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Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

Postal Subscription Code 80-967

2018 Impact Factor: 1.847

Front Med    2012, Vol. 6 Issue (2) : 122-133     DOI: 10.1007/s11684-012-0193-7
REVIEW |
Translational medicine in hepatocellular carcinoma
Qiang Gao1,2, Yinghong Shi1,2, Xiaoying Wang1,2, Jian Zhou1,2,3, Shuangjian Qiu1,2, Jia Fan1,2,3()
1. Liver Cancer Institute, Zhongshan Hospital, Shanghai Medical School, Fudan University, Shanghai 200032, China; 2. Key Labolatory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai 200032, China; 3. Institute of Biomedical Sciences, Fudan University, Shanghai 200032, China
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Abstract  

Hepatocellular carcinoma (HCC) is a highly complex disease that is generally resistant to commonly used chemotherapy and radiotherapy. Consequently, there is an urgent need for the development of new treatment strategies for this devastating disease. In the past decade, tremendous progress has been achieved in the molecular stratification of HCCs for diagnosis, prognosis, and therapeutic decision-making. To date, the molecular classification of HCCs has been carried out through transcriptomic, genetic and epigenetic profiling of tumors. Such research has led to identification of several potential molecular targets in HCC, and subsequently, development of novel systemic agents for the treatment of HCC has begun in earnest. In this article, we review the current knowledge of the molecular pathogenesis of HCC and outline potential areas for application of this knowledge in a clinical setting. As a typical virus and inflammation-associated cancer, both host immune response and tumor microenvironment have crucial roles in HCC pathogenesis. In addition, we examine the potential of immunotherapy and strategies targeting various components of the tumor microenvironment, as well as novel molecular and cellular targets in HCC such as cancer stem cells.

