Growth factor receptors and related signalling pathways as targets for novel treatment strategies of hepatocellular cancer

Table 1 Agents for anti-EGFR-based therapy of solid tumours

Name	Target	Mechanism	Current status
Small molecule inhibitors
Gefitinib (Iressa)	EGFR	Reversibly acting tyrosine kinase inhibitor	Approved for NSCLC with restricted indications
			PhaseIfor HCC[133]
Erlotinib (Tarceva)	EGFR	Reversibly acting tyrosine kinase inhibitor	Approved for NSCLC and pancreatic cancer
			Phase II for hepatocellular cancer[33]
EKB-569	EGFR	Irreversibly acting tyrosine kinase inhibitor	Phase I/II for colorectal cancer[134]
			Phase II for NSCLC[135]
Lapatinib (Tykerb)	EGFR, erbB2	Reversibly acting tyrosine kinase inhibitor	Phase III for breast cancer
			Phase II for HCC[136]
Canertinib (CI-1033)	Pan-erbB	Irreversibly acting tyrosine kinase inhibitor	Phase II for SCC and ovarian cancer[137]
BMS-599626	EGFR, erbB2	Reversibly acting tyrosine kinase inhibitor	Phase II for HCC [138]
Monoclonal antibodies
Cetuximab	EGFR		Approved for colorectal cancer
			Phase III for head and neck cancer, NSCLC and pancreatic cancer
			Phase II for HCC[139]
Trastuzumab	erbB2		Approved for breast cancer
ABX-EGF	EGFR		Phase III for colorectal-, head and neck-, and renal cell cancer
Matuzumab (EMD 72 000)	EGFR		Phase I/II for NSCLC[140], ovarian-[141], pancreatic cancer[142]

Table 2 Agents for anti-IGF-1R-based cancer treatment

Name	Target	Mechanism	Current status
Small moelcule inhibitors
INSM-18	IGF-1R and HER2	Substrate competitive inhibitor	Phase I[44]
NVP-AEW541	IGF-1R	ATP-competitive inhibitor	Preclinical[63]
NVP-ADW742	IGF-1R	ATP-competitive inhibitor, activation of proapoptotic pathways	Preclinical[62]
BMS-536924	IGF1R and IR	ATP competitive inhibitor,	Preclinical[143]
Cyclolignans	IGFR-1R	IGF competitive inhibitor	Preclinical[144]
Antibodies
CP-751, 871	IGF-1R	IGF1R downregulation	PhaseIfor multiple myeloma
			Phase II for Breast-[145], lung-[146], and prostate[147] cancer
A12	IGF-1R	IGF1R down-regulation, apoptosis, cell cycle arrest	Phase I[148]
scFv-Fc	IGF-1R	IGF1R downregulation	Preclinical[149]
AVE-1642	IGF-1R	IGF1R downregulation, cell-cycle arrest, induction of apoptosis	Preclinical[69]

Table 3 Agents for anti-VEGF/VEGFR-based therapy of solid tumours

Name	Target	Mechanism	Current status
Small molecule inhibitors
Sunitinib (Sutent)	PDGFR, VEGFR, c-KIT, FLT-3	Tyrosine kinase inhibitor	Approved for advanced renal cell carcinoma and GIST (with restricted indications)[87150]
			PhaseIfor HCC[151]
Zactima (ZD6474)	VEGFR, EGFR	Tyrosine kinase inhibitor	Phase III for NSCLC[156]
			Phase II for thyroid cancer[157]
Vatalanib (PTK787/ZK 222584)	VEGFR, PDGFR, C-KIT	Tyrosine kinase inhibitor	Phase II/III for colorectal cancer[152]
			PhaseIfor HCC[153]
Anti-ligand targeting
Bevacizumab	VEGF	VEGF-neutralizing antibody	Approved for colorectal cancer
			Phase III for NSCLC[166]
			Phase II for HCC[154]
VEGF trap	VEGF	Soluble decoy receptor which neutralizes all VEGF A isoforms	PhaseIfor advanced solid tumours[155]

Table 4 Agents of multi-kinase- and growth factor independent inhibition for the therapy of solid tumours

Name	Target	Mechanism	Current status
Sorafenib	c-Raf-1,	Tyrosine kinase inhibitor	Approved for advanced RCC
	B-Raf, VEGFR, PDGFR		Phase III for advanced HCC[108]
			Phase II for melanoma[106], breast cancer[158] and NSCLC[159]
			Phase Ifor advanced solid tumours[160]
Everolimus (RAD001)	mTOR	Tyrosine kinase inhibitor	Phase II for colorectal cancer[165]
			PhaseI/II for advanced HCC[117116]
			PhaseIfor endometrial and brain tumours[111112]
Temsirolimus (CCI-779)	mTOR	Tyrosine kinase inhibitor	Phase II for metastatic breast cancer[161], advanced RCC[162], and mantle cell lymphoma[163]
			PhaseIfor advanced solid tumours (e.g. colorectal, ovarian, lung cancer)[164]
AP23573	mTOR	Tyrosine kinase inhibitor	Phase II for sarcomas of soft tissue and bone[114]
			PhaseIfor advanced solid tumours
Bortezomib (Velcade)	Proetasome	Proteasome inhibitor	Approved for multiple myeloma and mantle cell lymphoma[125]
			Phase II for colorectal cancer[166], neuroendocrine tumours[128], sarcoma[126], RCC[127], and NSCLC[129]
			PhaseI/II for unresectable HCC[132]
			PhaseIfor advanced solid tumours[167]