原发性肝癌分子靶向治疗基础与临床研究进展
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摘要
原发性肝癌是世界上发病率第2的癌症,已成为我国癌症相关死亡原因中最常见的原因之一,对病人及患者家庭带来巨大的病痛和经济负担.传统的治疗方法迄今并未取得令人满意的效果,人们逐渐将目光转向有着精确性、不良反应小等诸多优点的靶向药物治疗.已有研究证实靶向药物索拉非尼的上市能改善原发性肝癌患者生存期,开启肿瘤靶向治疗的新纪元,近年来,肝癌的分子靶向治疗成为研究热点,随着研究的深入,已发现多种新型分子靶向药物能改善中晚期肝癌患者的预后.本文旨在阐述原发性肝癌分子靶向治疗基础与临床研究的最新进展.
As the second most common cancer in the world, primary liver cancer has become one of the most common causes of cancer-related death in China, causing great pain and financial burden to patients and their families. Traditional treatment methods have not achieved satisfactory results so far, and people are gradually turning their attention to targeted drug therapy, which has many advantages,such as accuracy and little adverse reactions. Previous studies have shown that the introduction of targeted drug sorafenib can improve the survival of patients with primary liver cancer and open a new era of tumor targeted therapy. In recent years, molecular targeted therapy for liver cancer has become a research hotspot.A variety of new molecular targeted drugs have been found to be able to improve the prognosis of patients with advanced liver cancer. The purpose of this article is to review the progress in basic and clinical research on molecular targeted therapy for primary hepatic carcinoma.
As the second most common cancer in the world, primary liver cancer has become one of the most common causes of cancer-related death in China, causing great pain and financial burden to patients and their families. Traditional treatment methods have not achieved satisfactory results so far, and people are gradually turning their attention to targeted drug therapy, which has many advantages,such as accuracy and little adverse reactions. Previous studies have shown that the introduction of targeted drug sorafenib can improve the survival of patients with primary liver cancer and open a new era of tumor targeted therapy. In recent years, molecular targeted therapy for liver cancer has become a research hotspot.A variety of new molecular targeted drugs have been found to be able to improve the prognosis of patients with advanced liver cancer. The purpose of this article is to review the progress in basic and clinical research on molecular targeted therapy for primary hepatic carcinoma.
引文
1黄赞松,仇仪英,周喜汉.原发性肝癌现代医学治疗的研究进展.医学综述2012;18:4169-4172
2黄赞松,仇仪英.中医药治疗原发性肝癌的研究现状.时珍国医国药2012;23:2851-2853[DOI:10.3969/j.issn.1008-0805.2012.11.088]
3孙燕.肿瘤治疗的新里程碑-靶向药物治疗.肿瘤药学2011;1:1-5
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2黄赞松,仇仪英.中医药治疗原发性肝癌的研究现状.时珍国医国药2012;23:2851-2853[DOI:10.3969/j.issn.1008-0805.2012.11.088]
3孙燕.肿瘤治疗的新里程碑-靶向药物治疗.肿瘤药学2011;1:1-5
4 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,H?ussinger 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[PMID:18650514 DOI:10.1056/NEJMoa0708857]
5 Kim JS,Choi GH,Jung Y,Kim KM,Jang SJ,Yu ES,Lee HC.Downregulation of Raf-1 kinase inhibitory protein as a sorafenib resistance mechanism in hepatocellular carcinoma cell lines.J Cancer Res Clin Oncol 2018;144:1487-1501[PMID:29858683 DOI:10.1007/s00432-018-2672-y]
6 Kudo M.Signaling pathway/molecular targets and new targeted agents under development in hepatocellular carcinoma.World J Gastroenterol 2012;18:6005-6017[PMID:23155330 DOI:10.3748/wjg.v18.i42.6005]
7 Pai SG,Carneiro BA,Mota JM,Costa R,Leite CA,BarrosoSousa R,Kaplan JB,Chae YK,Giles FJ.Wnt/beta-catenin pathway:modulating anticancer immune response.JHematol Oncol 2017;10:101[PMID:28476164 DOI:10.1186/s13045-017-0471-6]
8 Tien LT,Ito M,Nakao M,Niino D,Serik M,Nakashima M,Wen CY,Yatsuhashi H,Ishibashi H.Expression of beta-catenin in hepatocellular carcinoma.World J Gastroenterol 2005;11:2398-2401[PMID:15832407]
9 Jimeno A,Gordon M,Chugh R,Messersmith W,Mendelson D,Dupont J,Stagg R,Kapoun AM,Xu L,Uttamsingh S,Brachmann RK,Smith DC.A First-in-Human Phase I Study of the Anticancer Stem Cell Agent Ipafricept(OMP-54F28),a Decoy Receptor for Wnt Ligands,in Patients with Advanced Solid Tumors.Clin Cancer Res 2017;23:7490-7497[PMID:28954784 DOI:10.1158/1078-0432.CCR-17-2157]
10 Bhat M,Sonenberg N,Gores GJ.The mTOR pathway in hepatic malignancies.Hepatology 2013;58:810-818[PMID:23408390 DOI:10.1002/hep.26323]
11 Peyrou M,Bourgoin L,Foti M.PTEN in liver diseases and cancer.World J Gastroenterol 2010;16:4627-4633[PMID:20872961 DOI:10.3748/wjg.v16.i37.4627]
