肝细胞癌(HCC)靶向治疗的研究进展
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摘要
肝细胞癌(hepatocellular carcinoma,HCC)是最常见的恶性肿瘤之一,具有起病隐匿、进展快、复发早和预后差的临床特点,临床发现时大多已属晚期。随着对HCC分子信号通路研究的不断深入,靶向治疗在治疗晚期HCC方面已表现出明显优势,多靶点的酪氨酸激酶抑制剂索拉菲尼已在临床上广泛应用。本文归纳了HCC治疗的分子靶点、靶向治疗药物的作用机制、临床疗效、毒性作用和不良反应以及联合治疗方面的进展,并探讨目前研究中存在的机遇和挑战,以期为临床用药和进一步研究提供参考。
Hepatocellular carcinoma(HCC) is one of the most common malignant tumors.It has many clinical characteristics,such as onset,rapid progress,early recurrence and poor prognosis.Most of them are discovered late.With the further research on HCC signaling pathways,targeted therapy has shown obvious advantages in the treatment of advanced HCC.Sorafenib,a multitargeted tyrosine kinase inhibitor,has been widely used in clinic.This article summarizes HCC therapeutic targets,together with the mechanism,clinical efficacy,toxic side effects and combination therapy of the targeted therapies,and explores the opportunities and challenges in current research,in order to provide references for clinical medication and further research.
Hepatocellular carcinoma(HCC) is one of the most common malignant tumors.It has many clinical characteristics,such as onset,rapid progress,early recurrence and poor prognosis.Most of them are discovered late.With the further research on HCC signaling pathways,targeted therapy has shown obvious advantages in the treatment of advanced HCC.Sorafenib,a multitargeted tyrosine kinase inhibitor,has been widely used in clinic.This article summarizes HCC therapeutic targets,together with the mechanism,clinical efficacy,toxic side effects and combination therapy of the targeted therapies,and explores the opportunities and challenges in current research,in order to provide references for clinical medication and further research.
引文
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[31] 彭诗云,丁红.肝癌靶向治疗的功能影像学评价现状[J].中国医学影像学杂志,2017,25(2):151-154.
[32] LEE DW,JANG MJ,LEE KH,et al.TTP as a surrogate endpoint in advanced hepatocellular carcinoma treated with molecular targeted therapy:meta-analysis of randomised controlled trials[J].Br J Cancer,2016,115(10):1201-1205.
[33] THILLAI K,ROSS P,SARKER D.Molecularly targeted therapy for advanced hepatocellular carcinoma- a drug development crisis?[J].World J Gastrointest Oncol,2016,8(2):173-185.
[34] HE H,TU X,ZHANG J,et al.A novel antibody targeting CD24 and hepatocellular carcinoma in vivo by near-infrared fluorescence imaging[J].Immunobiology,2015,220(12):1328-1336.
[2] BRUIX J,REIG M,SHERMAN M.Evidence-based diagnosis,staging,and treatment of patients with hepatocellular carcinoma[J].Gastroenterology,2016,150(4):835-853.
[3] HOSHIDA Y,TOFFANIN S,LACHENMAYER A,et al.Molecular classification and novel targets in hepatocellular carcinoma:recent advancements[J].Semin Liver Dis,2010,30(1):35-51.
[4] HICKLIN DJ,ELLIS LM.Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis[J].J Clin Oncol,2005,23(5):1011-1027.
[5] WEI T,ZHANG LN,LV Y,et al.Overexpression of platelet-derived growth factor receptor alpha promotes tumor progression and indicates poor prognosis in hepatocellular carcinoma[J].Oncotarget,2014,5(21):10307-10317.
[6] SANDHU DS,BAICHOO E,ROBERTS LR.Fibroblast growth factor signaling in liver carcinogenesis[J].Hepatology,2014,59(3):1166-1173.
[7] LLOVET JM,RICCI S,MAZZAFERRO V,et al.Sorafenib in advanced hepatocellular carcinoma[J].N Engl J Med,2008,359(4):378-390.
[8] ABOU-ALFA GK,JOHNSON P,KNOX JJ,et al.Doxorubicin plus sorafenib vs doxorubicin alone in patients with advanced hepatocellular carcinoma:a randomized trial[J].JAMA,2010,304(19):2154-2160.
[9] BAI S,NASSER MW,WANG B,et al.MicroRNA-122 inhibits tumorigenic properties of hepatocellular carcinoma cells and sensitizes these cells to sorafenib[J].J Biol Chem,2009,284(46):32015-32027.
[10] SIEGEL AB,COHEN EI,OCEAN A,et al.Phase Ⅱ trial evaluating the clinical and biologic effects of bevacizumab in unresectable hepatocellular carcinoma[J].J Clin Oncol,2008,26(18):2992-2998.
[11] HSU CH,KANG YK,YANG TS,et al.Bevacizumab with erlotinib as first-line therapy in Asian patients with advanced hepatocellular carcinoma:a multicenter phase Ⅱ study[J].Oncology, 2013,85(1):44-52.
[12] SUN W,SOHAL D,HALLER DG,et al.Phase 2 trial of bevacizumab,capecitabine,and oxaliplatin in treatment of advanced hepatocellular carcinoma[J].Cancer,2011,117(14):3187-3192.
