引文著录:
杨哲, 李建基, 黄赞松. 原发性肝癌靶向药物治疗试验与临床研究进展.
世界华人消化杂志
2019; 27(7): 450-458
Progress in basic and clinical research of targeted drugs for primary hepatocellular carcinoma
Zhe Yang, Jian-Ji Li, Zan-Song Huang
Zhe Yang, Jian-Ji Li,
Graduate School of Youjiang Medical College for Nationalities, Baise 533000, Guangxi Zhuang Autonomous Region, China
Zan-Song Huang,
Department of Gastroenterology, Affiliated Hospital of Youjiang Medical College for Nationalities, Guangxi Clinical Research Center for Hepatobiliary Diseases, Baise 533000, Guangxi Zhuang Autonomous Region, China
Supported by
:
Guangxi Natural Science Foundation Project
, No.
Guicai Education 2014GXNSFAA118143
;
Guangxi Science and Technology Base and Talent Special Project (Guangxi Hepatobiliary Disease Clinical Medical Research Center Research Project)
, No.
Guike AD17129025
;
Guangxi Medical and Health Self-financing Project
, No.
Wei Z20170224
.
Corresponding author
: Zan-Song Huang, Professor, Chief Physician, Department of Gastroenterology, Affiliated Hospital of Youjiang Medical College for Nationalities, 18 Zhongshan Road, Baise 533000, Guangxi Zhuang Autonomous Region, China.
[email protected]
Received:
December 27, 2018
Revised:
January 22, 2019
Accepted:
March 15, 2019
Published online:
April 8, 2019
Hepatocellular carcinoma is one of the most common malignancies of the digestive system. Traditional treatment is not effective for advanced hepatocellular carcinoma. Sorafenib is the first molecule-targeted drug for hepatocellular carcinoma treatment. The emergence of molecule-targeted drugs provided a new choice for patients with advanced hepatocellular carcinoma. In recent years, thanks to the development of immunotherapy, many new molecule-targeted drugs have been found to significantly improve the prognosis of patients with hepatocellular carcinoma. Therefore, targeted drugs have become a research hotspot. This article reviews the progress in basic and clinical research of molecule-targeted drugs for hepatocellular carcinoma.
Chen W
, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, Jemal A, Yu XQ, He J. Cancer statistics in China, 2015.
CA Cancer J Clin
. 2016;
66
:115-132.
[
PubMed
]
[
DOI
]
Lan T
, Chang L, Rahmathullah MN, Wu L, Yuan YF. Comparative Efficacy of Interventional Therapies for Early-stage Hepatocellular Carcinoma: A PRISMA-compliant Systematic Review and Network Meta-analysis.
Medicine (Baltimore)
. 2016;
95
:e3185.
[
PubMed
]
[
DOI
]
Llovet JM
, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, de Oliveira AC, Santoro A, Raoul JL, Forner A, Schwartz M, Porta C, Zeuzem S, Bolondi L, Greten TF, Galle PR, Seitz JF, Borbath I, Häussinger D, Giannaris T, Shan M, Moscovici M, Voliotis D, Bruix J; SHARP Investigators Study Group. Sorafenib in advanced hepatocellular carcinoma.
N Engl J Med
. 2008;
359
:378-390.
[
PubMed
]
[
DOI
]
Zhu AX
. Beyond sorafenib: novel targeted therapies for advanced hepatocellular carcinoma.
Expert Opin Investig Drugs
. 2010;
19
:663-672.
[
PubMed
]
[
DOI
]
赵 海亮
, 黄 桂柳, 黄 赞松, 周 喜汉, 邓 志华, 覃 月秋. 苦参碱抑制人肝癌HepG2细胞增殖及其对VEGF、MMP-9表达的影响.
右江民族医学院学报
. 2016;
38
:1-5.
[
PubMed
]
[
DOI
]
胡 静
, 黄 赞松, 胡 高裕, 黄 明宜. 苦参素与顺铂合用对人肝癌裸鼠皮下移植瘤组织VEGF、CD31表达的影响和意义.
第三军医大学学报
. 2018;
40
:136-140.
[
PubMed
]
[
DOI
]
施 露
, 崔 世昌, 宫 琳, 袁 伟升, 徐 珞. 成纤维细胞生长因子19(FGF-19)在肝细胞癌组织中的表达及临床意义.
