Molecularly targeted therapy in hepatocellular carcinoma

Biochemical Pharmacology

Volumn 80, Issue 5, 2010, Pages 550-560

  Huynh, Hung ^a  

^a DIVISION OF MEDICAL ONCOLOGY   (Singapore)

Author keywords

Hepatocellular carcinoma; Molecular therapies; Tyrosine kinase inhibitors

Indexed keywords

2,4 DIMETHYL 5 (2 OXO 1H INDOL 3 YLMETHYLENE) 3 PYRROLEPROPIONIC ACID; AXITINIB; BEVACIZUMAB; BRIVANIB; BRIVANIB ALANINATE; CEDIRANIB; DOVITINIB; ERLOTINIB; FIBROBLAST GROWTH FACTOR RECEPTOR; FORETINIB; GEFITINIB; JANUS KINASE; LAPATINIB; MAMMALIAN TARGET OF RAPAMYCIN; MITOGEN ACTIVATED PROTEIN KINASE; MONOCLONAL ANTIBODY; MOTESANIB; PAZOPANIB; PHOSPHATIDYLINOSITOL 3 KINASE; PLACEBO; PLATELET DERIVED GROWTH FACTOR RECEPTOR; PROTEIN KINASE B; PROTEIN TYROSINE KINASE INHIBITOR; RAF PROTEIN; SCATTER FACTOR RECEPTOR; SORAFENIB; STAT PROTEIN; SUNITINIB; UNCLASSIFIED DRUG; VASCULOTROPIN; VASCULOTROPIN RECEPTOR; XL 184; XL 880;

ANGIOGENESIS; ANOREXIA; ARTERIAL THROMBOEMBOLISM; BLEEDING; CANCER COMBINATION CHEMOTHERAPY; CANCER SURVIVAL; CLINICAL TRIAL; DEHYDRATION; DESQUAMATION; DIARRHEA; DRUG DOSE ESCALATION; DRUG EFFICACY; DRUG ERUPTION; DRUG FATALITY; DRUG MECHANISM; DRUG SAFETY; DRUG TOLERABILITY; EDEMA; FATIGUE; GASTROINTESTINAL STROMAL TUMOR; HUMAN; HYPERTENSION; KIDNEY CARCINOMA; LIVER CELL CARCINOMA; MOLECULAR THERAPY; MOUTH PAIN; NAUSEA; NONHUMAN; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEINURIA; REVIEW; SIDE EFFECT; SKIN MANIFESTATION; SKIN TOXICITY; THROMBOCYTOPENIA; THROMBOEMBOLISM; TREATMENT RESPONSE; TUMOR GROWTH; URINARY TRACT CARCINOMA;

ANTINEOPLASTIC AGENTS; CARCINOMA, HEPATOCELLULAR; HUMANS; LIVER NEOPLASMS; NEOVASCULARIZATION, PATHOLOGIC; PROTEIN KINASE INHIBITORS;

EID: 77954218447     PISSN: 00062952     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bcp.2010.03.034     Document Type: Review

References (166)

1. Cancer.org [homepage on the Internet]. American Cancer Society: Global Cancer facts and Figures 2007 [updated 2010; cited 2010 January 16]. Available from: http://www.cancer.org/docroot/home/index.asp.
2. Jemal A., Murray T., Ward E., Samuels A., Tiwari R.C., Ghafoor A., et al. Cancer statistics, 2005. CA Cancer J Clin 2005, 55:10-30.
3. Smith R.A., Cokkinides V., Eyre H.J. American Cancer Society guidelines for the early detection of cancer, 2005. CA Cancer J Clin 2005, 55:31-44.
4. Okuda K., Ohtsuki T., Obata H., Tomimatsu M., Okazaki N., Hasegawa H., et al. Natural history of hepatocellular carcinoma and prognosis in relation to treatment. Study of 850 patients. Cancer 1985, 56:918-928.
5. Llovet J.M., Burroughs A., Bruix J. Hepatocellular carcinoma. Lancet 2003, 362:1907-1917.
6. Huguet C., Stipa F., Gavelli A. Primary hepatocellular cancer: western experience. Surgery of the liver and billary tract 2000, 1365-1369. Churchill Livingstone, London. L. Blumgart (Ed.).
7. Lai E.W.J. Hepatocellular carcinoma: the Asian experience. Surgery of the liver and the biliary tract 1994, 1349-1363. Churchill Livingstone, London. L. Blumgart (Ed.).
8. Colombo M. Hepatocellular carcinoma. J Hepatol 1992, 15:225-236.
9. Thorgeirsson S.S., Grisham J.W. Molecular pathogenesis of human hepatocellular carcinoma. Nat Genet 2002, 31:339-346.
10. Edmondson H.A., Peters R.L. Tumors of the liver: pathologic features. Semin Roentgenol 1983, 18:75-83.
11. Farazi P.A., DePinho R.A. Hepatocellular carcinoma pathogenesis: from genes to environment. Nat Rev Cancer 2006, 6:674-687.
12. Thomas M. Molecular targeted therapy for hepatocellular carcinoma. J Gastroenterol 2009, 44(Suppl. 19):136-141.
13. Yeo W., Mok T.S., Zee B., Leung T.W., Lai P.B., Lau W.Y., et al. A randomized phase III study of doxorubicin versus cisplatin/interferon alpha-2b/doxorubicin/fluorouracil (PIAF) combination chemotherapy for unresectable hepatocellular carcinoma. J Natl Cancer Inst 2005, 97:1532-1538.
14. Simonetti R.G., Liberati A., Angiolini C., Pagliaro L. Treatment of hepatocellular carcinoma: a systematic review of randomized controlled trials. Ann Oncol 1997, 8:117-136.
