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. 2012 Apr;69(4):911-21. doi: 10.1007/s00280-011-1740-7. Epub 2011 Nov 12.

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 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 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain Neoplasms / blood supply*
  • Brain Neoplasms / drug therapy*
  • Brain Neoplasms / enzymology
  • Cell Growth Processes / drug effects
  • Disease Models, Animal
  • Female
  • Glioma / blood supply*
  • Glioma / drug therapy*
  • Glioma / enzymology
  • Glioma / pathology
  • Immunohistochemistry
  • Indazoles / pharmacology*
  • Magnetic Resonance Angiography
  • Neovascularization, Pathologic / drug therapy
  • Neovascularization, Pathologic / pathology
  • Phenylurea Compounds / pharmacology*
  • Protein Kinase Inhibitors / pharmacology*
  • Rats
  • Rats, Inbred F344
  • Receptor Protein-Tyrosine Kinases / antagonists & inhibitors
  • Xenograft Model Antitumor Assays

Substances

  • Indazoles
  • N-(4-(3-amino-1H-indazol-4-yl)phenyl)-N1-(2-fluoro-5-methylphenyl)urea
  • Phenylurea Compounds
  • Protein Kinase Inhibitors
  • Receptor Protein-Tyrosine Kinases