军事医学
. 2014;
38
:893-896.
[
PubMed
]
[
DOI
]
You H
, Ding W, Dang H, Jiang Y, Rountree CB. c-Met represents a potential therapeutic target for personalized treatment in hepatocellular carcinoma.
Hepatology
. 2011;
54
:879-889.
[
PubMed
]
[
DOI
]
Chong H
, Vikis HG, Guan K. Mechanisms of regulating the Raf kinase family.
Cell Signal
. 2003;
15
:463-469.
[
PubMed
]
[
DOI
]
Huang M
, Huang B, Li G, Zeng S. Apatinib affect VEGF-mediated cell proliferation, migration, invasion via blocking VEGFR2/RAF/MEK/ERK and PI3K/AKT pathways in cholangiocarcinoma cell.
BMC Gastroenterol
. 2018;
18
:169.
[
PubMed
]
[
DOI
]
Li JX
, Bi YP, Wang J, Yang X, Tian YF, Sun ZF. JTC-801 inhibits the proliferation and metastasis of ovarian cancer cell SKOV3 through inhibition of the PI3K - AKT signaling pathway.
Pharmazie
. 2018;
73
:283-287.
[
PubMed
]
[
DOI
]
Pawlik TM
, Reyes DK, Cosgrove D, Kamel IR, Bhagat N, Geschwind JF. Phase II trial of sorafenib combined with concurrent transarterial chemoembolization with drug-eluting beads for hepatocellular carcinoma.
J Clin Oncol
. 2011;
29
:3960-3967.
[
PubMed
]
[
DOI
]
Lee S
, Kim BK, Kim SU, Park Y, Chang S, Park JY, Kim DY, Ahn SH, Chon CY, Han KH. Efficacy of sorafenib monotherapy versus sorafenib-based loco-regional treatments in advanced hepatocellular carcinoma.
PLoS One
. 2013;
8
:e77240.
[
PubMed
]
[
DOI
]
Goyal L
, Zheng H, Abrams TA, Miksad R, Bullock AJ, Allen JN, Yurgelun MB, Clark JW, Kambadakone A, Muzikansky A, Knowles M, Galway A, Afflitto AJ, Dinicola CF, Regan E, Hato T, Mamessier E, Shigeta K, Jain RK, Duda DG, Zhu AX. A Phase II and Biomarker Study of Sorafenib Combined with Modified FOLFOX in Patients with Advanced Hepatocellular Carcinoma.
Clin Cancer Res
. 2019;
25
:80-89.
[
PubMed
]
[
DOI
]
Guan DX
, Shi J, Zhang Y, Zhao JS, Long LY, Chen TW, Zhang EB, Feng YY, Bao WD, Deng YZ, Qiu L, Zhang XL, Koeffler HP, Cheng SQ, Li JJ, Xie D. Sorafenib enriches epithelial cell adhesion molecule-positive tumor initiating cells and exacerbates a subtype of hepatocellular carcinoma through TSC2-AKT cascade.
Hepatology
. 2015;
62
:1791-1803.
[
PubMed
]
[
DOI
]
Dong XF
, Liu TQ, Zhi XT, Zou J, Zhong JT, Li T, Mo XL, Zhou W, Guo WW, Liu X, Chen YY, Li MY, Zhong XG, Han YM, Wang ZH, Dong ZR. COX-2/PGE2 Axis Regulates HIF2α Activity to Promote Hepatocellular Carcinoma Hypoxic Response and Reduce the Sensitivity of Sorafenib Treatment.
Clin Cancer Res
. 2018;
24
:3204-3216.
[
PubMed
]
[
DOI
]
Sun X
, Niu X, Chen R, He W, Chen D, Kang R, Tang D. Metallothionein-1G facilitates sorafenib resistance through inhibition of ferroptosis.
Hepatology
. 2016;
64
:488-500.
[
PubMed
]
[
DOI
]
Bruix J
, Tak WY, Gasbarrini A, Santoro A, Colombo M, Lim HY, Mazzaferro V, Wiest R, Reig M, Wagner A, Bolondi L. Regorafenib as second-line therapy for intermediate or advanced hepatocellular carcinoma: multicentre, open-label, phase II safety study.