15. Lopez P.M., Patel P., Uva P., Villanueva A., Llovet J.M. Current management of liver cancer. Eur J Can Suppl 2007, 5(5):444-446.
16. Miura H., Miyazaki T., Kuroda M., Oka T., Machinami R., Kodama T., et al. Increased expression of vascular endothelial growth factor in human hepatocellular carcinoma. J Hepatol 1997, 27:854-861.
17. Torimura T., Sata M., Ueno T., Kin M., Tsuji R., Suzaku K., et al. Increased expression of vascular endothelial growth factor is associated with tumor progression in hepatocellular carcinoma. Hum Pathol 1998, 29:986-991.
18. Poon R.T., Ng I.O., Lau C., Yu W.C., Fan S.T., Wong J. Correlation of serum basic fibroblast growth factor levels with clinicopathological features and postoperative recurrence in hepatocellular carcinoma. Am J Surg 2001, 182:298-304.
19. Hicklin D.J., Ellis L.M. Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol 2005, 23:1011-1027.
20. Poon R.T., Ho J.W., Tong C.S., Lau C., Ng I.O., Fan S.T. Prognostic significance of serum vascular endothelial growth factor and endostatin in patients with hepatocellular carcinoma. Br J Surg 2004, 91:1354-1360.
21. Chao Y., Li C.P., Chau G.Y., Chen C.P., King K.L., Lui W.Y., et al. Prognostic significance of vascular endothelial growth factor, basic fibroblast growth factor, and angiogenin in patients with resectable hepatocellular carcinoma after surgery. Ann Surg Oncol 2003, 10:355-362.
22. Thomas M.B., Abbruzzese J.L. Opportunities for targeted therapies in hepatocellular carcinoma. J Clin Oncol 2005, 23:8093-8108.
23. Zhang T., Sun H.C., Xu Y., Zhang K.Z., Wang L., Qin L.X., et al. Overexpression of platelet-derived growth factor receptor alpha in endothelial cells of hepatocellular carcinoma associated with high metastatic potential. Clin Cancer Res 2005, 11:8557-8563.
24. Conway E.M., Collen D., Carmeliet P. Molecular mechanisms of blood vessel growth. Cardiovasc Res 2001, 49:507-521.
25. Pietras K., Hanahan D. A multitargeted, metronomic, and maximum-tolerated dose " chemo-switch" regimen is antiangiogenic, producing objective responses and survival benefit in a mouse model of cancer. J Clin Oncol 2005, 23:939-952.
26. Mise M., Arii S., Higashituji H., Furutani M., Niwano M., Harada T., et al. Clinical significance of vascular endothelial growth factor and basic fibroblast growth factor gene expression in liver tumor. Hepatology 1996, 23:455-464.
27. Kin M., Sata M., Ueno T., Torimura T., Inuzuka S., Tsuji R., et al. Basic fibroblast growth factor regulates proliferation and motility of human hepatoma cells by an autocrine mechanism. J Hepatol 1997, 27:677-687.
28. Ingber D. Extracellular matrix and cell shape: potential control points for inhibition of angiogenesis. J Cell Biochem 1991, 47:236-241.
29. El Assal O.N., Yamanoi A., Ono T., Kohno H., Nagasue N. The clinicopathological significance of heparanase and basic fibroblast growth factor expressions in hepatocellular carcinoma. Clin Cancer Res 2001, 7:1299-1305.
30. Yoshiji H., Kuriyama S., Yoshii J., Ikenaka Y., Noguchi R., Hicklin D.J., et al. Synergistic effect of basic fibroblast growth factor and vascular endothelial growth factor in murine hepatocellular carcinoma. Hepatology 2002, 35:834-842.
31. Finn R.S. Development of molecularly targeted therapies in hepatocellular carcinoma: where do we go now?. Clin Cancer Res 2010, 16(2):390-397.
32. Yamaguchi R., Yano H., Iemura A., Ogasawara S., Haramaki M., Kojiro M. Expression of vascular endothelial growth factor in human hepatocellular carcinoma. Hepatology 1998, 28:68-77.
33. Poon R.T., Fan S.T., Wong J. Clinical significance of angiogenesis in gastrointestinal cancers: a target for novel prognostic and therapeutic approaches. Ann Surg 2003, 238:9-28.
34. Jinno K., Tanimizu M., Hyodo I., Nishikawa Y., Hosokawa Y., Doi T., et al. Circulating vascular endothelial growth factor (VEGF) is a possible tumor marker for metastasis in human hepatocellular carcinoma. J Gastroenterol 1998, 33:376-382.
35. Finn R.S., Bentley G., Britten C.D., Amado R., Busuttil R.W. Targeting vascular endothelial growth factor with the monoclonal antibody bevacizumab inhibits human hepatocellular carcinoma cells growing in an orthotopic mouse model. Liver Int 2009, 29(2):284-290.
36. Siegel A.B., Cohen E.I., Ocean A., Lehrer D., Goldenberg A., Knox J.J., et al. Phase II trial evaluating the clinical and biologic effects of bevacizumab in unresectable hepatocellular carcinoma. J Clin Oncol 2008, 26:2992-2998.
37. Boige V., Baey C., Dromain C., Ducreux M., Malka D., Pignon J., et al. Circulating endothelial cells (CEC) and angiogenic proteins monitoring in patients (pts) with advanced hepatocellular carcinoma (HCC) treated with bevacizumab. J Clin Oncol 2009, 27:15s. [Abstract 4597].
