Davide Mangani1, Michael Weller1, Emad Seyed Sadr1, Edith Willscher1, Katharina Seystahl1, Guido Reifenberger1, Ghazaleh Tabatabai1, Hans Binder1, Hannah Schneider1. 1. Laboratory of Molecular Neuro-Oncology, Department of Neurology, University Hospital and University of Zurich, Zurich, Switzerland (D.M., M.W., E.S.S., K.S., G.T., H.S.); Center for Neuroscience, University of Zurich, Zurich, Switzerland (M.W., G.T.); Interdisciplinary Center for Bioinformatics, University of Leipzig, Leipzig, Germany (E.W., H.B.); Institute of Neuropathology, Heinrich Heine University, Düsseldorf, Germany (G.R.); German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ) Heidelberg, partner site, Essen/Düsseldorf, Germany (G.R.).
Abstract
BACKGROUND: The vascular endothelial growth factor (VEGF) and transforming growth factor (TGF)-β pathways regulate key biological features of glioblastoma. Here we explore whether the TGF-β pathway, which promotes angiogenesis, invasiveness, and immunosuppression, acts as an escape pathway from VEGF inhibition. METHODS: The role of the TGF-β pathway in escape from VEGF inhibition was assessed in vitro and in vivo and by gene expression profiling in syngeneic mouse glioma models. RESULTS: We found that TGF-β is an upstream regulator of VEGF, whereas VEGF pathway activity does not alter the TGF-β pathway in vitro. In vivo, single-agent activity was observed for the VEGF antibody B20-4.1.1 in 3 and for the TGF-β receptor 1 antagonist LY2157299 in 2 of 4 models. Reduction of tumor volume and blood vessel density, but not induction of hypoxia, correlated with benefit from B20-4.1.1. Reduction of phosphorylated (p)SMAD2 by LY2157299 was seen in all models but did not predict survival. Resistance to B20 was associated with anti-angiogenesis escape pathway gene expression, whereas resistance to LY2157299 was associated with different immune response gene signatures in SMA-497 and GL-261 on transcriptomic profiling. The combination of B20 with LY2157299 was ineffective in SMA-497 but provided prolongation of survival in GL-261, associated with early suppression of pSMAD2 in tumor and host immune cells, prolonged suppression of angiogenesis, and delayed accumulation of tumor infiltrating microglia/macrophages. CONCLUSIONS: Our study highlights the biological heterogeneity of murine glioma models and illustrates that cotargeting of the VEGF and TGF-β pathways might lead to improved tumor control only in subsets of glioblastoma.
BACKGROUND: The vascular endothelial growth factor (VEGF) and transforming growth factor (TGF)-β pathways regulate key biological features of glioblastoma. Here we explore whether the TGF-β pathway, which promotes angiogenesis, invasiveness, and immunosuppression, acts as an escape pathway from VEGF inhibition. METHODS: The role of the TGF-β pathway in escape from VEGF inhibition was assessed in vitro and in vivo and by gene expression profiling in syngeneic mouseglioma models. RESULTS: We found that TGF-β is an upstream regulator of VEGF, whereas VEGF pathway activity does not alter the TGF-β pathway in vitro. In vivo, single-agent activity was observed for the VEGF antibody B20-4.1.1 in 3 and for the TGF-β receptor 1 antagonist LY2157299 in 2 of 4 models. Reduction of tumor volume and blood vessel density, but not induction of hypoxia, correlated with benefit from B20-4.1.1. Reduction of phosphorylated (p)SMAD2 by LY2157299 was seen in all models but did not predict survival. Resistance to B20 was associated with anti-angiogenesis escape pathway gene expression, whereas resistance to LY2157299 was associated with different immune response gene signatures in SMA-497 and GL-261 on transcriptomic profiling. The combination of B20 with LY2157299 was ineffective in SMA-497 but provided prolongation of survival in GL-261, associated with early suppression of pSMAD2 in tumor and host immune cells, prolonged suppression of angiogenesis, and delayed accumulation of tumor infiltrating microglia/macrophages. CONCLUSIONS: Our study highlights the biological heterogeneity of murineglioma models and illustrates that cotargeting of the VEGF and TGF-β pathways might lead to improved tumor control only in subsets of glioblastoma.
Authors: J G Messer; E J Castillo; A M Abraham; J M Jiron; R Israel; J F Yarrow; S Thomas; M C Reynolds; R D Wnek; M Jorgensen; N Wanionok; C Van Poznak; I Bhattacharyya; D B Kimmel; J I Aguirre Journal: Bone Date: 2019-11-07 Impact factor: 4.398
Authors: David Capper; Andreas von Deimling; Alba A Brandes; Antoine F Carpentier; Santosh Kesari; Juan M Sepulveda-Sanchez; Helen R Wheeler; Olivier Chinot; Lawrence Cher; Joachim P Steinbach; Pol Specenier; Jordi Rodon; Ann Cleverly; Claire Smith; Ivelina Gueorguieva; Colin Miles; Susan C Guba; Durisala Desaiah; Shawn T Estrem; Michael M Lahn; Wolfgang Wick Journal: Int J Mol Sci Date: 2017-05-06 Impact factor: 5.923
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