Modulating Antiangiogenic Resistance by Inhibiting the Signal Transducer and Activator of Transcription 3 Pathway in Glioblastoma
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John de Groot1,*, Ji Liang1,*, Ling-Yuan Kong2, Jun Wei2, Yuji Piao1, Gregory Fuller3, Wei Qiao4, Amy B. Heimberger2
1 Department of Neuro-Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX
2 Department of Neurosurgery, The University of Texas M.D. Anderson Cancer Center, Houston, TX
3 Department of Neuropathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX
4 Department of Biostatistics, The University of Texas M.D. Anderson Cancer Center, Houston, TX
* denotes equal contribution
Amy B. Heimberger, email:
John de Groot, email:
Keywords: bevacizumab, anti-vascular endothelial growth factor, signal transducer and activator of transcription 3, treatment failure, invasion
Received: September 14, 2012, Accepted: September 18, 2012, Published: September 19, 2012
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.
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