Molecular targeted therapy for hepatocellular carcinoma. Infect Dis Info, 2009, Vol.22, No.2 HCC

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1 118 does not adversely impact survival [J]. Hepatology, 2001, 33 (6): [23] Duffy JP, Vardanian A, Benjamin E, et al. Liver transplantation criteria for hepatocellular carcinoma should be expanded: a 22- year experience with 67 patients at UCLA[J]. Ann Surg, 2007, 26(3): [2] Toso C, Asthana S, Bigam DL, et al. Reassessing selection criteria prior to liver transplantation for hepatocellular carcinoma utilizing the scientific registry of transplant recipients database[j]. Hepatology, 2008, 9(3): [25] [26] Heckman JT, Devera MB, Marsh JW, et al. Bridging locoregional therapy for hepatocellular carcinoma prior to liver transplantation[j]. Ann Surg Oncol, 2008, 15(11): [27] Poon RT, Fan ST, Lo CM, et al. Long- term survival and pattern of recurrence after resection of small hepatocellular carcinoma in patients with preserved liver function: implications for a strategy of salvage transplantation[j]. Ann Surg, 2002, 235(3): [28] Adam R, Azoulay D. Is primary resection and salvage transplantation for hepatocellular carcinoma a reasonable strategy? [J]. Ann Surg, 2005, 21(): [29] Gogia S, Befeler AS. Treating hepatocellular carcinoma without liver transplantation[j]. Curr Gastroenterol Rep, 2009, 11 (1): [30] Llovet JM.Updated treatment approach to hepatocellular carcinoma[j]. J Gastroenterol, 2005, 0(3): [31] Valle JW Dangoor A Beech J et al. Treatment of inoperable hepatocellular carcinoma with pegylated liposomal doxorubicin (PLD): results of a phase II study[j]. Br J Cancer, 2005, 92(): [32] Bronowicki JP, Vetter D, Dumas F, et al. Transcatheter oily. chemoembolization for hepatocellular carcinoma. A - year [J]. study of 127 French patients[j]. Cancer, 199, 7(1):16-2. [33] Simonetti RG, Liberati A, Angiolini C, et al. Treatment of hepatocellular carcinoma: a systematic review of randomized controlled trials[j]. Ann Oncol, 1997, 8(2): [3] Nowak AK, Chow PK, Findlay M. Systemic therapy for advanced hepatocellular carcinoma: a review[j]. Eur J Cancer, 200, 0(10): [35] Pollock R. UICC manual of clinical oncology[m]. 7th eds. New York: Wiley- Liss, 1999:07-2. [36]. [M] HCC HCC HCC R735.7 A (2009) Molecular targeted therapy for hepatocellular carcinoma Luo Rongcheng, Li Aimin South Hospital Affiliated to South Medical University,Guangzhou ,China Abstract In recent decade, molecular targeted therapy, as an important breakthrough in tumor therapies, has achieved success in the treatment of lung carcinoma, maligant gastrointestinal stromal tumors, maligant lymphadenoma, intestinal neoplasms and breast cancer. Great progress has been made in small molecular targeted therapy for HCC and sorafenib has been approved as a standard agent for molecular targeted therapy for HCC. Key words hepatocellular carcinoma;molecular targeted therapy; sorafenib HCC

2 % 7 HCC 2.3% 2 0.7% PR HCC complete remission CR HCC HCC Eastern Cooperative Oncology Group ECOG Onyx 80% Raf- 1 B- Raf 8% - vascular endothelial growth factor receptor 8% 2% VEGFR β [1-2] Raf- 1 HCC vascular endothelial growth factor VEGF HCC [3- ] HCC 137 [7] HCC 3 2.2% partial remission PR 8 5.8% minor response MR HCC III Oriental study % stable disease SD HCC [5] overall survival OS FDA OS HCC SFDA 3% 1 1% HCC HCC PR CR SHARP SHARP ORIENTAL SHARP ORIENTAL SHARP [6] HCC OS 21 HCC 602 HCC HCC 00 mg [ 2/d OS transcatheter arterial chemoembolization TACE TACE [8] OS ] Global OS HCC % sunitinib sutent

3 120 FR1 VEGFR2 VEGFR3 KIT FMS 3 EGFR FMS- like tyrosinekinase 3 FLT3 [ 1 RET ] [9-11] FDA [15-17] SFDA platelet derived growth factor PDGF - α PDGF- β VEG- Zhu [12] HCC 37.5 mg 2.1 IMC- C225 1/d EGFR progression- free survival PFS 19 HCC 3~ Asnacios [18] II mg/m mg/m 2 1/ GEMOX PR 8 SD 12 Faivre [13] mg/m mg/m % HCC ECOG 0~1 Child A B PFS.7 OS mg/d 2 6 2% 20% ~82 % 11% 3 92% 2 1~7 3~ 16% 3 3% 2% 2.2 erlotinib EGFR 2% 1% 1~2 ATP 68% HCC Philip [16] 25% < 38 HCC 50% 6% 50% 150 mg/d 3 8% 1 PR PR 12 32% 6 13 SD 59% HCC 13 Thomas [17] 2 epidermal growth factor receptor EGFR IMC- C225 ABX- EGF EGFR EGFR HCC PR 6% SD 69% 0 HCC 150 mg/d CR PR EGFR EGFR 3 - α HCC [1] EGFR [19] VEGF VEGF HCC