38. Huynh H., Chow P.K., Palanisamy N., Salto-Tellez M., Goh B.C., Lee C.K., et al. Bevacizumab and rapamycin induce growth suppression in mouse models of hepatocellular carcinoma. J Hepatol 2008, 49:52-60.
39. Thomas M.B., Morris J.S., Chadha R., Iwasaki M., Kaur H., Lin E., et al. Phase II trial of the combination of bevacizumab and erlotinib in patients who have advanced hepatocellular carcinoma. J Clin Oncol 2009, 27:843-850.
40. Kerbel R.S., Yu J., Tran J., Man S., Viloria-Petit A., Klement G., et al. Possible mechanisms of acquired resistance to anti-angiogenic drugs: implications for the use of combination therapy approaches. Cancer Metastasis Rev 2001, 20:79-86.
41. Miller K.D., Sweeney C.J., Sledge G.W. The Snark is a Boojum: the continuing problem of drug resistance in the antiangiogenic era. Ann Oncol 2003, 14:20-28.
42. Miller K.D., Sweeney C.J., Sledge G.W. Can tumor angiogenesis be inhibited without resistance?. Mechanisms of angiogenesis 2005, 95-112. Birkhäuser Basel, USA. M. Clauss, G. Breier (Eds.).
43. Leenders W.P., Kusters B., Verrijp K., Maass C., Wesseling P., Heerschap A., et al. Antiangiogenic therapy of cerebral melanoma metastases results in sustained tumor progression via vessel co-option. Clin Cancer Res 2004, 10:6222-6230.
44. Motzer R.J., Michaelson M.D., Redman B.G., Hudes G.R., Wilding G., Figlin R.A., et al. Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma. J Clin Oncol 2006, 24:16-24.
45. Xu L., Duda D.G., di Tomaso E., Ancukiewicz M., Chung D.C., Lauwers G.Y., et al. Direct evidence that bevacizumab, an Anti-VEGF antibody, up-regulates SDF1, CXCR4, CXCL6, and neuropilin 1 in tumors from patients with rectal cancer. Cancer Res 2009, 69(20):7905-7910.
46. Willett C.G., Boucher Y., Duda D.G., di Tomaso E., Munn L.L., Tong R.T., et al. Surrogate markers for antiangiogenic therapy and dose-limiting toxicities for bevacizumab with radiation and chemotherapy: continued experience of a phase I trial in rectal cancer patients. J Clin Oncol 2005, 23:8136-8139.
47. Nissen L.J., Cao R., Hedlund E.M., Wang Z., Zhao X., Wetterskog D., et al. Angiogenic factors FGF2 and PDGF-BB synergistically promote murine tumor neovascularization and metastasis. J Clin Invest 2007, 117:2766-2777.
48. Mancuso M.R., Davis R., Norberg S.M., O'Brien S., Sennino B., Nakahara T., et al. Rapid vascular regrowth in tumors after reversal of VEGF inhibition. J Clin Invest 2006, 116:2610-2621.
49. Wilhelm S.M., Carter C., Tang L., Wilkie D., McNabola A., Rong H., et al. BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res 2004, 64:7099-7109.
50. Wilhelm S., Carter C., Lynch M., Lowinger T., Dumas J., Smith R.A., et al. Discovery and development of sorafenib: a multikinase inhibitor for treating cancer. Nat Rev 2006, 5:835-844.
51. Huynh H., Ngo V.C., Koong H.N., Poon D., Choo S.P., Thng C.H., et al. Sorafenib and rapamycin induce growth suppression in mouse models of hepatocellular carcinoma. J Cell Mol Med 2009, 1-12.
52. Liu L., Cao Y., Chen C., Zhang X., McNabola A., Wilkie D., et al. Sorafenib blocks the RAF/MEK/ERK pathway, inhibits tumor angiogenesis, and induces tumor cell apoptosis in hepatocellular carcinoma model PLC/PRF/5. Cancer Res 2006, 66:11851-11858.
53. Strumberg D., Clark J.W., Awada A., Moore M.J., Richly H., Hendlisz A., et al. Safety, pharmacokinetics, and preliminary antitumor activity of sorafenib: a review of four phase I trials in patients with advanced refractory solid tumors. Oncologist 2007, 12:426-437.
54. Llovet J.M., Ricci S., Mazzaferro V., Hilgard P., Gane E., Blanc J.F., et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008, 359:378-390.
55. Cheng A., Kang Y., Chen Z., Tsao C., Qin S., Kim J., et al. Randomized phase III trial of sorafenib versus placebo in Asian patients with advanced hepatocellular carcinoma. J Clin Oncol 2008, 26:15s. [Abstract 4509].
56. Abou-Alfa G.K., Johnson P., Knox J., Davidenko I., Lacava J., Leung T., et al. 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). Proceedings of the 2008 gastrointestinal cancers symposium 2008.
57. Huynh H., Ngo V.C., Koong H.N., Poon D., Choo S.P., Toh H.C., et al. AZD6244 enhances the antitumor activity of sorafenib in ectopic and orthotopic models of human hepatocellular carcinoma (HCC). J Hepatol 2010, 52:79-87.
58. Eisen T., Joensuu H., Nathan P., Harper P., Wojtukiewicz M., Nicholson S., et al. Phase II study of BAY 73-4506, a multikinase inhibitor, in previously untreated patients with metastatic or unresectable renal cell cancer. Eur J Cancer Suppl 2009, 7(2):424.
59. Abrams T.J., Lee L.B., Murray L.J., Pryer N.K., Cherrington J.M. SU11248 inhibits KIT and platelet-derived growth factor receptor beta in preclinical models of human small cell lung cancer. Mol Cancer Ther 2003, 2:471-478.
