瑞戈非尼治疗肝细胞癌的研究进展
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摘要
肝细胞癌(HCC)是最常见的肝脏恶性肿瘤,对于晚期HCC患者,全身治疗方式有限。瑞戈非尼是一种口服多激酶抑制剂,Ⅲ期临床试验显示其可显著延长晚期HCC患者中位生存期2.8个月,这使得瑞戈非尼成为继索拉非尼后经美国食品药品监督管理局批准用于治疗晚期HCC的二线用药。综述了瑞戈非尼在HCC领域的相关基础和临床研究。
Hepatocellular carcinoma( HCC) is the most common malignant liver tumor,and there are limited systemic treatments for patients with advanced HCC. Regorafenib is an oral multi-kinase inhibitor,and phase III clinical trial has shown that regorafenib can significantly extend the median survival of patients with advanced HCC by 2. 8 months,which makes it a second-line drug approved by FDA for the treatment of advanced HCC,just after sorafenib. This article reviews the basic and clinical research on regorafenib in the field of HCC.
Hepatocellular carcinoma( HCC) is the most common malignant liver tumor,and there are limited systemic treatments for patients with advanced HCC. Regorafenib is an oral multi-kinase inhibitor,and phase III clinical trial has shown that regorafenib can significantly extend the median survival of patients with advanced HCC by 2. 8 months,which makes it a second-line drug approved by FDA for the treatment of advanced HCC,just after sorafenib. This article reviews the basic and clinical research on regorafenib in the field of HCC.
引文
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[9]CARR BI,CAVALLINI A,LIPPOLIS C,et al.Fluoro-Sorafenib(Regorafenib)effects on hepatoma cells:growth inhibition,quiescence,and recovery[J].J Cell Physiol,2013,228(2):292-297.
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[11]TSAI JJ,PAN PJ,HSU FT.Regorafenib induces extrinsic and intrinsic apoptosis through inhibition of ERK/NF-kappa B activation in hepatocellular carcinoma cells[J].Oncol Rep,2017,37(2):1036-1044.
[12]TAI WT,CHU PY,SHIAU CW,et al.STAT3 mediates regorafenib-induced apoptosis in hepatocellular carcinoma[J].Clin Cancer Res,2014,20(22):5768-5776.
[13]MROSS K,FROST A,STEINBILD S,et al.A phase I dose-escalation study of regorafenib(BAY 73-4506),an inhibitor of oncogenic,angiogenic,and stromal kinases,in patients with advanced solid tumors[J].Clin Cancer Res,2012,18(9):2658-2667.
[14]SUNAKAWA Y,FURUSE J,OKUSAKA T,et al.Regorafenib in Japanese patients with solid tumors:phase I study of safety,efficacy,and pharmacokinetics[J].Invest New Drugs,2014,32(1):104-112.
[15]SHIMIZU T,TOLCHER AW,PATNAIK A,et al.Phase I doseescalation study of continuously administered regorafenib(BAY 73-4506),an inhibitor of oncogenic and angiogenic kinases,in patients with advanced solid tumors[J].J Clin Oncol,2010,28(15):3035.
[16]RIMASSA L,PRESSIANI T,PERSONENI N,et al.Regorafenib for the treatment of unresectable hepatocellular carcinoma[J].Expert Rev Anticancer Ther,2017,17(7):567-576.
[17]Regorafenib Approved for Liver Cancer[J].Cancer Discov,2017,7(7):660.
[18]BRUIX J,TAK WY,GASBARRINI A,et al.Regorafenib as second-line therapy for intermediate or advanced hepatocellular carcinoma:multicentre,open-label,phase II safety study[J].Eur JCancer,2013,49(16):3412-3419.
[19]DUFFY AG,GRETEN TF.Liver cancer:regorafenib as secondline therapy in hepatocellular carcinoma[J].Nat Rev Gastroenterol Hepatol,2017,14(3):141-142.
[20]LLOVET JM,RICCI S,MAZZAFERRO V,et al.Sorafenib in advanced hepatocellular carcinoma[J].NEJM,2008,359(4):378-390.
