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Single agent efficacy of the VEGFR kinase inhibitor axitinib in preclinical models of glioblastoma

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Abstract

Anti-angiogenic therapy is a promising therapeutic strategy for the highly vascular and malignant brain tumor, glioblastoma (GBM), although current clinical trials have failed to demonstrate an extension in overall survival. The small molecule tyrosine kinase inhibitor axitinib that targets vascular endothelial growth factor receptor, potently inhibits angiogenesis and has single-agent clinical activity in non-small cell lung, thyroid, and advanced renal cell cancer. Here we show that axitinib exerts direct cytotoxic activity against a number of patient-derived GBM stem cell (GSCs) and an endothelial cell line, and inhibits endothelial tube formation in vitro. Axitinib treatment of mice bearing hypervascular intracranial tumors generated from human U87 glioma cells, MGG4 GSCs and mouse 005 GSCs significantly extended survival that was associated with decreases in tumor-associated vascularity. We thus show for the first time the anti-angiogenic effect and survival prolongation provided by systemic single agent treatment with axitinib in preclinical orthotopic GBM models including clinically relevant GSC models. These results support further investigation of axitinib as an anti-angiogenic agent for GBM.

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Acknowledgments

We thank Pfizer for providing axitinib, Drs. Giulia Fulci, Brent J. Passer, and David J. Waxman for technical advice, and Melissa R. Marinelli, Andrea Murphy, Tooba Cheema, and Shinichi Esaki for their experimental help. This work was supported by a grant from the National Institute of Health (Grant number R01NS032677).

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The authors declare no conflict of interest.

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Authors and Affiliations

  1. Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA

    Lei Lu, Dipongkor Saha, Robert L. Martuza, Samuel D. Rabkin & Hiroaki Wakimoto

  2. Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, 200040, China

    Lei Lu

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  1. Lei Lu
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Correspondence to Hiroaki Wakimoto.

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Lu, L., Saha, D., Martuza, R.L. et al. Single agent efficacy of the VEGFR kinase inhibitor axitinib in preclinical models of glioblastoma. J Neurooncol 121, 91–100 (2015). https://doi.org/10.1007/s11060-014-1612-1

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