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 tumor hypoxia and 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.
Highlights
Patients with glioblastoma (GB) invariably develop recurrence or disease progression, limiting their median survival time to only 14.8 months despite multimodality therapy [1]
Patients with recurrent GB who were treated with bevacizumab had a mean of 36.7 + 7.4% p-STAT3 expressing cells in comparison to a recurrent glioblastoma cohort that had never received any type of vascular endothelial growth factor (VEGF) signaling inhibitor therapy that had a mean of 13.3 + 1.6% p-STAT3 expressing cells (P=0.0008 by student t-test) (Fig. 1B)
Since antiangiogenic therapy-induced vascular pruning is suspected to modulate tumor hypoxia in glioblastoma and other solid tumors and STAT-3 is known to activate and stabilize HIF-1α [20] and promote VEGF expression, we evaluated tumor hypoxia in tumors at Cediranib the time of control and cediranib treatment failure (Fig. 4C)
Summary
Patients with glioblastoma (GB) invariably develop recurrence or disease progression, limiting their median survival time to only 14.8 months despite multimodality therapy [1]. Bevacizumab, a humanized monoclonal antibody that sequesters vascular endothelial growth factor (VEGF), has been approved for treatment of recurrent GB based on the radiographic endpoint of the reduction in gadolinium-enhancement seen on T1-weighted magnetic resonance images, defining a prolongation of progressionfree survival [2]. There can be a marked reduction in the contrast-enhancing component of the tumor, progression can be detected by either an increase in the abnormal fluid-attenuated inversion recovery (FLAIR) image hyperintensity, reflective of nonenhancing tumor infiltration [3, 4], or a re-establishment of contrast enhancement, reflecting VEGF-independent angiogenesis. It has been postulated that treatment with antiangiogenic therapy selects for the emergence of the infiltrative, VEGF-independent components of GBs, for which current www.impactjournals.com/oncotarget
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