Development of Molecularly Targeted Therapies in Hepatocellular Carcinoma: Where Do We Go Now?

Clinical Cancer Research - Tập 16 Số 2 - Trang 390-397 - 2010
Richard S. Finn1
1Author's Affiliation: Division of Hematology/Oncology, Geffen School of Medicine at the University of California at Los Angeles, Los Angeles, California

Tóm tắt

Abstract Hepatocellular carcinoma (HCC), once considered an orphan disease in the West, has become a global health concern. It is the third leading cause of cancer death worldwide, and its incidence continues to increase. Historically, the development of new systemic agents for advanced HCC has been lacking despite no clear benefit with traditional cytotoxic therapies. Although two randomized studies with sorafenib for the treatment of HCC patients have recently been completed, survival benefits have been modest and highlight the unmet medical need among patients with HCC. Given the clear need, clinical development of novel systemic agents in HCC has begun in earnest. These clinical studies are founded on a growing body of basic and translational science that has identified several potential molecular targets in HCC. The successful development of such targeted agents in the future will be linked to our ability to appropriately select patients for treatment based on their clinical stage (including extent of liver disease and extent of tumor) and on potential predictive markers of response. Here, we review these data in the context of rational drug development in HCC in the front-line setting and in previously treated patients. Clin Cancer Res; 16(2); 390–7.

Từ khóa


Tài liệu tham khảo

Jemal, 2008, Cancer statistics, 2008, CA Cancer J Clin, 58, 71, 10.3322/CA.2007.0010

El Serag, 2007, Hepatocellular carcinoma: epidemiology and molecular carcinogenesis, Gastroenterology, 132, 2557, 10.1053/j.gastro.2007.04.061

Moradpour, 2005, Pathogenesis of hepatocellular carcinoma, Eur J Gastroenterol Hepatol, 17, 477, 10.1097/00042737-200505000-00002

Bruix, 2005, Management of hepatocellular carcinoma, Hepatology, 42, 1208, 10.1002/hep.20933

Roxburgh, 2008, Systemic therapy of hepatocellular carcinoma: are we making progress?, Adv Ther, 25, 1089, 10.1007/s12325-008-0113-z

Bouza, 2009, Meta-analysis of percutaneous radiofrequency ablation versus ethanol injection in hepatocellular carcinoma, BMC Gastroenterol, 9, 31, 10.1186/1471-230X-9-31

Llovet, 2003, Systematic review of randomized trials for unresectable hepatocellular carcinoma: chemoembolization improves survival, Hepatology, 37, 429, 10.1053/jhep.2003.50047

Lencioni, 2005, A critical appraisal of the literature on local ablative therapies for hepatocellular carcinoma, Clin Liver Dis, 9, 301, 10.1016/j.cld.2004.12.002

Llovet, 2008, Design and endpoints of clinical trials in hepatocellular carcinoma, J Natl Cancer Inst, 100, 698, 10.1093/jnci/djn134

Villanueva, 2008, Linking molecular classification of hepatocellular carcinoma and personalized medicine: preliminary steps, Curr Opin Oncol, 20, 444, 10.1097/CCO.0b013e328302c9e9

Lee, 2006, A novel prognostic subtype of human hepatocellular carcinoma derived from hepatic progenitor cells, Nat Med, 12, 410, 10.1038/nm1377

Hoshida, 2009, Molecular profiling to predict hepatocellular carcinoma outcome, Expert Rev Gastroenterol Hepatol, 3, 101, 10.1586/egh.09.5

Farazi, 2006, Hepatocellular carcinoma pathogenesis: from genes to environment, Nat Rev Cancer, 6, 674, 10.1038/nrc1934

Zender, 2006, Identification and validation of oncogenes in liver cancer using an integrative oncogenomic approach, Cell, 125, 1253, 10.1016/j.cell.2006.05.030