Eur J Cancer
. 2013;
49
:3412-3419.
[
PubMed
]
[
DOI
]
D'Alessandro R
, Refolo MG, Lippolis C, Carella N, Messa C, Cavallini A, Carr BI. Modulation of Regorafenib effects on HCC cell lines by epidermal growth factor.
Cancer Chemother Pharmacol
. 2015;
75
:1237-1245.
[
PubMed
]
[
DOI
]
Tai WT
, Chu PY, Shiau CW, Chen YL, Li YS, Hung MH, Chen LJ, Chen PL, Su JC, Lin PY, Yu HC, Chen KF. STAT3 mediates regorafenib-induced apoptosis in hepatocellular carcinoma.
Clin Cancer Res
. 2014;
20
:5768-5776.
[
PubMed
]
[
DOI
]
Kudo M
, Finn RS, Qin S, Han KH, Ikeda K, Piscaglia F, Baron A, Park JW, Han G, Jassem J, Blanc JF, Vogel A, Komov D, Evans TRJ, Lopez C, Dutcus C, Guo M, Saito K, Kraljevic S, Tamai T, Ren M, Cheng AL. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial.
Lancet
. 2018;
391
:1163-1173.
[
PubMed
]
[
DOI
]
Kudo M
. Systemic Therapy for Hepatocellular Carcinoma: Latest Advances.
Cancers (Basel)
. 2018;
10
:pii: E412.
[
PubMed
]
[
DOI
]
Kimura T
, Kato Y, Ozawa Y, Kodama K, Ito J, Ichikawa K, Yamada K, Hori Y, Tabata K, Takase K, Matsui J, Funahashi Y, Nomoto K. Immunomodulatory activity of lenvatinib contributes to antitumor activity in the Hepa1-6 hepatocellular carcinoma model.
Cancer Sci
. 2018;
109
:3993-4002.
[
PubMed
]
[
DOI
]
Hsu CH
, Kang YK, Yang TS, Shun CT, Shao YY, Su WC, Sandoval-Tan J, Chiou TJ, Jin K, Hsu C, Cheng AL. Bevacizumab with erlotinib as first-line therapy in Asian patients with advanced hepatocellular carcinoma: a multicenter phase II study.
Oncology
. 2013;
85
:44-52.
[
PubMed
]
[
DOI
]
DE Pasquale MD
, de Ville de Goyet J, Monti L, Grimaldi C, Crocoli A, Castellano A. Bevacizumab Combined with Chemotherapy in Children Affected by Hepatocellular Carcinoma: a Single-center Experience.
Anticancer Res
. 2017;
37
:1489-1493.
[
PubMed
]
[
DOI
]
Zhu AX
, Park JO, Ryoo BY, Yen CJ, Poon R, Pastorelli D, Blanc JF, Chung HC, Baron AD, Pfiffer TE, Okusaka T, Kubackova K, Trojan J, Sastre J, Chau I, Chang SC, Abada PB, Yang L, Schwartz JD, Kudo M; REACH Trial Investigators. Ramucirumab versus placebo as second-line treatment in patients with advanced hepatocellular carcinoma following first-line therapy with sorafenib (REACH): a randomised, double-blind, multicentre, phase 3 trial.
Lancet Oncol
. 2015;
16
:859-870.
[
PubMed
]
[
DOI
]
Zhu AX
, Baron AD, Malfertheiner P, Kudo M, Kawazoe S, Pezet D, Weissinger F, Brandi G, Barone CA, Okusaka T, Wada Y, Park JO, Ryoo BY, Cho JY, Chung HC, Li CP, Yen CJ, Lee KD, Chang SC, Yang L, Abada PB, Chau I. Ramucirumab as Second-Line Treatment in Patients With Advanced Hepatocellular Carcinoma: Analysis of REACH Trial Results by Child-Pugh Score.
JAMA Oncol
. 2016;.
[
PubMed
]
[
DOI
]
Kudo M
, Hatano E, Ohkawa S, Fujii H, Masumoto A, Furuse J, Wada Y, Ishii H, Obi S, Kaneko S, Kawazoe S, Yokosuka O, Ikeda M, Ukai K, Morita S, Tsuji A, Kudo T, Shimada M, Osaki Y, Tateishi R, Sugiyama G, Abada PB, Yang L, Okusaka T, Zhu AX. Ramucirumab as second-line treatment in patients with advanced hepatocellular carcinoma: Japanese subgroup analysis of the REACH trial.
