Brivanib alaninate is a small molecule dual inhibitor currently under clinical evaluation that targets both the vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) signaling pathways. Brivanib has been shown to inhibit VEGF- and FGF2-induced proliferation in human umbilical vein endothelial cells in vitro, and is also capable of selectively inhibiting FGF2-induced proliferation based on a colorectal carcinoma cell line.1 In this study we expanded on those findings by evaluating the antiproliferative effects of brivanib across a panel of 16 human tumor cell lines following stimulation with either FGF2 or VEGF. We demonstrate that brivanib blocks FGF2-induced tumor cell proliferation at concentrations that may be obtained in the clinic, with the half maximal inhibitory concentration (IC50) values ranging from 0.7 µM to 10 µM, but did not have an effect with IC50 ≥ 10 µM when the tumor cell lines were grown in the presence of VEGF. These results suggest that FGF signaling is more likely to contribute to the direct tumor inhibitory effects observed with brivanib in vitro, whereas VEGF more likely contributes to indirect tumor growth effects by inhibiting host endothelial cell growth and formation of new tumor blood vessels. Gene expression profiling in both sensitive and resistant tumor cell lines was performed following stimulation with FGF2 (cell lines with IC50 ≤ 3 µM were considered sensitive). Gene Set Enrichment Analysis showed that of the 67 pathways tested, the FGF pathway-related genes were the most significantly induced in brivanib-sensitive cells. Such FGF pathway induction was diminished with the addition of 1 µM brivanib but not affected by the addition of 1 µM sunitinib, a small molecule inhibitor that targets VEGF and PDGF, but FGF signaling to a lesser degree. In conclusion, we demonstrate that brivanib can specifically block FGF2-induced proliferation across a panel of tumor cell lines. These data offer some insight into potential additional direct tumor inhibition properties of brivanib on FGF-dependent pathways independent of its anti-angiogenic effects. Further work is needed to better define populations of tumors that may be more dependent on FGF for growth signaling. Reference 1. Ayers M et al. Abstract presented at: American Association for Cancer Research; April 14-18 2007. Abstract 1618.
99th AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA