肝细胞癌的靶向治疗

张宁宁; 陆伟

doi:10.3969/j.issn.1001-5256.2021.08.003

肝细胞癌的靶向治疗

DOI: 10.3969/j.issn.1001-5256.2021.08.003

张宁宁,
陆伟^,

天津医科大学肿瘤医院肝癌防治研究中心，天津 300060

基金项目:

天津市科技厅项目 (19YFZCSY00020)

利益冲突声明：所有作者均声明不存在利益冲突。

作者贡献声明：张宁宁负责收集数据，资料分析，撰写论文；陆伟负责课题设计，拟定写作思路，指导撰写文章并最后定稿。

详细信息

通信作者:
陆伟，mail4luwei@163.com

中图分类号: R735.7
计量
- 文章访问数: 788
- HTML全文浏览量: 255
- PDF下载量: 196
- 被引次数: 0
出版历程
- 收稿日期: 2021-03-15
- 录用日期: 2021-04-15
- 出版日期: 2021-08-20

Targeted therapy for hepatocellular carcinoma

Ningning ZHANG,
Wei LU^,

Liver Cancer Center, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China

Research funding:

Project of Tianjin Municipal Bureau of Science and Technology (19YFZCSY00020)

摘要

摘要: 近年来，随着肝细胞癌(HCC)分子机制研究深入，靶向治疗也得到了迅猛发展，在延缓和改善患者疾病进展和预后方面作出了巨大贡献。由于HCC的发病机制错综复杂，单一的分子靶向治疗总体临床收益并不理想。因此，近年来靶向联合其他治疗方式的新方案不断出新，并取得了令人鼓舞的成果。就HCC分子靶向治疗药物、研究现状及临床联合应用治疗进展予以简要总结。
- 癌, 肝细胞 /
- 分子靶向治疗
Abstract: With the in-depth research on the molecular mechanism of hepatocellular carcinoma (HCC) in recent years, targeted therapy has achieved rapid development and made great contributions to delaying disease progression and improving prognosis. Due to the complex pathogenesis of HCC, molecular targeted therapy alone has unsatisfactory overall clinical benefits; therefore, new treatment regimens of targeted therapy in combination with other treatment modalities continue to appear in recent years and have obtained encouraging results. This article briefly summarizes the drugs used in molecular targeted therapy, the current research status of molecular targeted therapy, and the advances in its combination with other treatment modalities for HCC.
- Carcinoma, Hepatocellular /
- Molecular Targeted Therapy

HTML全文

参考文献(43)