J Gastroenterol
. 2017;
52
:494-503.
[
PubMed
]
[
DOI
]
Kudo M
. Ramucirumab as Second-Line Systemic Therapy in Hepatocellular Carcinoma.
Liver Cancer
. 2018;
7
:305-311.
[
PubMed
]
[
DOI
]
Liu L
, Qin S, Zheng Y, Han L, Zhang M, Luo N, Liu Z, Gu N, Gu X, Yin X. Molecular targeting of VEGF/VEGFR signaling by the anti-VEGF monoclonal antibody BD0801 inhibits the growth and induces apoptosis of human hepatocellular carcinoma cells in vitro and in vivo.
Cancer Biol Ther
. 2017;
18
:166-176.
[
PubMed
]
[
DOI
]
Chen YJ
, Chi CW, Su WC, Huang HL. Lapatinib induces autophagic cell death and inhibits growth of human hepatocellular carcinoma.
Oncotarget
. 2014;
5
:4845-4854.
[
PubMed
]
[
DOI
]
Chen JY
, Chen YJ, Yen CJ, Chen WS, Huang WC. HBx sensitizes hepatocellular carcinoma cells to lapatinib by up-regulating ErbB3.
Oncotarget
. 2016;
7
:473-489.
[
PubMed
]
[
DOI
]
Chen W
, Hu QD, Xia XF, Liang C, Liu H, Zhang Q, Ma T, Liang F, Liang TB. Rapamycin enhances cetuximab cytotoxicity by inhibiting mTOR-mediated drug resistance in mesenchymal hepatoma cells.
Cancer Biol Ther
. 2014;
15
:992-999.
[
PubMed
]
[
DOI
]
Geng J
, Li X, Lang X, Qiao C, Hu M, Yang J, Feng J, Lv M. Combination of cetuximab and rapamycin enhances the therapeutic efficacy in hepatocellular carcinoma.
Technol Cancer Res Treat
. 2014;
13
:377-385.
[
PubMed
]
[
DOI
]
Xue F
, Liu Y, Zhang H, Wen Y, Yan L, Tang Q, Xiao E, Zhang D. Let-7a enhances the sensitivity of hepatocellular carcinoma cells to cetuximab by regulating STAT3 expression.
Onco Targets Ther
. 2016;
9
:7253-7261.
[
PubMed
]
[
DOI
]
Santoro A
, Simonelli M, Rodriguez-Lope C, Zucali P, Camacho LH, Granito A, Senzer N, Rimassa L, Abbadessa G, Schwartz B, Lamar M, Savage RE, Bruix J. A Phase-1b study of tivantinib (ARQ 197) in adult patients with hepatocellular carcinoma and cirrhosis.
Br J Cancer
. 2013;
108
:21-24.
[
PubMed
]
[
DOI
]
Santoro A
, Rimassa L, Borbath I, Daniele B, Salvagni S, Van Laethem JL, Van Vlierberghe H, Trojan J, Kolligs FT, Weiss A, Miles S, Gasbarrini A, Lencioni M, Cicalese L, Sherman M, Gridelli C, Buggisch P, Gerken G, Schmid RM, Boni C, Personeni N, Hassoun Z, Abbadessa G, Schwartz B, Von Roemeling R, Lamar ME, Chen Y, Porta C. Tivantinib for second-line treatment of advanced hepatocellular carcinoma: a randomised, placebo-controlled phase 2 study.
Lancet Oncol
. 2013;
14
:55-63.
[
PubMed
]
[
DOI
]
Rimassa L
, Assenat E, Peck-Radosavljevic M, Pracht M, Zagonel V, Mathurin P, Rota Caremoli E, Porta C, Daniele B, Bolondi L, Mazzaferro V, Harris W, Damjanov N, Pastorelli D, Reig M, Knox J, Negri F, Trojan J, López López C, Personeni N, Decaens T, Dupuy M, Sieghart W, Abbadessa G, Schwartz B, Lamar M, Goldberg T, Shuster D, Santoro A, Bruix J. Tivantinib for second-line treatment of MET-high, advanced hepatocellular carcinoma (METIV-HCC): a final analysis of a phase 3, randomised, placebo-controlled study.