Keywords hepatocellular carcinoma      molecular classification      molecular targeted therapies      tumor microenvironment      immunotherapy     
Corresponding Authors: Fan Jia,Email:jiafan99@yahoo.com   
Issue Date: 05 June 2012
URL:  
http://academic.hep.com.cn/fmd/EN/10.1007/s11684-012-0193-7     OR     http://academic.hep.com.cn/fmd/EN/Y2012/V6/I2/122
DrugsPhasesTrials, nTargets
1Sorafenib1, 1–2, 2, 3, 467BRAF, VEGFR, PDGFR
2Brivanib1, 2, 36FGFR, VEGFR, PDGFR
3Sunitinib2, 36VEGFR, PDGFR, CKIT
4Linifanib2, 32VEGF, PDGFR
5Ramucirumab31VEGFR2
6Bevacizumab1, 1–2, 220VEGF
7Cediranib1, 23VEGFR
8AZD62441–2, 24MEK
9Bortezomib1, 24Proteasome
10TAC-1011–2, 24RAR-a
11Everolimus1, 1–2, 2, 37MTORC1
12Rapamycin1, 2–3, 36MTORC1
13Temsirolimus1, 24MTORC1
14AZD80551–21MTORC1, MTORC2
15ARQ1971, 22MET
16Foretinib11MET
17Erlotinib1, 1–2, 2, 313EGFR
18Cetuximab1, 23EGFR
19Ge?tinib22EGFR
20Lapatinib22EGFR, HER2/neu
21BIBF112022VEGFR, PDGFR, FGFR
22Pazopanib22VEGFR, PDGFR, CKIT
23Licartin2, 42HAb18G/CD147
24Alvocidib1, 22Cyclin-dependent kinase
25Cixutumumab1, 23IGF-1R
26OSI-90622IGF-1R, IR
27BIIB0221–21IGF-1R
28AVE16421, 21IGF-1R
29IMC-A1221IGF-1R
30PI-882, 33Endo-β-D-glucuronidase heparinase
31Mapatumumab1–21TRAIL
32CS-100821TRAIL
33CT-0111–21PD1
34Tremelimumab21B7-CD28
35AMG38621Angiopoietin
36Regorafenib21VEGFR, TIE-2
37E70801–21VEGFR, FGFR, SCFR
38IMC-1121B21VEGFR2
39TSU-681–21VEGFR, FGFR, PDGFR
40Axitinib21VEGFR, PDGFR, CKIT
41Vandetanib21EGFR, VEGFR, RET
42Lenalidomide11VEGF
43Dasatinib22BCR-ABL
44IDN-655621Caspase
45AEG351561–21XIAP
46Oblimersen21BCL2
47LY21813081–21Survivin
48Lonafarnib21Farnesyl-OH-transferase
49Ispinesib21Kinesin spindel protein
50MLN823721Aurora kinase
51GC3312GPC3
52Belinostat1–21Histone deacetylase
53LBH58911Histone deacetylase
54Panobinostat11Histone deacetylase
55Resminostat21Histone deacetylase
56Vorinostat11Histone deacetylase
57Talabostat11Dipeptidyl peptidases
58Z-2081–21RAR
59OPB-311211–21STAT3
Tab.1  Molecular therapies currently under evaluation in HCC
YearStrategiesPatients, nResponsesReferences
2000Adjuvant: activated autologous lymphocytes vs. no treatment75/75Longer RFS after transfer of activated lymphocytes[63]
Advanced HCC: IFN-α2b vs. no treatment28/30No survival difference[65]
Adjuvant: IFN-β vs. no treatment10/10Recurrence rate after 24 months: 0 vs. 100% without treatment[66]
2001Adjuvant: IFN-α vs. no treatment15/15Recurrence rate: 5/15 vs. 12/15 without treatment[67]
2002Advanced HCC: GM-CSF+ IFN-α15OS after 26 weeks: 40%[68]
Advanced HCC: low dose IL-2182/18 CR, 1/18 PR[69]
2003Advanced HCC: DC pulsed with autologous tumor10Feasibility[70]
Advanced HCC: 5-FU IFN-α2b431/36 CR, 8/36 PR[71]
Advanced HCC: doxorubicin+ 5-FU IFN-α2b302/30 PR[72]
2004Adjuvant: formalin-fixed tumor vaccine vs. no treatment9/13Recurrence rate: 3/18 vs. 13/21 without treatment[73]
Advanced HCC: CIK13Feasibility[74]
Advanced HCC: 131I-Hepama-1 mAb32Median survival: 3 months[75]
2005Advanced HCC: tumor lysate-pulsed DC314/31 PR[76]
Advanced HCC: cisplatin+ doxorubicin+ 5-FU+ IFN-2α264/26 PR[77]
Advanced HCC: local radiation+ intratumoral DC injection142/12 PR[78]
2006Advanced HCC: DC pulsed with AFP peptides10AFP-specific T cells in 6/10 patients[79]
Advanced HCC: 131I-labeled Hab18G/CD147- specific mAb1066/73 PR, 14/73 minor response, 43/73 stable disease; 21-month survival rate: 44.54%[80]
Adjuvant: IFN-α vs. no treatment150No difference in RFS; a benefit on late recurrences in HCV-pure patients (HR: 0.3; 95% CI: 0.09-0.9; P = 0.04)[81]
Adjuvant: IFN-α vs. no treatment236Median OS 63.8 months vs. 38.8 months in control group; Median RFS 31.2 vs. 17.7 months in control group[82]
2007Adjuvant: IFN-α vs. no treatment40No survival benefit for TNM stage I/II tumors; 5-year survival of stage III/IVA tumors 68% vs. 24% without treatment[83]
Adjuvant: IFN-α vs. no treatment1275-year survival rate 83% vs. 66% without treatment[84]
2008Advanced HCC: TACE+ autologous CIK85The 1-year and 18-month recurrence rates: 8.9% and 15.6% vs. 30.0% and 40.0% of the control group[85]
Advanced HCC: thymostimulin442/39 CR (one after RF), 5/39 PR, 24/39 disease[86]
2009Adjuvant: CIK vs. no treatment127Disease-free survival rates significantly higher in CIK-I (P = 0.001) and CIK-II groups (P = 0.004) than in control group[87]
Advanced HCC: DC pulsed with tumor lysate351/35 PR, 28% PR or stable disease[88]
2010Advanced HCC: low-dose cyclophosphamide13Decrease in frequency and function of regulatory T cells; unmask of AFP-specific T cell responses in 6/13[89]
2011Advanced HCC: HLA-A2-restricted GPC3 peptide vaccine14Increase in specific CTL frequency and function in 12/14[90]
Tab.2  Immunotherapy trials in HCC since 2000 (modified according to Greten [])
Fig.1  The immunosuppressive microenvironment of HCC. Antitumor response at the tumor microenvironment is rerouted in a tumor-promoting direction. Tumor suppression mediated by regulatory T cells (Tregs), tumor-associated macrophages (TAM) /neutrophils (TAN), myeloid-derived suppressor cells (MDSC) and various immuno-inhibitory molecules, such as B7-H1, B7-H3, HLA-G and soluble factors, counterbalances the antitumor effect of cytotoxic T cells (CTLs), T helper cells, natural killer cells (NKs), and dendritic cells (DCs). TAM and TAN are distinct M2 and N2 polarized populations, respectively, and promote tumor progression.
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