[21]SANOFF HK,CHANG Y,LUND JL,et al.Sorafenib effectiveness in advanced hepatocellular carcinoma[J].Oncologist,2016,21(9):1113-1120.
[22]PARIKH ND,SINGAL AG,HUTTON DW.Cost effectiveness of regorafenib as second-line therapy for patients with advanced hepatocellular carcinoma[J].Cancer,2017,123(19):3725-3731.
[23]D'ALESSANDRO R,REFOLO MG,LIPPOLIS C,et al.Reversibility of regorafenib effects in hepatocellular carcinoma cells[J].Cancer Chemother Pharmacol,2013,72(4):869-877.
[24]STRAUSSMAN R,MORIKAWA T,SHEE K,et al.Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion[J].Nature,2012,487(7408):500-504.
[25]D'ALESSANDRO R,REFOLO MG,LIPPOLIS C,et al.Antagonism of sorafenib and regorafenib actions by platelet factors in hepatocellular carcinoma cell lines[J].BMC Cancer,2014,14:351.
[26]D'ALESSANDRO R,REFOLO MG,LIPPOLIS C,et al.Modulation of Regorafenib effects on HCC cell lines by epidermal growth factor[J].Cancer Chemother Pharmacol,2015,75(6):1237-1245.
[27]LU KV,CHANG JP,PARACHONIAK CA,et al.VEGF inhibits tumor cell invasion and mesenchymal transition through a MET/VEGFR2 complex[J].Cancer Cell,2012,22(1):21-35.
[28]SENNINO B,ISHIGURO-OONUMA T,WEI Y,et al.Suppression of tumor invasion and metastasis by concurrent inhibition of cMet and VEGF signaling in pancreatic neuroendocrine tumors[J].Cancer Discov,2012,2(3):270-287.
[29]TOMIDA C,AIBARA K,YAMAGISHI N,et al.The malignant progression effects of regorafenib in human colon cancer cells[J].J Med Invest,2015,62(3-4):195-198.
[2]MA M,NIU TT,SHAO L,et al.Hepatic transcatheter arterial chemoembolization combined with stereotactic radiation of primary liver cancer[J].Trauma Crit Med,2017,5(1):32-35.(in Chinese)马明,牛婷婷,邵亮,等.肝动脉化疗栓塞术联合立体定向放疗治疗较大原发性肝癌临床研究[J].创伤与急危重病医学,2017,5(1):32-35.
[3]LI SY,WU S,CHEN TS,et al.Effect of portal venous perfusion cinobufacini injection combined with TACE in patients with intermediate hepatocellular carcinoma[J].Chin J Med Offic,2017,45(9):884-886.(in Chinese)李淑英,吴申,陈挺松,等.经导管肝动脉栓塞化疗联合华蟾素门静脉灌注治疗中期原发性肝癌疗效研究[J].临床军医杂志,2017,45(9):884-886.
[4]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.
[5]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.
[6]WILHELM SM,DUMAS J,ADNANE L,et al.Regorafenib(BAY73-4506):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.
[7]GROTHEY A,van CUTSEM E,SOBRERO A,et al.Regorafenib monotherapy for previously treated metastatic colorectal cancer(CORRECT):an international,multicentre,randomised,placebo-controlled,phase 3 trial[J].Lancet,2013,381(9863):303-312.
[8]DEMETRI GD,REICHARDT P,KANG YK,et al.Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib(GRID):an international,multicentre,randomised,placebo-controlled,phase 3 trial[J].Lancet,2013,381(9863):295-302.
[9]CARR BI,CAVALLINI A,LIPPOLIS C,et al.Fluoro-Sorafenib(Regorafenib)effects on hepatoma cells:growth inhibition,quiescence,and recovery[J].J Cell Physiol,2013,228(2):292-297.
[10]CARR BI,D'ALESSANDRO R,REFOLO MG,et al.Effects of low concentrations of regorafenib and sorafenib on human HCC cell AFP,migration,invasion,and growth in vitro[J].J Cell Physiol,2013,228(6):1344-1350.
[11]TSAI JJ,PAN PJ,HSU FT.Regorafenib induces extrinsic and intrinsic apoptosis through inhibition of ERK/NF-kappa B activation in hepatocellular carcinoma cells[J].Oncol Rep,2017,37(2):1036-1044.