12 Groner B,von Manstein V.Jak Stat signaling and cancer:Opportunities,benefits and side effects of targeted inhibition.Mol Cell Endocrinol 2017;451:1-14[PMID:28576744 DOI:10.1016/j.mce.2017.05.033]
13 Shen J,Xiao Z,Zhao Q,Li M,Wu X,Zhang L,Hu W,Cho CH.Anti-cancer therapy with TNFαand IFNγ:A comprehensive review.Cell Prolif 2018;51:e12441[PMID:29484738 DOI:10.1111/cpr.12441]
14 Herranz H,Hong X,Hung NT,Voorhoeve PM,Cohen SM.Oncogenic cooperation between SOCS family proteins and EGFR identified using a Drosophila epithelial transformation model.Genes Dev 2012;26:1602-1611[PMID:22802531 DOI:10.1101/gad.192021.112]
15 Zhao M,Gao FH,Wang JY,Liu F,Yuan HH,Zhang WY,Jiang B.JAK2/STAT3 signaling pathway activation mediates tumor angiogenesis by upregulation of VEGF and bFGF in non-smallcell lung cancer.Lung Cancer 2011;73:366-374[PMID:21333372DOI:10.1016/j.lungcan.2011.01.002]
16 Hou XG,Liu C,Xiang-Xin R.Study on the inhibition of small molecule compound of STAT3 LLL-HS-1 on proliferation of human lung cancer cells A549.J Chin Oncol 2016;22:565-568[DOI:10.11735/j.issn.1671-170X.2016.07.b008]
17 Yoshikawa H,Matsubara K,Qian GS,Jackson P,Groopman JD,Manning JE,Harris CC,Herman JG.SOCS-1,a negative regulator of the JAK/STAT pathway,is silenced by methylation in human hepatocellular carcinoma and shows growth-suppression activity.Nat Genet 2001;28:29-35[PMID:11326271 DOI:10.1038/88225]
18 Niwa Y,Kanda H,Shikauchi Y,Saiura A,Matsubara K,Kitagawa T,Yamamoto J,Kubo T,Yoshikawa H.Methylation silencing of SOCS-3 promotes cell growth and migration by enhancing JAK/STAT and FAK signalings in human hepatocellular carcinoma.Oncogene 2005;24:6406-6417[PMID:16007195 DOI:10.1038/sj.onc.1208788]
19 Chung CD,Liao J,Liu B,Rao X,Jay P,Berta P,Shuai K.Specific inhibition of Stat3 signal transduction by PIAS3.Science 1997;278:1803-1805[PMID:9388184]
20 Yang S,Luo C,Gu Q,Xu Q,Wang G,Sun H,Qian Z,Tan Y,Qin Y,Shen Y,Xu X,Chen SH,Chan CC,Wang H,Mao M,Fang DD.Activating JAK1 mutation may predict the sensitivity of JAK-STAT inhibition in hepatocellular carcinoma.Oncotarget 2016;7:5461-5469[PMID:26701727 DOI:10.18632/oncotarget.6684]
21 Gu FM,Li QL,Gao Q,Jiang JH,Huang XY,Pan JF,Fan J,Zhou J.Sorafenib inhibits growth and metastasis of hepatocellular carcinoma by blocking STAT3.World J Gastroenterol 2011;17:3922-3932[PMID:22025881 DOI:10.3748/wjg.v17.i34.3922]
22 Jayson GC,Kerbel R,Ellis LM,Harris AL.Antiangiogenic therapy in oncology:current status and future directions.Lancet 2016;388:518-529[PMID:26853587 DOI:10.1016/S0140-6736(15)01088-0]
23 Buckley AF,Burgart LJ,Sahai V,Kakar S.Epidermal growth factor receptor expression and gene copy number in conventional hepatocellular carcinoma.Am J Clin Pathol 2008;129:245-251[PMID:18208805 DOI:10.1309/WF10QAAED3PP93BH]
24 Fukushima T,Uchiyama S,Tanaka H,Kataoka H.Hepatocyte Growth Factor Activator:A Proteinase Linking Tissue Injury with Repair.Int J Mol Sci 2018;19[PMID:30388869 DOI:10.3390/ijms19113435]
25 Goyal L,Muzumdar MD,Zhu AX.Targeting the HGF/c-METpathway in hepatocellular carcinoma.Clin Cancer Res 2013;19:2310-2318[PMID:23388504 DOI:10.1158/1078-0432.CCR-12-2791]
26 B Peters ML,Miksad RA.Cabozantinib in the treatment of hepatocellular carcinoma.Future Oncol 2017[PMID:28703624DOI:10.2217/fon-2017-0169]
27 Roviello G,Bachelot T,Hudis CA,Curigliano G,Reynolds AR,Petrioli R,Generali D.The role of bevacizumab in solid tumours:A literature based meta-analysis of randomised trials.Eur J Cancer 2017;75:245-258[PMID:28242502 DOI:10.1016/j.ejca.2017.01.026]
28 Siegel AB,Cohen EI,Ocean A,Lehrer D,Goldenberg A,Knox JJ,Chen H,Clark-Garvey S,Weinberg A,Mandeli J,Christos P,Mazumdar M,Popa E,Brown RS Jr,Rafii S,Schwartz JD.Phase II trial evaluating the clinical and biologic effects of bevacizumab in unresectable hepatocellular carcinoma.J Clin Oncol 2008;26:2992-2998[PMID:18565886 DOI:10.1200/JCO.2007.15.9947]
29 Hainsworth JD,Spigel DR,Farley C,Thompson DS,Shipley DL,Greco FA;Minnie Pearl Cancer Research Network.Phase II trial of bevacizumab and erlotinib in carcinomas of unknown primary site:the Minnie Pearl Cancer Research Network.JClin Oncol 2007;25:1747-1752[PMID:17470864 DOI:10.1200/JCO.2006.09.3047]
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