60. Mendel D.B., Laird A.D., Xin X., Louie S.G., Christensen J.G., Li G., et al. In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: determination of a pharmacokinetic/pharmacodynamic relationship. Clin Cancer Res 2003, 9:327-337.
61. Murray L.J., Abrams T.J., Long K.R., Ngai T.J., Olson L.M., Hong W., et al. SU11248 inhibits tumor growth and CSF-1R-dependent osteolysis in an experimental breast cancer bone metastasis model. Clin Exp Metastasis 2003, 20:757-766.
62. O'Farrell A.M., Abrams T.J., Yuen H.A., Ngai T.J., Louie S.G., Yee K.W., et al. SU11248 is a novel FLT3 tyrosine kinase inhibitor with potent activity in vitro and in vivo. Blood 2003, 101:3597-3605.
63. Kim D.W., Jo Y.S., Jung H.S., Chung H.K., Song J.H., Park K.C., et al. An orally administered multitarget tyrosine kinase inhibitor, SU11248, is a novel potent inhibitor of thyroid oncogenic RET/papillary thyroid cancer kinases. J Clin Endocrinol Metab 2006, 91:4070-4076.
64. Chow L.Q., Eckhardt S.G. Sunitinib: from rational design to clinical efficacy. J Clin Oncol 2007, 25:884-896.
65. Motzer R.J., Hutson T.E., Tomczak P., Michaelson M.D., Bukowski R.M., Rixe O., et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 2007, 356:115-124.
66. Demetri G., Van Oosterom A., Garrett C., Blackstein M., Shah M., Verweij J., et al. Efficacy and safety of Sunitinib in patients with advanced GISTs after failure of imatinib: a randomized controlled trial. Lancet 2006, 368:1329-1338.
67. Huynh H., Ngo V.C., Choo S.P., Poon D., Koong H.N., Thng C.H., et al. Sunitinib (SUTENT, SU11248) suppresses tumor growth and induces apoptosis in xenograft models of human hepatocellular carcinoma. Curr Cancer Drug Targets 2009, 9:738-747.
68. Zhu A.X., Sahani D.V., di Tomaso E., Duda D., Sindhwani V., Yoon S.S., et al. A phase II study of sunitinib in patients with advanced hepatocellular carcinoma. J Clin Oncol 2007, 25:18S. [Abstract 4637A].
69. Faivre S.J., Raymond E., Douillard J., Boucher E., Lim H.Y., Kim J.S., et al. Phase II trial investigating the efficacy and safety of sunitinib in patients with unresectable hepatocellular carcinoma (HCC). Eur J Cancer Suppl 2007, 5(4):270.
70. Zhu A.X., Raymond E. Early development of sunitinib in hepatocellular carcinoma. Expert Rev Anticancer Ther 2009, 9:143-150.
71. Faivre S., Delbaldo C., Vera K., Robert C., Lozahic S., Lassau N., et al. Safety, pharmacokinetic, and antitumor activity of SU11248, a novel oral multitarget tyrosine kinase inhibitor, in patients with cancer. J Clin Oncol 2006, 24:25-35.
72. Zhu A.X., Duda D.G., Sahani D.V., Jain R.K. Development of sunitinib in hepatocellular carcinoma: rationale, early clinical experience, and correlative studies. Cancer J 2009, 15:263-268.
73. Faivre S.J., Raymond E., Douillard J., Boucher E., Lim H.Y., Kim J.S., et al. Assessment of safety and drug-induced tumor necrosis with sunitinib in patients (pts) with unresectable hepatocellular carcinoma (HCC). J Clin Oncol 2007, 25:18S. [Abstract 3546].
74. Pfizer. Study of sunitinib malate versus sorafenib in patients with inoperable liver cancer. Patent ; 2009. ctgov:NCT00699374.
75. Huynh H., Ngo V.C., Fargnoli J., Ayers M., Soo K.C., Koong H.N., et al. 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 2008, 14:6146-6153.
76. Rosen L.S., Wilding G., Sweeney C., Casale D., Kollia G., Wu C., et al. Phase I dose escalation study to determine the safety, pharmacokinetics and pharmacodynamics of BMS-582664, a VEGFR/FGFR inhibitor in patients with advanced/metastatic solid tumors. J Clin Oncol 2007, 24:18S. [Abstract 3051].
77. Jonker D.J., Rosen L.S., Sawyer M., Wilding G., Noberasco C., Jayson G., et al. A phase I study of BMS-582664 (brivanib alaninate), an oral dual inhibitor of VEGFR and FGFR tyrosine kinases, in patients (pts) with advanced/metastatic solid tumors: safety, pharmacokinetic (PK), and pharmacodynamic (PD) findings. J Clin Oncol 2007, 25:18S. [Abstract 3559].
78. Raoul J.L., Finn R.S., Kang Y.K., Park J.W., Harris R., Coric V., et al. An open-label phase II study of first- and second-line treatment with brivanib in patients with hepatocellular carcinoma (HCC). J Clin Oncol 2009, 27:15s. [Abstract 4577].
79. Lee S.H., Lopes D.M., Vora J., Harris A., Ye H., Nordahl L., et al. In vivo target modulation and biological activity of CHIR-258, a multitargeted growth factor receptor kinase inhibitor, in colon cancer models. Clin Cancer Res 2005, 11:3633-3641.
80. Lopes de Menezes D.E., Peng J., Garrett E.N., Louie S.G., Lee S.H., Wiesmann M., et al. CHIR-258: a potent inhibitor of FLT3 kinase in experimental tumor xenograft models of human acute myelogenous leukemia. Clin Cancer Res 2005, 11:5281-5291.