Zender, 2008, An oncogenomics-based in vivo RNAi screen identifies tumor suppressors in liver cancer, Cell, 135, 852, 10.1016/j.cell.2008.09.061

Finn, 2009, Targeting angiogenesis in hepatocellular carcinoma: focus on VEGF and bevacizumab, Expert Rev Anticancer Ther, 9, 503, 10.1586/era.09.6

Ng, 2001, Microvessel density, vascular endothelial growth factor and its receptors Flt-1 and Flk-1/KDR in hepatocellular carcinoma, Am J Clin Pathol, 116, 838, 10.1309/FXNL-QTN1-94FH-AB3A

Poon, 2007, High serum vascular endothelial growth factor levels predict poor prognosis after radiofrequency ablationof hepatocellular carcinoma: importance of tumor biomarker in ablative therapies, Ann Surg Oncol, 14, 1835, 10.1245/s10434-007-9366-z

Poon, 2003, Quantitative correlation of serum levels and tumor expression of vascular endothelial growth factor in patients with hepatocellular carcinoma, Cancer Res, 63, 3121

Jeng, 2004, Prognostic significance of preoperative circulating vascular endothelial growth factor messenger RNA expression in resectable hepatocellular carcinoma: a prospective study, World J Gastroenterol, 10, 643, 10.3748/wjg.v10.i5.643

Mise, 1996, Clinical significance of vascular endothelial growth factor and basic fibroblast growth factor gene expression in liver tumor, Hepatology, 23, 455, 10.1002/hep.510230309

Presta, 2005, Fibroblast growth factor/fibroblast growth factor receptor system in angiogenesis, Cytokine Growth Factor Rev, 16, 159, 10.1016/j.cytogfr.2005.01.004

Hsu, 1997, Implications of serum basic fibroblast growth factor levels in chronic liver diseases and hepatocellular carcinoma, Anticancer Res, 17, 2803

Yoshiji, 2002, Suppression of the renin-angiotensin system attenuates vascular endothelial growth factor-mediated tumor development and angiogenesis in murine hepatocellular carcinoma cells, Int J Oncol, 20, 1227

Mas, 2007, Angiogenesis soluble factors as hepatocellular carcinoma noninvasive markers for monitoring hepatitis C virus cirrhotic patients awaiting liver transplantation, Transplantation, 84, 1262, 10.1097/01.tp.0000287596.91520.1a

Jin-no, 1997, Plasma level of basic fibroblast growth factor increases with progression of chronic liver disease, J Gastroenterol, 32, 119, 10.1007/BF01213308

El Assal, 2001, The clinicopathological significance of heparanase and basic fibroblast growth factor expressions in hepatocellular carcinoma, Clin Cancer Res, 7, 1299

Uematsu, 2005, Altered expression of vascular endothelial growth factor, fibroblast growth factor-2 and endostatin in patients with hepatocellular carcinoma, J Gastroenterol Hepatol, 20, 583, 10.1111/j.1440-1746.2005.03726.x

Poon, 2001, Correlation of serum basic fibroblast growth factor levels with clinicopathologic features and postoperative recurrence in hepatocellular carcinoma, Am J Surg, 182, 298, 10.1016/S0002-9610(01)00708-5

Huang, 2006, Ectopic activity of fibroblast growth factor receptor 1 in hepatocytes accelerates hepatocarcinogenesis by driving proliferation and vascular endothelial growth factor-induced angiogenesis, Cancer Res, 66, 1481, 10.1158/0008-5472.CAN-05-2412

Ogasawara, 1996, Expressions of basic fibroblast growth factor and its receptors and their relationship to proliferation of human hepatocellular carcinoma cell lines, Hepatology, 24, 198, 10.1002/hep.510240132

Desnoyers, 2008, Targeting FGF19 inhibits tumor growth in colon cancer xenograft and FGF19 transgenic hepatocellular carcinoma models, Oncogene, 27, 85, 10.1038/sj.onc.1210623