Lancet Oncol
. 2018;
19
:682-693.
[
PubMed
]
[
DOI
]
Kelley RK
, Verslype C, Cohn AL, Yang TS, Su WC, Burris H, Braiteh F, Vogelzang N, Spira A, Foster P, Lee Y, Van Cutsem E. Cabozantinib in hepatocellular carcinoma: results of a phase 2 placebo-controlled randomized discontinuation study.
Ann Oncol
. 2017;
28
:528-534.
[
PubMed
]
[
DOI
]
Abou-Alfa GK
, Meyer T, Cheng AL, El-Khoueiry AB, Rimassa L, Ryoo BY, Cicin I, Merle P, Chen Y, Park JW, Blanc JF, Bolondi L, Klümpen HJ, Chan SL, Zagonel V, Pressiani T, Ryu MH, Venook AP, Hessel C, Borgman-Hagey AE, Schwab G, Kelley RK. Cabozantinib in Patients with Advanced and Progressing Hepatocellular Carcinoma.
N Engl J Med
. 2018;
379
:54-63.
[
PubMed
]
[
DOI
]
Decaens T
, Luciani A, Itti E, Hulin A, Roudot-Thoraval F, Laurent A, Zafrani ES, Mallat A, Duvoux C. Phase II study of sirolimus in treatment-naive patients with advanced hepatocellular carcinoma.
Dig Liver Dis
. 2012;
44
:610-616.
[
PubMed
]
[
DOI
]
Huynh H
, Chow KH, Soo KC, Toh HC, Choo SP, Foo KF, Poon D, Ngo VC, Tran E. RAD001 (everolimus) inhibits tumour growth in xenograft models of human hepatocellular carcinoma.
J Cell Mol Med
. 2009;
13
:1371-1380.
[
PubMed
]
[
DOI
]
Finn RS
, Poon RT, Yau T, Klümpen HJ, Chen LT, Kang YK, Kim TY, Gomez-Martin C, Rodriguez-Lope C, Kunz T, Paquet T, Brandt U, Sellami D, Bruix J. Phase I study investigating everolimus combined with sorafenib in patients with advanced hepatocellular carcinoma.
J Hepatol
. 2013;
59
:1271-1277.
[
PubMed
]
[
DOI
]
Zhu AX
, Kudo M, Assenat E, Cattan S, Kang YK, Lim HY, Poon RT, Blanc JF, Vogel A, Chen CL, Dorval E, Peck-Radosavljevic M, Santoro A, Daniele B, Furuse J, Jappe A, Perraud K, Anak O, Sellami DB, Chen LT. Effect of everolimus on survival in advanced hepatocellular carcinoma after failure of sorafenib: the EVOLVE-1 randomized clinical trial.
JAMA
. 2014;
312
:57-67.
[
PubMed
]
[
DOI
]
Zhang H
, Li XX, Yang Y, Zhang Y, Wang HY, Zheng XFS. Significance and mechanism of androgen receptor overexpression and androgen receptor/mechanistic target of rapamycin cross-talk in hepatocellular carcinoma.
Hepatology
. 2018;
67
:2271-2286.
[
PubMed
]
[
DOI
]
Wahl K
, Siegemund M, Lehner F, Vondran F, Nüssler A, Länger F, Krech T, Kontermann R, Manns MP, Schulze-Osthoff K, Pfizenmaier K, Bantel H. Increased apoptosis induction in hepatocellular carcinoma by a novel tumor-targeted TRAIL fusion protein combined with bortezomib.
Hepatology
. 2013;
57
:625-636.
[
PubMed
]
[
DOI
]
El Khoueiry AB
, Sangro B, Yau T, Crocenzi TS, Kudo M, Hsu C, Kim TY, Choo SP, Trojan J, Welling TH RD, Meyer T, Kang YK, Yeo W, Chopra A, Anderson J, Dela Cruz C, Lang L, Neely J, Tang H, Dastani HB, Melero I. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial.
Lancet
. 2017;
389
:2492-2502.
[
PubMed
]
[
DOI
]
