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A novel multi-targeted tyrosine kinase inhibitor, linifanib (ABT-869), produces functional and structural changes in tumor vasculature in an orthotopic rat glioma model

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Abstract

Tyrosine kinase inhibitors represent a class of targeted therapy that has proven to be successful for cancer treatment. Linifanib is a novel, orally active multi-targeted receptor tyrosine kinase (RTK) inhibitor that exhibits potent antitumor and antiangiogenic activities against a broad spectrum of experimental tumors and malignancies in patients. The compound is currently being evaluated in phase 2 and 3 clinical trials. To investigate the effectiveness of linifinib against gliomas and the mechanism of drug action, we characterized treatment-induced antitumor and antiangiogenic responses to linifanib in an orthotopic rat glioma model. The effect of linifanib treatment on tumor growth was determined by tumor volume assessment using anatomical magnetic resonance imaging (MRI). Changes in tumor microvessel function were evaluated with dynamic contrast-enhanced MRI (DCE-MRI). Immunohistochemistry (IHC) was applied to excised tumor samples to examine underlying changes in vascular structures and target receptor expression. Linifanib (10 mg/kg) given twice daily inhibited tumor growth following treatment for 7 days with tumor volumes being 149 ± 30 and 66 ± 7 mm3 for vehicle-and linifanib-treated groups, respectively. A significant reduction of 37 ± 13% in tumor perfusion and microvessel permeability (measured by K trans) was observed as early as 2 h after administration compared with vehicle treatment. Continuous linifanib administration further reduced K trans at later time points until the end of the study (7 days post-treatment). At day 7, K trans was reduced by 75 ± 32% for linifanib treatment compared with vehicle treatment. Significant reduction in total blood vessel density and improved vessel wall integrity were observed, and staining for target receptor expression confirmed inhibition of phospho VEGFR-2 and PDGFR-β by linifanib treatment. These results demonstrate significant antitumor and antiangiogenic activity against gliomas by linifanib, a property that may result from the inhibition of VEGFR-2 and PDGFR-β-mediated vascular changes. DCE-MRI measured K trans changes at early treatment stages may be a useful pharmacodynamic marker for linifanib activity in clinical trials, and basal K trans may provide predictive value for tumor progression.

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Acknowledgments

The authors acknowledge Dr. Ke Zhang for his help with statistical analysis and Timothy Bowlin for his contribution to the experiments. The authors also wish to thank Drs. Jaymin Upadhyay, Feng Luo, Sarah Mudd, and Rikki Waterhouse for editing the manuscript and Prasant Chandran for help with preparation of the manuscript. All studies were supported by Abbott Laboratories research funding.

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Authors and Affiliations

  1. Advanced Technology, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL, USA

    Yanping Luo, Todd B. Cole, Vincent P. Hradil, Bryan F. Cox & Gerard B. Fox

  2. Cancer Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL, USA

    Fang Jiang, David Reuter, Daniel H. Albert, Steven K. Davidsen & Evelyn M. McKeegan

  3. Exploratory Statistics, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL, USA

    Arunava Chakravartty

  4. Department R4DF, Abbott Laboratories, Building AP4A-1, 100 Abbott Park Road, Abbott Park, IL, 60064, USA

    Yanping Luo

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  1. Yanping Luo
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Correspondence to Yanping Luo.

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Luo, Y., Jiang, F., Cole, T.B. et al. A novel multi-targeted tyrosine kinase inhibitor, linifanib (ABT-869), produces functional and structural changes in tumor vasculature in an orthotopic rat glioma model. Cancer Chemother Pharmacol 69, 911–921 (2012). https://doi.org/10.1007/s00280-011-1740-7

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  • DOI: https://doi.org/10.1007/s00280-011-1740-7

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