[1]	FERLAY J, COLOMBET M, SOERJOMATARAM I, et al. Estimating the global cancer incidence and mortality in 2018: GLOBOCAN sources and methods[J]. Int J Cancer, 2019, 144(8): 1941-1953. DOI: 10.1002/ijc.31937.
[2]	ALQAHTANI A, KHAN Z, ALLOGHBI A, et al. Hepatocellular carcinoma: Molecular mechanisms and targeted therapies[J]. Medicina (Kaunas), 2019, 55(9): 526. DOI: 10.3390/medicina55090526.
[3]	BRAY F, FERLAY J, SOERJOMATARAM I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2018, 68(6): 394-424. DOI: 10.3322/caac.21492.
[4]	NORDENSTEDT H, WHITE DL, EL-SERAG HB. The changing pattern of epidemiology in hepatocellular carcinoma[J]. Dig Liver Dis, 2010, 42(Suppl 3): s206-s214. DOI: 10.1016/S1590-8658(10)60507-5.
[5]	LIU M, JIANG L, GUAN XY. The genetic and epigenetic alterations in human hepatocellular carcinoma: A recent update[J]. Protein Cell, 2014, 5(9): 673-691. DOI: 10.1007/s13238-014-0065-9.
[6]	DIMRI M, SATYANARAYANA A. Molecular signaling pathways and therapeutic targets in hepatocellular carcinoma[J]. Cancers (Basel), 2020, 12(2): 491. DOI: 10.3390/cancers12020491.
[7]	GONG X, QIN S. Study progression of anti-angiogenetic therapy and its combination with other agents for the treatment of advanced hepatocellular carcinoma[J]. Hepatobiliary Surg Nutr, 2018, 7(6): 466-474. DOI: 10.21037/hbsn.2018.11.04.
[8]	LLOVET JM, RICCI S, MAZZAFERRO V, et al. Sorafenib in advanced hepatocellular carcinoma[J]. N Engl J Med, 2008, 359(4): 378-390. DOI: 10.1056/NEJMoa0708857.
[9]	CHENG AL, KANG YK, CHEN Z, et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: A phase Ⅲ randomised, double-blind, placebo-controlled trial[J]. Lancet Oncol, 2009, 10(1): 25-34. DOI: 10.1016/S1470-2045(08)70285-7.
[10]	KUDO M, FINN RS, QIN S, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: A randomised phase 3 non-inferiority trial[J]. Lancet, 2018, 391(10126): 1163-1173. DOI: 10.1016/S0140-6736(18)30207-1.
[11]	MATSUKI M, HOSHI T, YAMAMOTO Y, et al. Lenvatinib inhibits angiogenesis and tumor fibroblast growth factor signaling pathways in human hepatocellular carcinoma models[J]. Cancer Med, 2018, 7(6): 2641-2653. DOI: 10.1002/cam4.1517.
[12]	WILHELM SM, DUMAS J, ADNANE L, et al. Regorafenib (BAY 73-4506): A new oral multikinase inhibitor of angiogenic, stromal and oncogenic receptor tyrosine kinases with potent preclinical antitumor activity[J]. Int J Cancer, 2011, 129(1): 245-255. DOI: 10.1002/ijc.25864.
[13]	FONDEVILA F, MÉNDEZ-BLANCO C, FERNÁNDEZ-PALANCA P, et al. Anti-tumoral activity of single and combined regorafenib treatments in preclinical models of liver and gastrointestinal cancers[J]. Exp Mol Med, 2019, 51(9): 1-15. DOI: 10.1038/s12276-019-0308-1.
[14]	CERRITO L, PONZIANI FR, GARCOVICH M, et al. Regorafenib: A promising treatment for hepatocellular carcinoma[J]. Expert Opin Pharmacother, 2018, 19(17): 1941-1948. DOI: 10.1080/14656566.2018.1534956.
[15]	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. DOI: 10.1016/S0140-6736(16)32453-9.
[16]	FINN RS, MERLE P, GRANITO A, et al. Outcomes of sequential treatment with sorafenib followed by regorafenib for HCC: Additional analyses from the phase Ⅲ RESORCE trial[J]. J Hepatol, 2018, 69(2): 353-358. DOI: 10.1016/j.jhep.2018.04.010.
[17]	DEEKS ED. Cabozantinib: A review in advanced hepatocellular carcinoma[J]. Target Oncol, 2019, 14(1): 107-113. DOI: 10.1007/s11523-019-00622-y.
[18]	SCOTT AJ, ARCAROLI JJ, BAGBY SM, et al. Cabozantinib exhibits potent antitumor activity in colorectal cancer patient-derived tumor xenograft models via autophagy and signaling mechanisms[J]. Mol Cancer Ther, 2018, 17(10): 2112-2122. DOI: 10.1158/1535-7163.MCT-17-0131.
[19]	ABOU-ALFA GK, MEYER T, CHENG AL, et al. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma[J]. N Engl J Med, 2018, 379(1): 54-63. DOI: 10.1056/NEJMoa1717002.
[20]	LIAO W, HUANG J, HUTTON D, et al. Cost-effectiveness analysis of cabozantinib as second-line therapy in advanced hepatocellular carcinoma[J]. Liver Int, 2019, 39(12): 2408-2416. DOI: 10.1111/liv.14257.
[21]	KUDO M, HATANO E, OHKAWA S, et al. Ramucirumab as second-line treatment in patients with advanced hepatocellular carcinoma: Japanese subgroup analysis of the REACH trial[J]. J Gastroenterol, 2017, 52(4): 494-503. DOI: 10.1007/s00535-016-1247-4.
[22]	ZHU AX, KANG YK, YEN CJ, et al. Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased α-fetoprotein concentrations (REACH-2): A randomised, double-blind, placebo-controlled, phase 3 trial[J]. Lancet Oncol, 2019, 20(2): 282-296. DOI: 10.1016/S1470-2045(18)30937-9.