Yoshiji, 2002, Synergistic effect of basic fibroblast growth factor and vascular endothelial growth factor in murine hepatocellular carcinoma, Hepatology, 35, 834, 10.1053/jhep.2002.32541

Dempke, 2009, Resistance to EGF-R (erbB-1) and VEGF-R modulating agents, Eur J Cancer, 45, 1117, 10.1016/j.ejca.2008.11.038

Bergers, 2008, Modes of resistance to anti-angiogenic therapy, Nat Rev Cancer, 8, 592, 10.1038/nrc2442

Casanovas, 2005, Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors, Cancer Cell, 8, 299, 10.1016/j.ccr.2005.09.005

Kopetz, 2009, Angiogenic cytokines are increased prior to disease progression in metastatic colorectal cancer patients treated with bevacizumab, abstract 292

Loges, 2009, Silencing or fueling metastasis with VEGF inhibitors: antiangiogenesis revisited, Cancer Cell, 15, 167, 10.1016/j.ccr.2009.02.007

Paez-Ribes, 2009, Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis, Cancer Cell, 15, 220, 10.1016/j.ccr.2009.01.027

Ebos, 2009, Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis, Cancer Cell, 15, 232, 10.1016/j.ccr.2009.01.021

Ito, 2001, Expression and clinical significance of erb-B receptor family in hepatocellular carcinoma, Br J Cancer, 84, 1377, 10.1054/bjoc.2000.1580

Philip, 2006, Phase II study of erlotinib in patients with advanced biliary cancer, J Clin Oncol, 24, 3069, 10.1200/JCO.2005.05.3579

Thomas, 2007, Phase 2 study of erlotinib in patients with unresectable hepatocellular carcinoma, Cancer, 110, 1059, 10.1002/cncr.22886

Ramanathan, 2009, A phase II study of lapatinib in patients with advanced biliary tree and hepatocellular cancer, Cancer Chemother Pharmacol, 10.1007/s00280-009-0927-7

Zhu, 2007, Phase 2 study of cetuximab in patients with advanced hepatocellular carcinoma, Cancer, 110, 581, 10.1002/cncr.22829

Bekaii-Saab, 2009, A multi-institutional phase II study of the efficacy and tolerability of lapatinib in patients with advanced hepatocellular carcinomas, Clin Cancer Res, 15, 5895, 10.1158/1078-0432.CCR-09-0465

Fuchs, 2008, Epithelial-to-mesenchymal transition and integrin-linked kinase mediate sensitivity to epidermal growth factor receptor inhibition in human hepatoma cells, Cancer Res, 68, 2391, 10.1158/0008-5472.CAN-07-2460

Jabari, 2009, Cellular plasticity of trans- and dedifferentiation markers in human hepatoma cells in vitro and in vivo, Int J Oncol, 35, 69

Kaposi-Novak, 2006, Met-regulated expression signature defines a subset of human hepatocellular carcinomas with poor prognosis and aggressive phenotype, J Clin Invest, 116, 1582, 10.1172/JCI27236

Osada, 2008, Clinical significance of serum HGF and c-Met expression in tumor tissue for evaluation of properties and treatment of hepatocellular carcinoma, Hepatogastroenterology, 55, 544

Comoglio, 2008, Drug development of MET inhibitors: targeting oncogene addiction and expedience, Nat Rev Drug Discov, 7, 504, 10.1038/nrd2530

Pena, 2008, Hepatocyte growth factor (HGF) is a aprognostic biomarker for overall survival and a pharmacodynamic biomarker for sorafenib response in the SHARP phase III HCC trial

Scharf, 2001, The IGF axis and hepatocarcinogenesis, Mol Pathol, 54, 138, 10.1136/mp.54.3.138

Rikhof, 2009, The insulin-like growth factor system and sarcomas, J Pathol, 217, 469, 10.1002/path.2499

Hopfner, 2006, Blockade of IGF-1 receptor tyrosine kinase has antineoplastic effects in hepatocellular carcinoma cells, Biochem Pharmacol, 71, 1435, 10.1016/j.bcp.2006.02.006