[13] PINTER M,ULBRICH G,SIEGHART W,et al.Hepatocellular carcinoma:a phase Ⅱ randomized controlled double-blind trial of transarterial chemoembolization in combination with biweekly intravenous administration of bevacizumab or a placebo[J].Radiology,2015,277(3):903-912.
[14] BRUIX J,QIN S,MERLE P,et al.Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE):a randomised,double-blind,placebo-controlled,phase 3 trial[J].Lancet,2017,389(10064):56-66.
[15] ZHU AX,SAHANI DV,DUDA DG,et al.Efficacy,safety,and potential biomarkers of sunitinib monotherapy in advanced hepatocellular carcinoma:a phase Ⅱ study[J].J Clin Oncol,2009,27(18):3027-3035.
[16] LLOVET JM,DECAENS T,RAOUL JL,et al.Brivanib in patients with advanced hepatocellular carcinoma who were intolerant to sorafenib or for whom sorafenib failed:results from the randomized phase Ⅲ BRISK-PS study[J].J Clin Oncol,2013,31(28):3509-3516.
[17] ASNACIOS A,FARTOUX L,ROMANO O,et al.Gemcitabine plus oxaliplatin (GEMOX) combined with cetuximab in patients with progressive advanced stage hepatocellular carcinoma:results of a multicenter phase 2 study[J].Cancer,2008,112(12):2733-2739.
[18] THOMAS MB,CHADHA R,GLOVER K,et al.Phase 2 study of erlotinib in patients with unresectable hepatocellular carcinoma[J].Cancer,2007,110(5):1059-1067.
[19] ZHU AX,ROSMORDUC O,EVANS TR,et al.SEARCH:a phase III,randomized,double-blind,placebo-controlled trial of sorafenib plus erlotinib in patients with advanced hepatocellular carcinoma[J].J Clin Oncol,2015,33(6):559-566.
[20] SANTORO A,RIMASSA L,BORBATH I,et al.Tivantinib for second-line treatment of advanced hepatocellular carcinoma:a randomised,placebo-controlled phase 2 study[J].Lancet Oncol,2013,14(1):55-63.
[21] SANTARPIA L,LIPPMAN SM,EL-NAGGAR AK.Targeting the MAPK-RAS-RAF signaling pathway in cancer therapy[J].Expert Opin Ther Targets,2012,16(1):103-119.
[22] TAI WM,YONG W P,LIM C,et al.A phase Ib study of selumetinib (AZD6244,ARRY-142886) in combination with sorafenib in advanced hepatocellular carcinoma (HCC)[J].Ann Oncol,2018,29(2):526.
[23] OU DL,LEE BS,LIN LI,et al.Vertical blockade of the IGFR- PI3K/Akt/mTOR pathway for the treatment of hepatocellular carcinoma:the role of survivin[J].Mol Cancer,2014,13:2.
[24] ZHU AX,ABRAMS TA,MIKSAD R,et al.Phase 1/2 study of everolimus in advanced hepatocellular carcinoma[J].Cancer,2011,117(22):5094-5102.
[25] KOEBERLE D,DUFOUR JF,DEMETER G,et al.Sorafenib with or without everolimus in patients with advanced hepatocellular carcinoma (HCC):a randomized multicenter,multinational phase Ⅱ trial (SAKK 77/08 and SASL 29)[J].Ann Oncol,2016,27(5):856-861.
[26] CHOW AK,YAU TC,NG L,et al. A preclinical study on the combination therapy of everolimus and transarterial chemoembolization in hepatocellular carcinoma[J].Am J Cancer Res,2015,5(8):2376-2386.
[27] PLIMACK ER,LORUSSO PM,MCCOON P,et al.AZD1480:a phase I study of a novel JAK2 inhibitor in solid tumors[J].Oncologist,2013,18(7):819-820.
[28] WANG R,ZHAO N,LI S,et al.MicroRNA-195 suppresses angiogenesis and metastasis of hepatocellular carcinoma by inhibiting the expression of VEGF,VAV2,and CDC42[J].Hepatology,2013,58(2):642-653.
[29] ZHENG F,LIAO YJ,CAI MY,et al.The putative tumour suppressor microRNA-124 modulates hepatocellular carcinoma cell aggressiveness by repressing ROCK2 and EZH2[J].Gut, 2012,61(2):278-289.
[30] 汤阳,王文平.超声分子成像在肝癌诊治中的研究进展[J].肿瘤影像学,2015,24(2):148-153.
[31] 彭诗云,丁红.肝癌靶向治疗的功能影像学评价现状[J].中国医学影像学杂志,2017,25(2):151-154.
[32] LEE DW,JANG MJ,LEE KH,et al.TTP as a surrogate endpoint in advanced hepatocellular carcinoma treated with molecular targeted therapy:meta-analysis of randomised controlled trials[J].Br J Cancer,2016,115(10):1201-1205.
[33] THILLAI K,ROSS P,SARKER D.Molecularly targeted therapy for advanced hepatocellular carcinoma- a drug development crisis?[J].World J Gastrointest Oncol,2016,8(2):173-185.
[34] HE H,TU X,ZHANG J,et al.A novel antibody targeting CD24 and hepatocellular carcinoma in vivo by near-infrared fluorescence imaging[J].Immunobiology,2015,220(12):1328-1336.