81. Kim K.B., Saro J., Moschos S.S., Hwu P., Tarhini A.A., Hwu W., et al. A phase I dose finding and biomarker study of TKI258 (dovitinib lactate) in patients with advanced melanoma. J Clin Oncol 2008, 26:15s. [Abstract 9026].
82. Harada K., Shiota G., Kawasaki H. Transforming growth factor-alpha and epidermal growth factor receptor in chronic liver disease and hepatocellular carcinoma. Liver 1999, 19:318-325.
83. Hisaka T., Yano H., Haramaki M., Utsunomiya I., Kojiro M. Expressions of epidermal growth factor family and its receptor in hepatocellular carcinoma cell lines: relationship to cell proliferation. Int J Oncol 1999, 14:453-460.
84. Ito Y., Takeda T., Higashiyama S., Sakon M., Wakasa K.I., Tsujimoto M., et al. Expression of heparin binding epidermal growth factor-like growth factor in hepatocellular carcinoma: an immunohistochemical study. Oncol Rep 2001, 8:903-907.
85. Matsuo M., Sakurai H., Saiki I. ZD1839, a selective epidermal growth factor receptor tyrosine kinase inhibitor, shows antimetastatic activity using a hepatocellular carcinoma model. Mol Cancer Ther 2003, 2:557-561.
86. Liu Y., Poon R.T., Shao W., Sun X., Chen H., Kok T.W., et al. Blockage of epidermal growth factor receptor by quinazoline tyrosine kinase inhibitors suppresses growth of human hepatocellular carcinoma. Cancer Lett 2007, 248:32-40.
87. Hopfner M., Schuppan D., Scherubl H. Growth factor receptors and related signalling pathways as targets for novel treatment strategies of hepatocellular cancer. World J Gastroenterol 2008, 14:1-14.
88. Huether A., Hopfner M., Baradari V., Schuppan D., Scherubl H. EGFR blockade by cetuximab alone or as combination therapy for growth control of hepatocellular cancer. Biochem Pharmacol 2005, 70:1568-1578.
89. Hopfner M., Sutter A.P., Huether A., Schuppan D., Zeitz M., Scherubl H. Targeting the epidermal growth factor receptor by gefitinib for treatment of hepatocellular carcinoma. J Hepatol 2004, 41:1008-1016.
90. Zhu A.X., Stuart K., Blaszkowsky L.S., Muzikansky A., Reitberg D.P., Clark J.W., et al. Phase 2 study of cetuximab in patients with advanced hepatocellular carcinoma. Cancer 2007, 110:581-589.
91. Gruenwald V., Wilkens L., Gebel M., Greten T.F., Kubicka S., Ganser A., et al. A phase II open-label study of cetuxiamb in unresectable hepatocellular carcinoma: final results. J Clin Oncol 2007, 25:4598.
92. Wierzbicki R., Jonker D.J., Moore M.J., Berry S.R., Loehrer P.J., Fox F., et al. A phase II multicenter study of cetuximab monotherapy in patients with EGFR-undetectable refractory metastatic colorectal carcinoma (mCRC). J Clin Oncol 2008, 26. [Abstract 4065].
93. Louafi S., Hebbar M., Rosmorduc O., Tesmoingt C., Asnasios A., Romano O., et al. Gemcitabine, oxalaplatin and cetuximab for treatment of hepatocellular carcinoma: results of phase II study ERGO. J Clin Oncol 2007, 25:18S. [Abstract 4594].
94. Ramanathan R.K., Belani C.P., Singh D.A., Tanaka M., Lenz H.J., Yen Y., et al. A phase II study of lapatinib in patients with advanced biliary tree and hepatocellular cancer. Cancer Chemother Pharmacol 2009, 64:777-783.
95. Burris H.A., Hurwitz H.I., Dees E.C., Dowlati A., Blackwell K.L., O'Neil B., et al. Phase I safety, pharmacokinetics, and clinical activity study of lapatinib (GW572016), a reversible dual inhibitor of epidermal growth factor receptor tyrosine kinases, in heavily pretreated patients with metastatic carcinomas. J Clin Oncol 2005, 23:5305-5313.
96. O'Dwyer P.J., Giantonio B.J., Levy D.E., Kauh J.S., Fitzgerald D.B., Benson A.B. Gefitinib in advanced unresectable hepatocellular carcinoma: results from the Eastern Cooperative Oncology Group's Study E1203 Gefitinib in advanced unresectable hepatocellular carcinoma: results from the Eastern Cooperative Oncology Group's Study E1203. J Clin Oncol 2007, 24:18S. [Abstract 4143].
97. Philip P.A., Mahoney M.R., Allmer C., Thomas J., Pitot H.C., Kim G., et al. Phase II study of Erlotinib (OSI-774) in patients with advanced hepatocellular cancer. J Clin Oncol 2005, 23:6657-6663.
98. Breuhahn K., Longerich T., Schirmacher P. Dysregulation of growth factor signaling in human hepatocellular carcinoma. Oncogene 2006, 25:3787-3800.
99. Huynh H., Chow P.K., Ooi L.L., Soo K.C. A possible role for insulin-like growth factor-binding protein-3 autocrine/paracrine loops in controlling hepatocellular carcinoma cell proliferation. Cell Growth Differ 2002, 13:115-122.
100. Tsai T.F., Yauk Y.K., Chou C.K., Ting L.P., Chang C., Hu C.P., et al. Evidence of autocrine regulation in human hepatoma cell lines. Biochem Biophys Res Commun 1988, 153:39-45.
101. Alexia C., Fallot G., Lasfer M., Schweizer-Groyer G., Groyer A. An evaluation of the role of insulin-like growth factors (IGF) and of type-I IGF receptor signalling in hepatocarcinogenesis and in the resistance of hepatocarcinoma cells against drug-induced apoptosis. Biochem Pharmacol 2004, 68:1003-1015.