4 HCC VEGF 20 endostatin ES VEGF HCC VEGF Flt I HCC CD17 [20-21] HCC CD HCC CD17 [22-25] 5 mg/m 2 10 mg/m 2 1/2 HCC 12.5%~ [28-29] CD17 15.% disease control rate DCR 65%~ 80% PFS 6.5~6.9 HCC [30] Seldinger 2006 Zhu [26] 131 I GEMOX- B HCC HCC 0.75 mci/kg 36 HCC HCC % 58.3% 53.0%.% 20% DCR 89% PFS OS ES ES [1] Wilhelm SM Carter C Tang L et al. BAY exhibits broad spectrum oral antitumor activity and targets the RAF/ MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis[j]. Cancer Res 200 6(19): [2] Chang YS Adnane J Trail PA et al. Sorafenib (BAY3-9006) NP inhibits tumor growth and vascularization and induces tumor apoptosis and hypoxia in RCC xenograft models[j]. Cancer Chemother Pharmacol (5): [3] Villanueva A Newell P ChiangDY et al. Genomics and signaling pathways in hepatocellular carcinoma[j]. Semin Liver [27] ES Dis (1): [] Calvisi DF Ladu S Gorden A et al. Ubiquitous activation of Ras and Jak/Stat pathways in human HCC[J]. Gastroenterology (): ES % [5] Abou- Alfa GK Schwartz L Ricci S et al. Phase II study of sorafenib in patients with advanced hepatocellular carcinoma AFP 2 [J]. J Clin Oncol (26): [6] Llovet JM Ricci S Mazzaferro V et al. Sorafenib in advanced

5 122 hepatocellular carcinoma[j]. N Engl J Med (): [7] 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, doubleblind, placebo- controlled trial[j]. Lancet Oncol (1): [8] Abou- Alfa G Johnson P Knox J et al. Preliminary results from a phase, randomized, double blind study of sorafenib plus doxorubicin versus placebo plus doxorubicin in patients with advanced hepatocellular carcinoma[eb/ol]. [ ]. [9] Mendel DB Laird AD Xin X et al. In vivo antitumor activity of SU1128, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet- derived growth factor receptors: determination of a pharmacokinetic/pharmacodynamic relationship[j]. Clin Cancer Res (1): [10] Abrams TJ Lee LB Murray LJ et al. SU1128 inhibits KIT and platelet- derived growth factor receptor beta in preclinical models of human small cell lung cancer[j]. Mol Cancer Ther (5): [11] ChowLQ Eckhardt SG. Sunitinib: from rational design to clinical efficacy[j]. J Clin Oncol (7): [12] Zhu X Sahani DV di Tomaso E et al. A phase study of sunitinib in patients with advanced hepatocellular carcinoma [EB/OL]. [ ]. +%26+Virtual+Me- el+meeting/abstracts?&vmview=abst_ detail_view&confid=7&abstractid=3306. [13] Faivre SJ Raymond E Douillard J et al. Assessment of safety and drug- induced tumor necrosis with sunitinib in patients (pts) with unresectable hepatocellular carcinoma (HCC) [EB/ OL]. [ ] Virtual+Meeting/Abstracts?&vmview=abst_detail_view& confid=7&abstractid= [1] Cerea G, Ricotta R, Schiavetto I et al. Cetuximab for treatment of metastatic colorectal cancer[j]. Ann Oncol (Suppl 7): S66- S67. [15] O'Dwyer PJ Giantonio BJ Levy DE et al. Gefitinib in advanced unresectable hepatocellular carcinoma: results from the Eastern Cooperative Oncology Groups Study E1203[EB/ OL]. [ ] Virtual+Meeting/Abstracts?&vmview=abst_detail_view& confid=0&abstractid=3532. [16] Philip PA Mahoney MR Allmer C et al. Phase II study of erlotinib (OSI- 77) in patients with advanced hepatocellular cancer[j]. J Clin Oncol (27): [17] Thomas MB Chadha R Glover K et al. Phase 2 study of erlotinib in patients with unresectable hepatocellular carcinoma [J]. Cancer (5): [18] 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 (12): [19] Kraizer Y Mawasi N, Seagal J et al. Vascular endothelial growth factor and angiopoietin in liver regeneration[j]. Biochem Biophys Res Commun (1): [20] Ferrara N Hillan KJ Gerber HP et al. Discovery and development of bevacizumab, an anti- VEGF antibody for treating cancer[j]. Nat Rev Drug Discov 200 3(5): [21] Kim KJ Li B Winer J et al. Inhibition of vascular endothelial growth factor- induced angiogenesis suppresses tumour growth in vivo[j]. Nature (623):81-8. [22] Schwartz JD Schwartz M Lehrer D et al. Bevacizumab in hepatocellular carcinoma (HCC) in patients without metastasis and without invasion of the portal vein[eb/ol]. [ ]. [23] Schwartz JD Schwartz M Lehrer D et al. Bevacizumab in unresectable hepatocellular carcinoma (HCC) for patients without metastasis and without invasion of the portal vein [EB/OL]. [ ]. view&confid=0&abstractid= [2] Malka D Dromain C Farace F et al. Bevacizumab in patients (pts) with advanced hepatocellular carcinoma (HCC): preliminary results of a phase II study with circulating endothelial cell(cec) monitoring[eb/ol]. [ ]. http: // 26+Virtual+Meeting/Abstracts?&vmview=abst_detail_view&confID=7&abstractID= 381. [25] 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 (18): [26] Zhu AX Blaszkowsky LS Ryan DP et al. Phase II study of gemcitabine and oxaliplatin in combination with bevacizumab in patients with advanced hepatocellular carcinoma[j]. J Clin Oncol (12): [27]. [J] (1):5-7. [28]. [M]. : 2002: [29] Yang LJ Sui YF Chen ZN. Preparation and activity of conjugate of monoclonal antibody HAb18 against hepatoma F (ab')(2) fragment and staphylococcal enterotoxin A[J]. World J Gastroenterol (2): [30]. 131 I HAb18F (ab)2 [J]. 2005(6):

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