The Antiangiogenic Activity in Xenograft Models of Brivanib, a Dual Inhibitor of Vascular Endothelial Growth Factor Receptor-2 and Fibroblast Growth Factor Receptor-1 Kinases

Abstract

Tumor angiogenesis is a complex and tightly regulated network mediated by various proangiogenic factors. The fibroblast growth factor (FGF) and vascular endothelial growth factor (VEGF) family of growth factors, and associated tyrosine kinase receptors have a major influence in tumor growth and dissemination and may work synergistically to promote angiogenesis. Brivanib alaninate is the orally active prodrug of brivanib, a selective dual inhibitor of FGF and VEGF signaling. Here, we show that brivanib demonstrates antitumor activity in a broad range of xenograft models over multiple dose levels and that brivanib alaninate shows dose-dependent efficacy equivalent to brivanib in L2987 human tumor xenografts. Brivanib alaninate (107 mg/kg) reduced tumor cell proliferation as determined by a 76% reduction in Ki-67 staining and reduced tumor vascular density as determined by a 76% reduction in anti-CD34 endothelial cell staining. Furthermore, Matrigel plug assays in athymic mice showed that brivanib alaninate inhibited angiogenesis driven by VEGF or basic FGF alone, or combined. Dynamic contrast-enhanced magnetic resonance imaging, used to assess the effects of brivanib alaninate on tumor microcirculation, showed a marked decrease in gadopentetate dimeglumine contrast agent uptake at 107 mg/kg dose, with a reduction in area under the plasma concentrationtime curve from time 0 to 60 minutes at 24 and 48 hours of 54% and 64%, respectively. These results show that brivanib alaninate is an effective antitumor agent in preclinical models across a range of doses, and that efficacy is accompanied by changes in cellular and vascular activities. Mol Cancer Ther; 9(2); 369-78. ©2010 AACR.

Receptor Tyrosine Kinases and Targeted Cancer Therapeutics

“…Brivanib alaninate, the orally administrated L-alanine ester prodrug, has strong antiangiogenic effects, as well as potent direct effects, on tumor cells across a range of tumor types, including liver and colon. [66][67][68][69] Sorafenib, 4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)phenoxy)-N-methylpicolinamide 4-methylbenzenesulfonate, a kinase inhibitor of VEGFR, PDGFR, c-Kit, and Raf, has been approved for the treatment of hepatocellular carcinoma. Because brivanib targets both the FGF and VEGF signaling pathways, it may gain an advantage over sorafenib for the treatment of hepatocellular carcinoma.…”

Phase II, Open-Label Study of Brivanib as Second-Line Therapy in Patients with Advanced Hepatocellular Carcinoma

“…Brivanib, an oral, selective dual inhibitor of FGFR and VEGF receptor (VEGFR) tyrosine kinases, has shown antitumor activity in preclinical models of various cancers, including HCC (23)(24)(25)(26)(27). Brivanib has a half-life of 12 hours and is administered once daily at a dose of 800 mg.…”

Phase II, Open-Label Study of Brivanib as First-Line Therapy in Patients with Advanced Hepatocellular Carcinoma

“…Brivanib, the first oral selective dual inhibitor of FGF and VEGF signaling, is formulated as an orally administered L-alanine ester prodrug, brivanib alaninate (14). Brivanib has strong antiangiogenic effects, as well as potent direct effects, on tumor cells across a range of tumor types, including liver and colon (15)(16)(17). In addition, brivanib has demonstrated antitumor activity in xenograft HCC models expressing FGF receptors (17).…”