102. Scharf J.G., Schmidt-Sandte W., Pahernik S.A., Ramadori G., Braulke T., Hartmann H. Characterization of the insulin-like growth factor axis in a human hepatoma cell line (PLC). Carcinogenesis 1998, 19:2121-2128.
103. Yu H., Rohan T. Role of the insulin-like growth factor family in cancer development and progression. J Natl Cancer Inst 2000, 92:1472-1489.
104. Rowinsky E.K., Youssoufian H., Tonra J.R., Solomon P., Burtrum D., Ludwig D.L. IMC-A12, a human IgG1 monoclonal antibody to the insulin-like growth factor I receptor. Clin Cancer Res 2007, 13:5549s-5555s.
105. Higano C.S., Yu E.Y., Whiting S.H., Gordon M.S., LoRusso P., Fox F., et al. A phase I, first in man study of weekly IMC-A12, a fully human insulin like growth factor-I receptor IgG1 monoclonal antibody, in patients with advanced solid tumors. J Clin Oncol 2007, 25:18S. [Abstract 3505].
106. Manara M.C., Landuzzi L., Nanni P., Nicoletti G., Zambelli D., Lollini P.L., et al. Preclinical in vivo study of new insulin-like growth factor-I receptor--specific inhibitor in Ewing's sarcoma. Clin Cancer Res 2007, 13:1322-1330.
107. Hofmann F., Brueggen J., Capraro H.G., Cozens R., Evans D.B., Fabbro D., et al. In vitro and in vivo profiling of selective and potent IGF-IR kinase inhibitors. Proc AACR 2003, 44:37985.
108. Burtrum D., Zhu Z., Lu D., Anderson D.M., Prewett M., Pereira D.S., et al. A fully human monoclonal antibody to the insulin-like growth factor I receptor blocks ligand-dependent signaling and inhibits human tumor growth in vivo. Cancer Res 2003, 63:8912-8921.
109. Higano C.S., Alumkal J.J., Ryan C.J., Yu E.Y., Beer T.M., Fox F.E., et al. A phase II study of cixutumumab (IMC-A12), a monoclonal antibody (MAb) against the insulin-like growth factor 1 receptor (IGF-IR), monotherapy in metastatic castration-resistant prostate cancer (mCRPC): feasibility of every 3-week dosing and updated result. J Clin Oncol 2010, [Abstract 189].
110. Carboni J.M., Wittman M., Yang Z., Lee F., Greer A., Hurlburt W., et al. BMS-754807, a small molecule inhibitor of insulin-like growth factor-1R/IR. Mol Cancer Ther 2009, 12(8):3341-3349.
111. Desbois-Mouthon C., Cacheux W., Blivet-Van Eggelpoel M.J., Barbu V., Fartoux L., Poupon R., et al. Impact of IGF-1R/EGFR cross-talks on hepatoma cell sensitivity to gefitinib. Int J Cancer 2006, 119:2557-2566.
112. Hopfner M., Huether A., Sutter A.P., Baradari V., Schuppan D., Scherubl H. Blockade of IGF-1 receptor tyrosine kinase has antineoplastic effects in hepatocellular carcinoma cells. Biochem Pharmacol 2006, 71:1435-1448.
113. Huether A., Hopfner M., Sutter A.P., Schuppan D., Scherubl H. Erlotinib induces cell cycle arrest and apoptosis in hepatocellular cancer cells and enhances chemosensitivity towards cytostatics. J Hepatol 2005, 43:661-669.
114. Kaposi-Novak P., Lee J.S., Gomez-Quiroz L., Coulouarn C., Factor V.M., Thorgeirsson S.S. Met-regulated expression signature defines a subset of human hepatocellular carcinomas with poor prognosis and aggressive phenotype. J Clin Invest 2006, 116:1582-1595.
115. Osada S., Kanematsu M., Imai H., Goshima S. Clinical significance of serum HGF and c-Met expression in tumor tissue for evaluation of properties and treatment of hepatocellular carcinoma. Hepatogastroenterology 2008, 55:544-549.
116. Park W.S., Dong S.M., Kim S.Y., Na E.Y., Shin M.S., Pi J.H., et al. Somatic mutations in the kinase domain of the Met/hepatocyte growth factor receptor gene in childhood hepatocellular carcinomas. Cancer Res 1999, 59:307-310.
117. Lee J.H., Han S.U., Cho H., Jennings B., Gerrard B., Dean M., et al. A novel germ line juxtamembrane Met mutation in human gastric cancer. Oncogene 2000, 19:4947-4953.
118. Pena C., Shan M., Wilhelm S., Lathia C. Hepatocyte growth factor (HGF) is a prognostic biomarker for overall survival and a pharmacodynamic biomarker for sorafenib response in the SHARP phase III HCC trial. Proceedings of the ESMO Congress 2008.
119. Comoglio P.M., Giordano S., Trusolino L. Drug development of MET inhibitors: targeting oncogene addiction and expedience. Nat Rev Drug Discov 2008, 7:504-516.
120. Qian F., Engst S., Yamaguchi K., Yu P., Won K.A., Mock L., et al. Inhibition of tumor cell growth, invasion, and metastasis by EXEL-2880 (XL880, GSK1363089), a novel inhibitor of HGF and VEGF receptor tyrosine kinases. Cancer Res 2009, 69(20):8009-8016.
121. LoRusso P., Eder J.P., Sherman L., McCallum S., Liu Y., Bottaro D., et al. Final results of a phase I dose escalation study of the safety and pharmacokinetics of foretinib administered orally daily to patients with solid tumors. Mol Cancer Ther 2009, [Abstract A8].