Yuan, 2008, PI3K pathway alterations in cancer: variations on a theme, Oncogene, 27, 5497, 10.1038/onc.2008.245

Sahin, 2004, mTOR and p70 S6 kinase expression in primary liver neoplasms, Clin Cancer Res, 10, 8421, 10.1158/1078-0432.CCR-04-0941

Sieghart, 2007, Mammalian target of rapamycin pathway activity in hepatocellular carcinomas of patients undergoing liver transplantation, Transplantation, 83, 425, 10.1097/01.tp.0000252780.42104.95

Villanueva, 2008, Pivotal role of mTOR signaling in hepatocellular carcinoma, Gastroenterology, 135, 1972, 10.1053/j.gastro.2008.08.008

Treiber, 2009, mTOR inhibitors for hepatocellular cancer: a forward-moving target, Expert Rev Anticancer Ther, 9, 247, 10.1586/14737140.9.2.247

Wang, 2008, Effect of rapamycin alone and in combination with sorafenib in an orthotopic model of human hepatocellular carcinoma, Clin Cancer Res, 14, 5124, 10.1158/1078-0432.CCR-07-4774

Huynh, 2007, Targeted inhibition of the extracellular signal-regulated kinase kinase pathway with AZD6244 (ARRY-142886) in the treatment of hepatocellular carcinoma, Mol Cancer Ther, 6, 138, 10.1158/1535-7163.MCT-06-0436

Zimmerman, 2008, Sirolimus-based immunosuppression following liver transplantation for hepatocellular carcinoma, Liver Transpl, 14, 633, 10.1002/lt.21420

Newell, 2009, Ras pathway activation in hepatocellular carcinoma and anti-tumoral effect of combined sorafenib and rapamycin in vivo, J Hepatol, 51, 725, 10.1016/j.jhep.2009.03.028

Roberts, 2007, Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer, Oncogene, 26, 3291, 10.1038/sj.onc.1210422

Abou-Alfa, 2006, Phase II study of sorafenib in patients with advanced hepatocellular carcinoma, J Clin Oncol, 24, 4293, 10.1200/JCO.2005.01.3441

Ito, 2000, Survivin promotes cell proliferation in human hepatocellular carcinoma, Hepatology, 31, 1080, 10.1053/he.2000.6496

Ikeguchi, 2002, Expression of survivin messenger RNA correlates with poor prognosis in patients with hepatocellular carcinoma, Diagn Mol Pathol, 11, 33, 10.1097/00019606-200203000-00007

Sun, 2006, Suppression of tumor growth using antisense oligonucleotide against survivin in an orthotopic transplant model of human hepatocellular carcinoma in nude mice, Oligonucleotides, 16, 365, 10.1089/oli.2006.16.365

Finn, 2009, Effect of dasatinib, an orally active small molecule inhibitor of both src and abl kinases, on growth of hepatic progenitor subtype human hepatocellular carcinoma cells in vitro

Cheng, 2009, 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, Lancet Oncol, 10, 25, 10.1016/S1470-2045(08)70285-7

Llovet, 2008, Sorafenib in advanced hepatocellular carcinoma, N Engl J Med, 359, 378, 10.1056/NEJMoa0708857

Zhu, 2009, Commentary: Sorafenib use in patients with advanced hepatocellular carcinoma and underlying Child-Pugh B cirrhosis: evidence and controversy, Oncologist, 14, 67, 10.1634/theoncologist.2008-0281

Zhu, 2009, Efficacy, safety, and potential biomarkers of sunitinib monotherapy in advanced hepatocellular carcinoma: a phase II study, J Clin Oncol, 27, 3027, 10.1200/JCO.2008.20.9908

Thomas, 2009, Phase II trial of the combination of bevacizumab and erlotinib in patients who have advanced hepatocellular carcinoma, J Clin Oncol, 27, 843, 10.1200/JCO.2008.18.3301

