Novel molecular targets in hepatocellular carcinoma

Table 1 Summary of current molecular targeted compounds under phase II/III clinical studies for the treatment of hepatocellular carcinoma

Drug	Targets	Descriptions	Ref./ClinicalTrials.gov identifier
Phase II
Bevacizumab	VEGF	Monoclonal antibody	[116-118]
		Inhibits tumour growth of HCC cell line or patient-derived HCC xenografts
		Shows significant antitumour activity in patients with non-metastatic HCC, but serious bleeding complications occurs in 11% of patients.
Cediranib	VEGFR	Tyrosine kinase inhibitor	[119]
		Shows high toxicity and ineffective for patients with unresectable or metastatic HCC
Cetuximab	EGFR	Human-mouse chimeric monoclonal antibody	[120]
		Shows no obvious response in patients with advanced HCC
Dovitinib	c-KIT, Flt-3, FGFR, VEGFR	Multikinase inhibitor	[38,121]
		Significantly prolongs survival and inhibits primary tumour growth and lung metastasis in HCC xenograft models
		Shows less antitumour activity than sorafenib as a frontline systemic therapy for HCC
Erlotinib	EGFR	Tyrosine kinase inhibitor	[122,123]
		Shows modest prolonged progression-free survival and overall survival in patients with unresectable HCC
Gefitinib	EGFR	Tyrosine kinase inhibitor	NCT00071994, [124]
		Inhibits tumour growth of HCC xenografts in mouse model
Selumetinib	MEK1	Tyrosine kinase inhibitor	[125,126]
		Suppresses tumour growth of HCC xenografts in mouse model
		Shows inadequate antitumour activity with no radiographic response and short progression-free survival in patients with locally advanced or metastatic HCC
Phase III
Brivanib	FGFR, VEGFR	Tyrosine kinase inhibitor	[127-129]
		Inhibits tumour growth of patient-derived HCC xenografts by increasing apoptosis, reducing microvessel density and decreasing VEGFR phosphorylation
		Shows promising antitumour activity in patients with advanced HCC
Linifanib	PDGFR, VEGFR	Receptor tyrosine kinase inhibitor	[39,130,131]
		Inhibits tumour growth of HCC xenografts in mouse model
		Shows similar overall survival in patients with advanced HCC as compared with sorafenib
Sunitinib	c-Kit, Flt-3, PDGFP, VEGFR	Multi-targeted receptor tyrosine kinase inhibitor	[132-134]
		Inhibits tumour growth of patient-derived HCC xenografts by increasing apoptosis and reducing microvessel density
		Shows significantly poorer overall survival than sorafenib in patients with advanced HCC, and shows more frequent and severe toxicity in treated patients
TSU-68 (Orantinib)	FGFR, PDGFR, VEGFR	Tyrosine kinase inhibitor	[135-137]
		Suppresses the tumour growth of subcutaneously co-injected HCC cell lines (Huh7/WI-38) xenografts
		Orantinib combined with TACE shows no improvement in overall survival in patients with unresectable HCC

EGFR: Epidermal growth factor receptor; FGFR: Fibroblast growth factor receptor; Flt-3: FMS-like tyrosine kinase-3; HCC: Hepatocellular carcinoma; MEK1: Mitogen-activated protein kinase (MAPK) kinase; PDGFR: Platelet-derived growth factor receptor; TACE: Transcatheter arterial chemoembolization; VEGF: Vascular endothelial growth factor; VEGFR: Vascular endothelial growth factor receptor.