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Limited role for transforming growth factor-β pathway activation-mediated escape from VEGF inhibition in murine
Davide Mangani1, Michael Weller1, Emad Seyed Sadr1
1Laboratory 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.).
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.
Insights
Transforming growth factor-beta (TGF-β) can be an escape pathway from vascular endothelial growth factor (VEGF) inhibition in glioblastoma. Cotargeting these pathways may improve tumor control in specific patient subsets.
Area of Science:
- Oncology
- Cancer Biology
- Molecular Biology
Background:
- Glioblastoma growth is regulated by vascular endothelial growth factor (VEGF) and transforming growth factor-beta (TGF-β) pathways.
- The TGF-β pathway promotes angiogenesis, invasiveness, and immunosuppression, suggesting it may act as an escape mechanism from VEGF inhibition.
Purpose of the Study:
- To investigate whether the TGF-β pathway serves as an escape pathway from VEGF inhibition in glioblastoma.
- To assess the efficacy of targeting both VEGF and TGF-β pathways in preclinical glioblastoma models.
Main Methods:
- In vitro and in vivo experiments using syngeneic mouse glioma models.
- Gene expression profiling and transcriptomic analysis to identify escape pathways.
- Treatment with a VEGF antibody (B20-4.1.1) and a TGF-β receptor 1 antagonist (LY2157299), individually and in combination.
Main Results:
- TGF-β was identified as an upstream regulator of VEGF.
- Single-agent activity varied across models; B20-4.1.1 reduced tumor volume and vascular density, while LY2157299 reduced pSMAD2 levels.
- Resistance mechanisms involved distinct gene expression signatures related to angiogenesis and immune responses.
- Combination therapy showed efficacy in only one model (GL-261), associated with suppressed pSMAD2, angiogenesis, and altered immune cell infiltration.
Conclusions:
- Glioblastoma models exhibit significant biological heterogeneity.
- Combined targeting of VEGF and TGF-β pathways may offer therapeutic benefits but only in specific glioblastoma subsets.
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