ORIGINAL ARTICLE A novel multi-targeted tyrosine kinase inhibitor, linifanib (ABT-869), produces functional and structural changes in tumor vasculature in an orthotopic rat glioma model Yanping Luo • Fang Jiang • Todd B. Cole • Vincent P. Hradil • David Reuter • Arunava Chakravartty • Daniel H. Albert • Steven K. Davidsen • Bryan F. Cox • Evelyn M. McKeegan • Gerard B. Fox Received: 1 February 2011 / Accepted: 6 September 2011 / Published online: 12 November 2011 Ó Springer-Verlag 2011 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 effective- ness 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). Immunohistochemis- try (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 mm 3 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 con- firmed inhibition of phospho VEGFR-2 and PDGFR-b 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-b-mediated vascular changes. DCE-MRI measured K trans changes at early treatment stages may be a useful pharmacodynamic marker for li- nifanib activity in clinical trials, and basal K trans may provide predictive value for tumor progression. Keywords Glioma Á Blood vessel Á Angiogenesis Á Perfusion Á Permeability Á Linifanib Á DCE-MRI Introduction Sustained angiogenesis is required for the growth of all solid cancers. Signaling through the vascular endothelial growth factor receptor (VEGFR) family plays a key role in angiogenesis and other processes necessary for tumor progression [12]. Targeting VEGF/VEGFR signaling has been proven an effective antiangiogenic approach for Y. Luo Á T. B. Cole Á V. P. Hradil Á B. F. Cox Á G. B. Fox Advanced Technology, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL, USA Y. Luo (&) Department R4DF, Abbott Laboratories, Building AP4A-1, 100 Abbott Park Road, Abbott Park, IL 60064, USA e-mail: yanping.luo@abbott.com F. Jiang Á D. Reuter Á D. H. Albert Á S. K. Davidsen Á E. M. McKeegan Cancer Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL, USA A. Chakravartty Exploratory Statistics, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL, USA 123 Cancer Chemother Pharmacol (2012) 69:911–921 DOI 10.1007/s00280-011-1740-7