Current Status of Molecular Targeted Therapies in Hepatocellular Carcinoma

Sang Jun Suh; Hyung Joon Yim

doi:10.4166/kjg.2013.61.3.136

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Suh and Yim: Current Status of Molecular Targeted Therapies in Hepatocellular Carcinoma

Review Article

Korean J Gastroenterol 2013;61(3):136-146.

Published online: 4 October 2013

DOI: https://doi.org/10.4166/kjg.2013.61.3.136

Current Status of Molecular Targeted Therapies in Hepatocellular Carcinoma

Sang Jun Suh, Hyung Joon Yim

Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea

Correspondence to: Hyung Joon Yim, Department of Internal Medicine, Korea University Ansan Hospital, Korea University College of Medicine, 123 Jeokgeum-ro, Danwon-gu, Ansan 425-707, Korea. Tel: +82-31-412-6565, Fax: +82-31-412-5582, E-mail: gudwns21@medimail.co.kr

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer death in Korea. Curative treatment is only possible when the disease is diagnosed at the early stage. The prognosis of patients with HCC is even dismal in advanced stages. No systemic cytotoxic chemotherapy has proven to be beneficial in overall survival. Recently, the understanding of the molecular pathogenesis led to the development of new therapies. With the evidence of dysregulation of critical genes associated with cellular proliferation, growth factor signaling, cell cycling, apoptosis, and angiogenesis in HCC, a number of molecular target agents are under clinical trials. Sorafenib is the first systemic anticancer drug which has proven to gain survival benefit in the global as well as Asia-Pacific trials. However, the survival gain is still modest, and further efforts to improve outcomes in patients with HCC are necessary by developing novel drugs or combining other forms of therapies. This article will review signaling pathways in HCC and introduce molecular target agents under investigation currently.

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Keywords: Hepatocellular carcinoma, Pathogenesis, Signaling pathway, Molecular targeted therapy, Sorafenib

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Fig. 1.

Potential molecular targets and intracellular signaling pathways in hepatocellular carcinoma (modified from Fig. 2 in the article of Llovet and Bruix [Hepatology 2008;48:1312–1327]³ with the copyright holder' s permission). EGF, epidermal growth factor; VEGF, vascular endothelial growth factor; PDGF, platelet-derived growth factor; FGF, fibroblast growth factor; SCF, stem cell factor; IGF, insulin-like growth factor; IGFBP, insulin-like growth factor binding protein; HGF, hepatocyte growth factor; EGFR, EGF receptor; VEGFR, VEGF receptor; PDGFR, PDGF receptor; FGFR, FGF receptor; IGFR, IGF receptor; MEK, mitogen-activated protein kinase/extracellular signaling-regulated kinase kinase; ERK, extracellular signaling-regulated kinase; PI3K, phosphoinositide 3-kinase; PTEN, phosphatase and tensin homolog; mTOR, mammalian target of rapamycin; HIF, hypoxia-inducible factor; LRP5/6, low-density lipoprotein-related protein 5/6; GSK-3β, glycogen synthase kinase 3β; CK1, casein kinase 1; β-cat, β-catenin; APC, adenomatous polyposis coli; TCF, T-cell factor; Dvl, dishevelled.

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Table 1.

Molecular Targets and Pathways in Hepatocellular Carcinoma ^a

Mechanism	Target	Examples of agents
Signal transduction	Ras	Inhibitors of farnesyl transferase
	Raf	Raf kinase inhibitor (sorafenib)
	MEK	Selumetinib (AZD6244)
	PI3K	RG7321
	Akt	MK2206
	mTOR	Everolimus (RAD001), temsirolimus, AZD8055
	c-Met	ARQ197
	c-kit	Dasatinib
Angiogenesis	VEGF	Bevacizumab
	VEGFR	Tyrosine kinase inhibitor (e.g., sorafenib, sunitinib, brivanib, linifanib [ABT869], AZD2171, TSU68, E7080)
	PDGFR	Tyrosine kinase inhibitor (e.g., sunitinib)
	FGFR	Brivanib, TSU68
Growth factors	EGFR	Monoclonal antibody (e.g., cetuximab)
		Tyrosine kinase inhibitor (e.g., erlotinib, gefitinib, lapatinib)
	IGF	IMC-A12, AVE1642, OSI-906

^a New molecular agents targeting extrinsic/intrinsic apoptotic pathway, hedgehog signaling, JAK/STAT signaling, TGF-β signaling, notch pathway, ubiquitin-proteosome pathway, nuclear factor-κ B signaling, cell cycle control, and the role of the tumor micro-environment are under investigating, but in the very early stage. MEK, mitogen-activated protein kinase/extracellular signaling-re-gulated kinase kinase; PI3K, phosphoinositide 3-kinase; mTOR, mammalian target of rapamycin; VEGF, vascular endothelial growth factor; VEGFR, VEGF receptor; PDGFR, platelet-derived growth factor receptor; FGFR, fibroblast growth factor receptor; EGFR, epidermal growth factor receptor; IGF, insulin-like growth factor.

Table 2.

Ongoing Clinical Trials (Phase II or III)

Molecular targeted therapies under clinical trials	Status
First line
Comparison study between sorafenib and single agent (head to head)
Sunitinib → endpoint not met	Phase III terminated
Brivanib → endpoint not met	Phase III completed
Linifanib (ABT-869) → endpoint not met	Phase III terminated
Combination of sorafenib and another agent
Sorafenib＋ erlotinib	Phase III
Sorafenib＋ AVE1642	Phase I/II
Sorafenib＋ OSI-906	Phase III
Sorafenib＋ temsirolimus (Torisel)	Phase I/II
Sorafenib＋ selumetinib (AZD6244)	Phase I/II
Combination of new agents
Erlotinib＋ bevacizumab	Phase II
Erlotinib＋ AVE1642	Phase I/II
Erlotinib＋ celecoxib	Phase I/II
Bevacizumab＋ everolimus	Phase II
Combination of new agents and cytotoxic agents
Erlotinib＋ GEMOX	Phase II
Erlotinib＋ docetaxel	Phase II
Cetuximab＋ CAPEOX	Phase II
Bevacizumab＋ TACE	Phase II
Bevacizumab＋ GEMOX	Phase II
Second line
Sorafenib failure
Brivanib → endpoint not met	Phase III completed
Everolimus (RAD001), ramucirumab, axitinib, etc.	Phase III
Combination of sorafenib to standard therapies
Adjuvant setting after surgery or RFA: STORM	Phase III
Combination with TACE: SPACE, BRISK-TA, TACTICS	Phase III

GEMOX, gemcitabine-oxaliplatin; CAPEOX, capecitabine-oxaliplatin; TACE, transarterial chemoembolisation; RFA, radiofrequency ablation; STORM, sorafenib as adjuvant treatment in the prevention of recurrence of hepatocellular carcinoma (NCT00692770); SPACE, sorafenib (SOR) or placebo (PL) in combination with TACE for intermediate-stage hepatocellular carcinoma; BRISK-TA, phase III transarterial chemoembolization (TACE) adjuvant HCC (NCT00908752); TACTICS, transcatheter arterial chemoembolization therapy in combination with sorafenib (NCT01217034).

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