[12]TAI WT,CHU PY,SHIAU CW,et al.STAT3 mediates regorafenib-induced apoptosis in hepatocellular carcinoma[J].Clin Cancer Res,2014,20(22):5768-5776.
[13]MROSS K,FROST A,STEINBILD S,et al.A phase I dose-escalation study of regorafenib(BAY 73-4506),an inhibitor of oncogenic,angiogenic,and stromal kinases,in patients with advanced solid tumors[J].Clin Cancer Res,2012,18(9):2658-2667.
[14]SUNAKAWA Y,FURUSE J,OKUSAKA T,et al.Regorafenib in Japanese patients with solid tumors:phase I study of safety,efficacy,and pharmacokinetics[J].Invest New Drugs,2014,32(1):104-112.
[15]SHIMIZU T,TOLCHER AW,PATNAIK A,et al.Phase I doseescalation study of continuously administered regorafenib(BAY 73-4506),an inhibitor of oncogenic and angiogenic kinases,in patients with advanced solid tumors[J].J Clin Oncol,2010,28(15):3035.
[16]RIMASSA L,PRESSIANI T,PERSONENI N,et al.Regorafenib for the treatment of unresectable hepatocellular carcinoma[J].Expert Rev Anticancer Ther,2017,17(7):567-576.
[17]Regorafenib Approved for Liver Cancer[J].Cancer Discov,2017,7(7):660.
[18]BRUIX J,TAK WY,GASBARRINI A,et al.Regorafenib as second-line therapy for intermediate or advanced hepatocellular carcinoma:multicentre,open-label,phase II safety study[J].Eur JCancer,2013,49(16):3412-3419.
[19]DUFFY AG,GRETEN TF.Liver cancer:regorafenib as secondline therapy in hepatocellular carcinoma[J].Nat Rev Gastroenterol Hepatol,2017,14(3):141-142.
[20]LLOVET JM,RICCI S,MAZZAFERRO V,et al.Sorafenib in advanced hepatocellular carcinoma[J].NEJM,2008,359(4):378-390.
[21]SANOFF HK,CHANG Y,LUND JL,et al.Sorafenib effectiveness in advanced hepatocellular carcinoma[J].Oncologist,2016,21(9):1113-1120.
[22]PARIKH ND,SINGAL AG,HUTTON DW.Cost effectiveness of regorafenib as second-line therapy for patients with advanced hepatocellular carcinoma[J].Cancer,2017,123(19):3725-3731.
[23]D'ALESSANDRO R,REFOLO MG,LIPPOLIS C,et al.Reversibility of regorafenib effects in hepatocellular carcinoma cells[J].Cancer Chemother Pharmacol,2013,72(4):869-877.
[24]STRAUSSMAN R,MORIKAWA T,SHEE K,et al.Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion[J].Nature,2012,487(7408):500-504.
[25]D'ALESSANDRO R,REFOLO MG,LIPPOLIS C,et al.Antagonism of sorafenib and regorafenib actions by platelet factors in hepatocellular carcinoma cell lines[J].BMC Cancer,2014,14:351.
[26]D'ALESSANDRO R,REFOLO MG,LIPPOLIS C,et al.Modulation of Regorafenib effects on HCC cell lines by epidermal growth factor[J].Cancer Chemother Pharmacol,2015,75(6):1237-1245.
[27]LU KV,CHANG JP,PARACHONIAK CA,et al.VEGF inhibits tumor cell invasion and mesenchymal transition through a MET/VEGFR2 complex[J].Cancer Cell,2012,22(1):21-35.
[28]SENNINO B,ISHIGURO-OONUMA T,WEI Y,et al.Suppression of tumor invasion and metastasis by concurrent inhibition of cMet and VEGF signaling in pancreatic neuroendocrine tumors[J].Cancer Discov,2012,2(3):270-287.
[29]TOMIDA C,AIBARA K,YAMAGISHI N,et al.The malignant progression effects of regorafenib in human colon cancer cells[J].J Med Invest,2015,62(3-4):195-198.