Modulation of antiangiogenic resistance: Targeting the JAK/STAT3 pathway in glioblastoma.

Abstract

2011 Background: Determining the mechanism of treatment failure of antiangiogenic therapies would provide insight into either potential combination approaches or salvage therapies. Methods: Tumor and monocyte expression of phosphorylated-signal transducer and activator of transcription 3 (p-STAT3) was compared between recurrent glioblastoma patients treated with either conventional chemotherapy or bevacizumab (BEV), and secondarily validated in murine model systems of intracerebral glioma treated with either BEV or cediranib. The JAK/STAT3 inhibitor AZD1480 alone and in combination with cediranib was evaluated in immunocompetent mice bearing intracerebral GL261 xenografts to evaluate therapeutic synergy. Results: Human glioblastoma patients failing BEV have an increase in intratumoral p-STAT3- expression with a mean number of p-STAT3 expressing cells of 36.5 + 8.6% (n=7) compared to a mean of 20.2 + 4 % (n=5) in patients never receiving antiangiogenic therapy. In a separate cohort of recurrent glioblastoma patients, the up-regulation of p-STAT3 was detected in monocytes within 24 hours after initial BEV administration. In intracranial xenograft models, both BEV and cediranib extended median animal survival time, but during treatment failure BEV increased the mean percentage of p-STAT3-expressing cells to 24.6 + 6.4% (P=0.0011), and cediranib increased this to 16.2 + 1.8% (P=0.0125) relative to 9.0 + 4.4% in controls. Administration of the JAK/STAT3 inhibitor AZD1480 alone and in combination with cediranib reduced tumor hypoxia and infiltration of VEGF inhibitor-induced p-STAT3 macrophages. The combination reduced tumor volume by 80% compared to untreated controls, and by 65% compared to cediranib or AZD1480 treatment alone. Microvascular density and tumor de-differentiation were reduced, indicating that up-regulation of the STAT3 pathway can mediate resistance to antiangiogenic therapy. Conclusions: Cumulatively, these data suggest that a prominent mechanism of failure of anti-VEGF therapy in malignant glioma patients involves up-regulation of the STAT3 pathway, and resistance to antiangiogenic therapy can be modulated with inhibitors of the JAK/STAT pathway.