122. Hynes N.E., Lane H.A. ERBB receptors and cancer: the complexity of targeted inhibitors. Nat Rev Cancer 2005, 5:341-354.
123. Giambartolomei S., Covone F., Levrero M., Balsano C. Sustained activation of the Raf/MEK/Erk pathway in response to EGF in stable cell lines expressing the Hepatitis C Virus (HCV) core protein. Oncogene 2001, 20:2606-2610.
124. Hwang Y.H., Choi J.Y., Kim S., Chung E.S., Kim T., Koh S.S., et al. Over-expression of c-raf-1 proto-oncogene in liver cirrhosis and hepatocellular carcinoma. Hepatol Res 2004, 29:113-121.
125. Lee H.C., Tian B., Sedivy J.M., Wands J.R., Kim M. Loss of Raf kinase inhibitor protein promotes cell proliferation and migration of human hepatoma cells. Gastroenterology 2006, 131:1208-1217.
126. Villanueva A., Newell P., Chiang D.Y., Friedman S.L., Llovet J.M. Genomics and signaling pathways in hepatocellular carcinoma. Semin Liver Dis 2007, 27:55-76.
127. Mckillop I.H., Schmidt C.M., Cahill P.A., Sitzmann J.V. Altered expression of mitogen-activated protein kinases in a rat model of experimental hepatocellular carcinoma. Hepatology 1997, 26:1484-1491.
128. Schmidt C.M., McKillop I.H., Cahill P.A., Sitzmann J.V. Increased MAPK expression and activity in primary human hepatocellular carcinoma. Biochem Biophys Res Commun 1997, 236:54-58.
129. Wentz S.C., Wu H., Yip-Schneider M.T., Hennig M., Klein P.J., Sebolt-Leopold J., et al. Targeting MEK is effective chemoprevention of hepatocellular carcinoma in TGF-alpha-transgenic mice. J Gastrointest Surg 2008, 12:30-37.
130. Huynh H., Soo K.C., Chow P.K., Tran E. Targeted inhibition of the extracellular signal-regulated kinase kinase pathway with AZD6244 (ARRY-142886) in the treatment of hepatocellular carcinoma. Mol Cancer Ther 2007, 6:138-146.
131. Huynh H. AZD6244 (ARRY-142886) enhances the antitumor activity of rapamycin in mouse models of human hepatocellular carcinoma. Cancer 2010, 116(5):1315-1325.
132. Vivanco I., Sawyers C.L. The phosphatidylinositol 3-kinase AKT pathway in human cancer. Nat Rev Cancer 2002, 2:489-501.
133. Schmitz K.J., Wohlschlaeger J., Lang H., Sotiropoulos G.C., Malago M., Steveling K., et al. Activation of the ERK and AKT signalling pathway predicts poor prognosis in hepatocellular carcinoma and ERK activation in cancer tissue is associated with hepatitis C virus infection. J Hepatol 2008, 48:83-90.
134. Boyault S., Rickman D.S., de Reynies A., Balabaud C., Rebouissou S., Jeannot E., et al. Transcriptome classification of HCC is related to gene alterations and to new therapeutic targets. Hepatology 2007, 45:42-52.
135. Sahin F., Kannangai R., Adegbola O., Wang J., Su G., Torbenson M. mTOR and P70 S6 kinase expression in primary liver neoplasms. Clin Cancer Res 2004, 10:8421-8425.
136. Horie Y., Suzuki A., Kataoka E., Sasaki T., Hamada K., Sasaki J., et al. Hepatocyte-specific Pten deficiency results in steatohepatitis and hepatocellular carcinomas. J Clin Invest 2004, 113:1774-1783.
137. Amaravadi R., Thompson C.B. The survival kinases Akt and Pim as potential pharmacological targets. J Clin Invest 2005, 115:2618-2624.
138. Lee T.K., Man K., Ho J.W., Sun C.K., Ng K.T., Wang X.H., et al. FTY720 induces apoptosis of human hepatoma cell lines through PI3-K-mediated Akt dephosphorylation. Carcinogenesis 2004, 25:2397-2405.
139. Semela D., Piguet A.C., Kolev M., Schmitter K., Hlushchuk R., Djonov V., et al. Vascular remodelling and antitumoral effects of mTOR inhibition in a rat model of hepatocellular carcinoma. J Hepatol 2007, 46:840-848.
140. Huynh H., Chow P., Soo K.C., Toh H.C., Choo S.P., Foo K.F., et al. RAD001 (Everolimus) inhibits tumor growth in xenograft models of human hepatocellular carcinoma. J Cell Mol Med 2009, 13(7):1371-1380.
141. Dudkin L., Dilling M.B., Cheshire P.J., Harwood F.C., Hollingshead M., Arbuck S.G., et al. Biochemical correlates of mTOR inhibition by the rapamycin ester CCI-779 and tumor growth inhibition. Clin Cancer Res 2001, 7:1758-1764.
142. Wullschleger S., Loewith R., Hall M.N. TOR signaling in growth and metabolism. Cell 2006, 124:471-484.
143. Rizell M., Andersson M., Cahlin C., Hafstrom L., Olausson M., Lindner P. Effects of the mTOR inhibitor sirolimus in patients with hepatocellular and cholangiocellular cancer. Int J Clin Oncol 2008, 13:66-70.
144. Rizell M., Lindner P. Inhibition of mTOR suppresses experimental liver tumors. Anticancer Res 2005, 25:789-793.
145. Fouladi M., Laningham F., Wu J., O'Shaughnessy M.A., Molina K., Broniscer A., et al. Phase I study of everolimus in pediatric patients with refractory solid tumors. J Clin Oncol 2007, 25:4806-4812.