[23]	LI Q, QIN SK, GU SZ, et al. Apatinib as second-line therapy in Chinese patients with advanced hepatocellular carcinoma: A randomized, placebo-controlled, double-blind, phase Ⅲ study[J]. J Clin Oncol, 2020, 38(15_suppl): 4507. DOI: 10.1200/JCO.2020.38.15_suppl.4507.
[24]	Guidelines Working Committee of Chinese Society of Clinical Oncology. Guidelines for the diagnosis and treatment of primary liver cancer (2020 edition)[M]. Beijing: People's Medical Publishing House, 2020. 中国临床肿瘤学会指南工作委员会. 原发性肝癌诊疗指南2020[M]. 北京: 人民卫生出版社, 2020.
[25]	BI F, QIN SK, GU SZ, et al. Donafenib versus sorafenib as first-line therapy in advanced hepatocellular carcinoma: An open-label, randomized, multicenter phase Ⅱ/Ⅲ trial[J]. J Clin Oncol, 38(15_suppl): 4506. DOI: 10.1200/JCO.2020.38.15_suppl.4506.
[26]	VENEPALLI NK, GOFF L. Targeting the HGF-cMET axis in hepatocellular carcinoma[J]. Int J Hepatol, 2013, 2013: 341636. DOI: 10.1155/2013/341636.
[27]	GHERARDI E, BIRCHMEIER W, BIRCHMEIER C, et al. Targeting MET in cancer: Rationale and progress[J]. Nat Rev Cancer, 2012, 12(2): 89-103. DOI: 10.1038/nrc3205.
[28]	BOUATTOUR M, RAYMOND E, QIN S, et al. Recent developments of c-Met as a therapeutic target in hepatocellular carcinoma[J]. Hepatology, 2018, 67(3): 1132-1149. DOI: 10.1002/hep.29496.
[29]	XIANG Q, CHEN W, REN M, et al. Cabozantinib suppresses tumor growth and metastasis in hepatocellular carcinoma by a dual blockade of VEGFR2 and MET[J]. Clin Cancer Res, 2014, 20(11): 2959-2970. DOI: 10.1158/1078-0432.CCR-13-2620.
[30]	ZHAO H, LV F, LIANG G, et al. FGF19 promotes epithelial-mesenchymal transition in hepatocellular carcinoma cells by modulating the GSK3β/β- catenin signaling cascade via FGFR4 activation[J]. Oncotarget, 2016, 7(12): 13575-13586. DOI: 10.18632/oncotarget.6185.
[31]	RAJA A, PARK I, HAQ F, et al. FGF19-FGFR4 signaling in hepatocellular carcinoma[J]. Cells, 2019, 8(6): 536. DOI: 10.3390/cells8060536.
[32]	LIN BC, DESNOYERS LR. FGF19 and cancer[J]. Adv Exp Med Biol, 2012, 728: 183-194. DOI: 10.1007/978-1-4614-0887-1_12.
[33]	VILLANUEVA A, CHIANG DY, NEWELL P, et al. Pivotal role of mTOR signaling in hepatocellular carcinoma[J]. Gastroenterology, 2008, 135(6): 1972-1983. DOI: 10.1053/j.gastro.2008.08.008.
[34]	HUYNH H, CHOW KH, SOO KC, et al. RAD001 (everolimus) inhibits tumour growth in xenograft models of human hepatocellular carcinoma[J]. J Cell Mol Med, 2009, 13(7): 1371-1380. DOI: 10.1111/j.1582-4934.2008.00364.x.
[35]	SHIAH HS, CHEN CY, DAI CY, et al. Randomised clinical trial: Comparison of two everolimus dosing schedules in patients with advanced hepatocellular carcinoma[J]. Aliment Pharmacol Ther, 2013, 37(1): 62-73. DOI: 10.1111/apt.12132.
[36]	FINN RS, QIN S, IKEDA M, et al. Atezolizumab plus Bevacizumab in unresectable hepatocellular carcinoma[J]. N Engl J Med, 2020, 382(20): 1894-1905. DOI: 10.1056/NEJMoa1915745.
[37]	FINN RS, IKEDA M, ZHU AX, et al. Phase Ib study of lenvatinib plus pembrolizumab in patients with unresectable hepatocellular carcinoma[J]. J Clin Oncol, 2020, 38(26): 2960-2970. DOI: 10.1200/JCO.20.00808.
[38]	YAU T, ZAGONEL V, SANTORO A, et al. Nivolumab (NIVO) + ipilimumab (IPI) + cabozantinib (CABO) combination therapy in patients (pts) with advanced hepatocellular carcinoma (aHCC): Results from CheckMate 040[J]. J Clin Oncol, 38(4_suppl): 478. DOI: 10.1200/JCO.2020.38.4_suppl.478.
[39]	European Association for the Study of the Liver. EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma[J]. J Hepatol, 2018, 69(1): 182-236. DOI: 10.1016/j.jhep.2018.03.019.
[40]	KUDO M, UESHIMA K, IKEDA M, et al. Randomised, multicentre prospective trial of transarterial chemoembolisation (TACE) plus sorafenib as compared with TACE alone in patients with hepatocellular carcinoma: TACTICS trial[J]. Gut, 2020, 69(8): 1492-1501. DOI: 10.1136/gutjnl-2019-318934.
[41]	CHEN JH, LU L, WEN TF, et al. Adjuvant lenvatinib in combination with TACE for hepatocellular carcinoma patients with high risk of postoperative relapse (LANCE): Interim results from a muticenter prospective cohort study[J]. J Clin Oncol, 2020, 38(15_Suppl): 4580.
[42]	HE M, LI Q, ZOU R, et al. Sorafenib plus hepatic arterial infusion of oxaliplatin, fluorouracil, and leucovorin vs sorafenib alone for hepatocellular carcinoma with portal vein invasion: A randomized clinical trial[J]. JAMA Oncol, 2019, 5(7): 953-960. DOI: 10.1001/jamaoncol.2019.0250.
[43]	FENG X, XU R, DU X, et al. Combination therapy with sorafenib and radiofrequency ablation for BCLC Stage 0-B1 hepatocellular carcinoma: A multicenter retrospective cohort study[J]. Am J Gastroenterol, 2014, 109(12): 1891-1899. DOI: 10.1038/ajg.2014.343.