Targeting angiogenesis driven by fibroblast growth factor using RPT835, an FGFR2 inhibitor.

Abstract

e22097 Background: The fibroblast growth factor (FGF)/FGF receptors (FGFR) signaling axis plays a key role in driving tumor angiogenesis. There is little data on the targeting of FGF-induced angiogenesis. We describe here the targeting angiogenesis driven by FGF using RPT835, novel inhibitor of the FGFR2 extracellular domain (received from RusPharmTech, LLC). Methods: To assess the efficacy of RPT835 on FGF-mediated endothelial cells proliferation, the human umbilical vein endothelial FGFR-expressing cells (HUVEC) were incubated in a 96-well microculture plate and were treated with serially diluted RPT835 or Brivanib as a control. Basic FGF was added at a concentration of 25 ng/ml. Control wells were left untreated. Cell growth inhibition was determined using Promega’s Cell Titer-Glo assay. In vivo angiogenesis was measured with subcutaneously implanted Matrigel plugs containing bFGF (100 ng/ml) or bFGF (100 ng/ml) + bevacizumab (10 mg/kg) or bFGF (100 ng/ml) + RPT835 (15 mg/kg). Control group was without stimulation and treatment. Each group included 3 mice. Number of endothelial cells/vessels was calculated. Results: Basic FGF significantly increased proliferation of the HUVEC cells (P=0.001) in untreated control group. RPT835 significantly inhibited FGF-triggered endothelial cell proliferation when compared with control (P<0.001) or brivanib (P<0.001, IC50=289 nmol/L) with IC50 of 11 nmol/L. In vivo, bFGF induced proliferation of endotheliocytes and mature vessels formation (P<0.001). There were no vessels in FGFR2 inhibitor group. Bevacizumab did not decrease number of vessels in comparison with FGF-stimulated angiogenesis (P=0.9). Conclusions: Inhibition of bFGF/FGFR2 pathway resulted in effects on endothelial cells proliferation andmature vessels formation. Bevacizumab had no activity in FGF-induced angiogenesis.