146. Sieghart W., Fuereder T., Schmid K., Cejka D., Werzowa J., Wrba F., et al. Mammalian target of rapamycin pathway activity in hepatocellular carcinomas of patients undergoing liver transplantation. Transplantation 2007, 83:425-432.
147. Ribatti D., Nico B., Mangieri D., Longo V., Sansonno D., Vacca A., et al. In vivo inhibition of human hepatocellular carcinoma related angiogenesis by vinblastine and rapamycin. Histol Histopathol 2007, 22:285-289.
148. Bromberg J.F. Activation of STAT proteins and growth control. Bioessays 2001, 23:161-169.
149. Kisseleva T., Bhattacharya S., Braunstein J., Schindler C.W. Signaling through the JAK/STAT pathway, recent advances and future challenges. Gene 2002, 285:1-24.
150. Yun C., Cho H., Kim S.J., Lee J.H., Park S.Y., Chan G.K., et al. Mitotic aberration coupled with centrosome amplification is induced by hepatitis B virus X oncoprotein via the Ras-mitogen-activated protein/extracellular signal-regulated kinase-mitogen-activated protein pathway. Mol Cancer Res 2004, 2:159-169.
151. Yoshida T., Hanada T., Tokuhisa T., Kosai K., Sata M., Kohara M., et al. Activation of STAT3 by the hepatitis C virus core protein leads to cellular transformation. J Exp Med 2002, 196:641-653.
152. Hayashi J., Aoki H., Kajino K., Moriyama M., Arakawa Y., Hino O. Hepatitis C virus core protein activates the MAPK/ERK cascade synergistically with tumor promoter TPA, but not with epidermal growth factor or transforming growth factor alpha. Hepatology 2000, 32:958-961.
153. Calvisi D.F., Ladu S., Gorden A., Farina M., Conner E.A., Lee J.S., et al. Ubiquitous activation of Ras and Jak/Stat pathways in human HCC. Gastroenterology 2006, 130:1117-1128.
154. Isaacs J.S., Xu W., Neckers L. Heat shock protein 90 as a molecular target for cancer therapeutics. Cancer Cell 2003, 3:213-217.
155. Zhang H., Burrows F. Targeting multiple signal transduction pathways through inhibition of Hsp90. J Mol Med 2004, 82:488-499.
156. Pascale R.M., Simile M.M., Calvisi D.F., Frau M., Muroni M.R., Seddaiu M.A., et al. Role of HSP90, CDC37, and CRM1 as modulators of P16(INK4A) activity in rat liver carcinogenesis and human liver cancer. Hepatology 2005, 42:1310-1319.
157. Lang S.A., Moser C., Fichnter-Feigl S., Schachtschneider P., Hellerbrand C., Schmitz V., et al. Targeting heat-shock protein 90 improves efficacy of rapamycin in a model of hepatocellular carcinoma in mice. Hepatology 2009, 49:523-532.
158. Nowakowski G.S., McCollum A.K., Ames M.M., Mandrekar S.J., Reid J.M., Adjei A.A., et al. A phase I trial of twice-weekly 17-allylamino-demethoxy-geldanamycin in patients with advanced cancer. Clin Cancer Res 2006, 12:6087-6093.
159. Sydor J.R., Normant E., Pien C.S., Porter J.R., Ge J., Grenier L., et al. Development of 17-allylamino-17-demethoxygeldanamycin hydroquinone hydrochloride (IPI-504), an anti-cancer agent directed against Hsp90. Proc Natl Acad Sci USA 2006, 103:17408-17413.
160. Breinig M., Caldas-Lopes E., Goeppert B., Malz M., Rieker R., Bergmann F., et al. Targeting heat shock protein 90 with non-quinone inhibitors: a novel chemotherapeutic approach in human hepatocellular carcinoma. Hepatology 2009, 50:102-112.
161. Kefford R., Millward M., Hersey P., Brady B., Graham M., Johnson R.G., et al. Phase II trial of tanespimycin (KOS-953), a heat shock protein-90 (Hsp90) inhibitor in patients with metastatic melanoma. J Clin Oncol 2007, 25:18S. [Abstract 8558].
162. Ciardiello F., Troiani T., Bianco R., Orditura M., Morgillo F., Martinelli E., et al. Interaction between the epidermal growth factor receptor (EGFR) and the vascular endothelial growth factor (VEGF) pathways: a rational approach for multi-target anticancer therapy. Ann Oncol 2006, 17(Suppl. 7):vii109-vii114.
163. Tortora G., Caputo R., Damiano V., Melisi D., Bianco R., Fontanini G., et al. Combination of a selective cyclooxygenase-2 inhibitor with epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 and protein kinase A antisense causes cooperative antitumor and antiangiogenic effect. Clin Cancer Res 2003, 9:1566-1572.
164. Ganslmayer M., Ocker M., Kraemer G., Zopf S., Hahn E.G., Schuppan D., et al. The combination of tamoxifen and 9cis retinoic acid exerts overadditive anti-tumoral efficacy in rat hepatocellular carcinoma. J Hepatol 2004, 40:952-956.
165. Ganslmayer M., Ocker M., Zopf S., Leitner S., Hahn E.G., Schuppan D., et al. A quadruple therapy synergistically blocks proliferation and promotes apoptosis of hepatoma cells. Oncol Rep 2004, 11:943-950.
166. Herold C., Ganslmayer M., Ocker M., Blauberger S., Zopf S., Hahn E.G., et al. Overadditive anti-proliferative and pro-apoptotic effects of a combination therapy on colorectal carcinoma cells. Int J Oncol 2003, 23:751-756.