Modulating antiangiogenic resistance by inhibiting the signal transducer and activator of transcription 3 pathway in glioblastoma

John de Groot*, Ji Liang, Ling Yuan Kong, Jun Wei, Yuji Piao, Gregory Fuller, Wei Qiao, Amy B. Heimberger

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Determining the mechanism of treatment failure of VEGF signaling inhibitors for malignant glioma patients would provide insight into approaches to overcome therapeutic resistance. In this study, we demonstrate that human glioblastoma tumors failing bevacizumab have an increase in the mean percentage of p-STAT3-expressing cells compared to samples taken from patients failing non-antiangiogenic therapy containing regimens. Likewise, in murine xenograft models of glioblastoma, the mean percentage of p-STAT3-expressing cells in the gliomas resistant to antiangiogenic therapy was markedly elevated relative to controls. Administration of the JAK/STAT3 inhibitor AZD1480 alone and in combination with cediranib reduced the infiltration of VEGF inhibitor-induced p-STAT3 macrophages. Thus, the combination of AZD1480 with cediranib markedly reduced tumor volume, and microvascular density, indicating that up regulation of the STAT3 pathway can mediate resistance to antiangiogenic therapy and combinational approaches may delay or overcome resistance.

Original languageEnglish (US)
Pages (from-to)1036-1048
Number of pages13
JournalOncotarget
Volume3
Issue number9
DOIs
StatePublished - Sep 2012
Externally publishedYes

Keywords

  • Anti-vascular endothelial growth factor
  • Bevacizumab
  • Invasion
  • Signal transducer and activator of transcription 3
  • Treatment failure

ASJC Scopus subject areas

  • Oncology

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