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.

Table 2 Summary of potential pipeline compounds targeting novel molecular targets in several cancers

Drug	Descriptions	Phase	Type of tumour	Ref./ClinicalTrials.gov identifier
Hh signaling pathway
Erismodegib, (LDE-225)	Smo antagonist	0	Pancreatic cancer	NCT01694589
	In vitro and in vivo test results on HCC cells are not available	I	Advanced solid tumours	NCT00880308
		I	SCLC	NCT01579929
		II	Advanced or metastatic basal cell carcinoma	NCT01327053
		I/II	Medulloblastoma	NCT01125800
Vismodegib	Smo antagonist	I	HCC and lymphoma	NCT01546519
	Promotes regression of liver fibrosis and HCC tumour growth in a murine model of primary liver cancer[138]	I	Advanced or metastatic basal cell carcinoma
		II	Ovarian cancer	NCT00739661
	Shows no obvious response in patients with hepatic impairment[139]
Notch signaling pathway
MK-0752	γ-secretase inhibitor	I	Advanced solid tumour	[63]
	In vitro and in vivo test results on HCC cells are not available	I	Brain and central nervous system tumours	[64]
RO4929097	γ-secretase inhibitor	I	Refractory metastatic or locally advanced solid tumours	[65]
	Prevents tumour development and decreases liver fibrosis in mouse model[141]
		II	Metastatic colorectal cancer	[66]
Plk1
HMN-214	Stilbene derivative interferes with the subcellular spatial distribution of Plk1 at centrosomes	I	Advanced solid tumours	[79]
	In vitro and in vivo test results on HCC cells are not available
GSK461364	Reversible ATP-competitive Plk1 inhibitor	I	Advanced solid tumours and non-Hodgkin’s lymphoma	[81]
	In vitro and in vivo test results on HCC cells are not available
Arginine deprivation
ADI-PEG-20	Arginine deiminase	I	Pediatric ASS-deficient tumour	NCT01528384
	Shows its safe and efficacious in stabilizing the progression of advanced HCC in an Asian population
		II	SCLC	[142], NCT01266018
		II	Advanced melanoma	[143]
	Shows no overall survival benefit in second line setting for patients with advanced HCC
		II	Malignant pleural mesothelioma	NCT01279967
		II/III	Advanced HCC	[87,144]
BCT100/ Peg-rhArg1	Recombinant human arginase I	I	Leukemia and lymphoma	NCT01551628
	Inhibits tumour growth of HCC xenografts in mouse model[85]
		I/II	Advanced HCC	[90], NCT01092091
HDACs
Resminostat	HDACs (1, 3 & 6) inhibitor[145]	I/II	Advanced HCC	[146]
	Combined with sorafenib shows no significant efficacy advantage over sorafenib monotherapy in patients with advanced HCC in East Asian populations	II	Hodgkin's lymphoma	NCT01037478
		I/II	Advanced colorectal carcinoma	NCT01277406
Chidamide	HDACs inhibitor (1, 2, 3 & 10)[147]	I	Advanced solid tumours and lymphomas	[148]
	Inhibits proliferation of HCC cells in vitro[95]
Panobinostat,(LBH-589)	Pan-HDAC inhibitor Inhibits tumour growth and lung metastasis of HCC xenografts in mouse model[149]	I	Prostate carcinoma	[150]
		I	Advanced solid tumours	[151]
		II	Refractory metastatic renal cell carcinoma	[152]
Glypican-3
Codrituzumab (GC33)	Anti-GPC3 monoclonal antibody	I	Advanced or metastatic HCC	[153]
	Inhibits tumour growth of HCC xenografts in mouse model[102]
	Shows no clinical benefit in advanced HCC patients who has failed prior systemic therapy

HCC: Hepatocellular carcinoma; HDAC: Histone deacetylase; Plk1: Polo-like kinase-1; SCLC: Small cell lung cancer; Smo: Proto-oncoprotein smoothened.

Table 3 Clinical study of combined molecular targeted therapy based on sorafenib treatment for hepatocellular carcinoma

Drug + Sorafenib	Phase	Ref./ClinicalTrials.gov identifier
VEGF inhibitors
Bevacizumab	I/II	NCT00867321
Lenvatinib	I/II (HCC)	NCT01271504
mTOR inhibitor
Everolimus (RAD001)	II	NCT01005199
	I/II	[154]
Temsirolimus	I/II	NCT01335074, NCT01687673, NCT01008917
HDAC inhibitors
Resminostat	II (Advanced HCC)	NCT00943449
Panobinostat	I (HCC)	NCT00823290
Anti-GPC3 antibody
GC33	I	NCT00976170
MEK1 inhibitor
Selumetinib (AZD6244)	I/II	NCT01029418
HGFR inhibitor
Tivantinib (ARQ197)	I	NCT00827177
TNF-α secretion inhibitor
Lenalidomide	I	NCT01348503
TRAIL receptor 1 antibody
Mapatumumab	I/II	NCT00712855, NCT01258608

HGFR: Hepatocyte growth factor receptor; TNF-α: Tumour necrosis factor-α; TRAIL: Anti-TNF-related apoptosis-inducing ligand; HCC: Hepatocellular carcinoma; VEGF: Vascular endothelial growth factor; mTOR: Mammalian target of rapamycin.