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

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.

A combination of sorafenib and SC-43 is a synergistic SHP-1 agonist duo to advance hepatocellular carcinoma therapy

“…Sorafenib is a multiple kinase inhibitor [28], and inhibits a number of angiogenic factors including RAF-1 and VEGFR [29], among others. However, several clinical trials employing other antiangiogenesis agents, such as brivanib and linifanib, to treat HCC have failed [30,31].…”

Mast Cell Positivity to Tryptase Correlates with Metastatic Lymph Nodes in Gastrointestinal Cancer Patients Treated Surgically

“…Mast cells (MCs) intervene in this process via the release of classical proangiogenic factors, such as vascular endothelial growth factor (VEGF), thymidine phosphorylase and fibroblast growth factor-2, and nonclassical proangiogenic factors, such as tryptase and chymase, which are stored in their secretory granules [4,5,6,7,8]. The role of MCs has been broadly studied both in animal and human cancers, such as MC tumors, head-and-neck, gastric, colorectal, lung and cutaneous malignancies, indicating that MC density is highly correlated with the extent of tumor angiogenesis [9,10,11,12].…”

The important roles of RET, VEGFR2 and the RAF/MEK/ERK pathway in cancer treatment with sorafenib

“…Activated ERK1 or ERK2 then either phosphorylates its target proteins in the cytoplasm or translocates to the nucleus, where the main targets are transcription factors that regulate proliferation-, differentiation-or survival-related genes. Therefore, the RAF/MEK/ERK serine/threonine kinase cascade is a key pathway that is involved in the development of cancers and is considered a potential important target for sorafenib treatment [18] . However, the mechanism by which sorafenib inhibits tumor cells and how kinases respond to sorafenib treatment are largely unclear.…”