Kaseb, 2009, Biological activity of bevacizumab and erlotinib in patients with advanced hepatocellular carcinoma (HCC), J Clin Oncol, 27, 10.1200/jco.2009.27.15_suppl.4522

Hsu, 2009, A Phase II study of bevacizumab (B) and erlotinib (E) in combination for Asian patients (pts) with advanced/metastatic hepatocellular carcinoma (HCC): An interim safety report, J Clin Oncol, 27, abstract 4585., 10.1200/jco.2009.27.15_suppl.4585

Huynh, 2008, Brivanib alaninate, a dual inhibitor of vascular endothelial growth factor receptor and fibroblast growth factor receptor tyrosine kinases, induces growth inhibition in mouse models of human hepatocellular carcinoma, Clin Cancer Res, 14, 6146, 10.1158/1078-0432.CCR-08-0509

Raoul, 2009, An open-label phase II study of first- and second-line treatment with brivanib in patients with hepatocellular carcinoma (HCC), 10.1200/jco.2009.27.15_suppl.4577

Finn, Time-to-progression sub-analysis of second-line treatment with brivanib after failure of prior antiangiogenic therapy in patients with unresectable, locally advanced, or metastatic hepatocellular carcinoma, Am Assoc for the Study of Liver Disease Annual Meeting, 2009 abstract

Thomas, 2005, Hepatocellular carcinoma: the need for progress, J Clin Oncol, 23, 2892, 10.1200/JCO.2005.03.196

Hurwitz, 2004, Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer, N Engl J Med, 350, 2335, 10.1056/NEJMoa032691

Abou-Alfa, 2008, Final results from a phase II (PhII), randomized, double-blind study of sorafenib plus doxorubicin (S+D) versus placebo plus doxorubicin (P+D) in patients (pts) with advanced hepatocellular carcinoma (AHCC), abstract 128

Zhu, 2006, Phase II study of gemcitabine and oxaliplatin in combination with bevacizumab in patients with advanced hepatocellular carcinoma, J Clin Oncol, 24, 1898, 10.1200/JCO.2005.04.9130

Britten, 2005, A pilot study of IV bevacizumab in hepatocellular cancer patients undergoing chemoembolization, J Clin Oncol, 23, abstract 4138, 10.1200/jco.2005.23.16_suppl.4138

Sherman, 2008, Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma and vascular invasion or extrahepatic spread: a subanalysis from the SHARP trial, J Clin Oncol, 26, abstract 4584, 10.1200/jco.2008.26.15_suppl.4584

Raoul, 2008, Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma according to ECOG performance status: a subanalysis from the SHARP trial, J Clin Oncol, 26, abstract 4587, 10.1200/jco.2008.26.15_suppl.4587

Faivre, 2007, Assessment of safety and drug-induced tumor necrosis with sunitinib in patients (pts) with unresectable hepatocellular carcinoma (HCC), J Clin Oncol, 25, abstract 3546, 10.1200/jco.2007.25.18_suppl.3546

Philip, 2005, Phase II study of erlotinib (OSI-774) in patients with advanced hepatocellular cancer, J Clin Oncol, 23, 6657, 10.1200/JCO.2005.14.696

O'Dwyer, 2006, Gefitinib in advanced unresectable hepatocellular carcinoma: results from the Eastern Cooperative Oncology Group's Study E1203, J Clin Oncol, 24, abstract 4143, 10.1200/jco.2006.24.18_suppl.4143

Gruenwald, 2007, A phase II open-label study of cetuximab in unresectable hepatocellular carcinoma: final results, J Clin Oncol, 25, abstract 4598, 10.1200/jco.2007.25.18_suppl.4598

Siegel, 2008, Phase II trial evaluating the clinical and biologic effects of bevacizumab in unresectable hepatocellular carcinoma, J Clin Oncol, 26, 2992, 10.1200/JCO.2007.15.9947