control in syngeneic mouse glioma models. <jats:styled-content style="fixed-case">BAY</jats:styled-content>‐826 inhibits <jats:styled-content style="fixed-case">TIE</jats:styled-content>‐2 phosphorylation <jats:italic>in vitro</jats:italic> and <jats:italic>in vivo</jats:italic> as demonstrated by suppression of Angiopoietin‐1‐ or Na<jats:sub>3</jats:sub><jats:styled-content style="fixed-case">VO</jats:styled-content><jats:sub>4</jats:sub>‐induced <jats:styled-content style="fixed-case">TIE</jats:styled-content>‐2 phosphorylation in glioma cells or extracts of lungs from <jats:styled-content style="fixed-case">BAY</jats:styled-content>‐826‐treated mice. There was a trend toward prolonged survival upon single‐agent treatment in two of four models (<jats:styled-content style="fixed-case">SMA</jats:styled-content>‐497 and <jats:styled-content style="fixed-case">SMA</jats:styled-content>‐540) and there was a significant survival benefit in one model (<jats:styled-content style="fixed-case">SMA</jats:styled-content>‐560). Co‐treatment with <jats:styled-content style="fixed-case">BAY</jats:styled-content>‐826 and irradiation was ineffective in one model (<jats:styled-content style="fixed-case">SMA</jats:styled-content>‐497), but provided synergistic prolongation of survival in another (<jats:styled-content style="fixed-case">SMA</jats:styled-content>‐560). Decreased vessel densities and increased leukocyte infiltration were observed, but might be independent processes as the effect was also observed in single treatment modalities. These data demonstrate that <jats:styled-content style="fixed-case">TIE</jats:styled-content>‐2 inhibition may improve tumor response to treatment in highly vascularized tumors such as glioblastoma.</jats:p></jats:sec><jats:sec><jats:label /><jats:p>
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