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.