Sorafenib (BAY 43-9006) in Hepatocellular Carcinoma Patients: From Discovery to Clinical Development

G.      Ranieri; G.      Gadaleta-Caldarola; V.      Goffredo; R.      Patruno; A.      Mangia; A.      Rizzo; R.      L. Sciorsci; C.      D. Gadaleta

Abstract

Angiogenesis and signaling through the RAS/RAF/mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK cascade have been reported to play important roles in the development of hepatocellular carcinoma (HCC). Sorafenib (Nexavar), a novel bi-aryl urea BAY 43-9006, is an orally administered multikinase inhibitor with activity against RAS/RAF kinases multikinase inhibitor with activity against RAF kinases and several receptor tyrosine kinases, including vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), FLT3, Ret, and c-Kit. It is involved in angiogenic pathway and cell proliferation. Sorafenib has demonstrated potent anti-tumor activity in in vitro studies, preclinical xenograft models of different tumor types and human clinical trials. This review summarizes the history of sorafenib from its discovery by the medicinal chemistry approach through to clinical development and ongoing trials on the combination between sorafenib and trans-arterial chemoembolization (TACE) in HCC patients.

Keywords: Bi-aryl urea BAY 43-9006, sorafenib, RAS/RAF signaling pathway, tyrosine kinase angiogenesis, VEGFR, TACE, HCC, Angiogenesis, chemoembolization, endothelial growth factor