Treatment of gastrointestinal neuroendocrine tumors with inhibitors of growth factor receptors and their signaling pathways: Recent advances and future perspectives

World Journal of Gastroenterology

Volumn 14, Issue 16, 2008, Pages 2461-2473

  Höpfner, Michael ^a   Schuppan, Detlef ^b   Scherübl, Hans ^c  

^a CHARITÉ UNIVERSITÄTSMEDIZIN BERLIN   (Germany)

^b HARVARD MEDICAL SCHOOL   (United States)

^c Klinikum Am Urban   (Germany)

Author keywords

Growth factor receptor; Monoclonal antibody; Multi kinase inhibition; Neuroendocrine gastrointestinal tumor; Small molecule inhibitor

Indexed keywords

2 METHOXYESTRADIOL; ANGIOGENESIS INHIBITOR; ANTINEOPLASTIC AGENT; BEVACIZUMAB; BORTEZOMIB; CAPECITABINE; CETUXIMAB; CYTOTOXIC AGENT; EVEROLIMUS; FLUOROURACIL; FOLINIC ACID; GEFITINIB; GROWTH FACTOR RECEPTOR; HISTONE DEACETYLASE INHIBITOR; IMATINIB; MAMMALIAN TARGET OF RAPAMYCIN INHIBITOR; N (3,3 DIMETHYL 6 INDOLINYL) 2 (4 PYRIDINYLMETHYLAMINO)NICOTINAMIDE; NVP AEW 541; OXALIPLATIN; PAZOPANIB; PEGINTERFERON ALPHA2B; PLACEBO; PROTEASOME INHIBITOR; SORAFENIB; SUNITINIB; TEMOZOLOMIDE; TEMSIROLIMUS; THALIDOMIDE; UNINDEXED DRUG; VATALANIB;

ADVANCED CANCER; ANTIANGIOGENIC ACTIVITY; BLEEDING TENDENCY; CANCER IMMUNOTHERAPY; CLINICAL TRIAL; COMBINATION CHEMOTHERAPY; DRUG EFFICACY; DRUG TARGETING; EDITORIAL; GASTROINTESTINAL SYMPTOM; GASTROINTESTINAL TUMOR; HUMAN; MONOTHERAPY; NEUROENDOCRINE TUMOR; NEUROTOXICITY; NONHUMAN; PROTEIN EXPRESSION; SENSORY NEUROPATHY; SIGNAL TRANSDUCTION; TUMOR VASCULARIZATION;

EID: 47849130260     PISSN: 10079327     EISSN: None     Source Type: Journal    
DOI: 10.3748/wjg.14.2461     Document Type: Editorial

References (154)

1. Kulke MH. Gastrointestinal neuroendocrine tumors: a role for targeted therapies? Endocr Relat Cancer 2007; 14: 207-219
2. Scherubl H, Faiss S, Zeitz M. Neuroendocrine tumors of the gastrointestinal tract - diagnosis and therapy] Dtsch Med Wochenschr 2003; 128 Suppl 2: S81-S83
3. Oberg K. Chemotherapy and biotherapy in the treatment of neuroendocrine tumours. Ann Oncol 2001; 12 Suppl 2: S111-S114
4. Wimmel A, Wiedenmann B, Rosewicz S. Autocrine growth inhibition by transforming growth factor beta-1 (TGFbeta-1) in human neuroendocrine tumour cells. Gut 2003; 52: 1308-1316
5. von Marschall Z, Scholz A, Cramer T, Schafer G, Schirner M, Oberg K, Wiedenmann B, Hocker M, Rosewicz S. Effects of interferon alpha on vascular endothelial growth factor gene transcription and tumor angiogenesis. J Natl Cancer Inst 2003; 95: 437-448
6. Chaudhry A, Papanicolaou V, Oberg K, Heldin CH, Funa K. Expression of platelet-derived growth factor and its receptors in neuroendocrine tumors of the digestive system. Cancer Res 1992; 52: 1006-1012
7. Wulbrand U, Remmert G, Zofel P, Wied M, Arnold R, Fehmann HC. mRNA expression patterns of insulin-like growth factor system components in human neuroendocrine tumours. Eur J Clin Invest 2000; 30: 729-739
8. von Wichert G, Jehle PM, Hoeflich A, Koschnick S, Dralle H, Wolf E, Wiedenmann B, Boehm BO, Adler G, Seufferlein T. Insulin-like growth factor-I is an autocrine regulator of chromogranin A secretion and growth in human neuroendocrine tumor cells. Cancer Res 2000; 60: 4573-4581
9. Nilsson O, Wangberg B, Theodorsson E, Skottner A, Ahlman H. Presence of IGF-I in human midgut carcinoid tumours - an autocrine regulator of carcinoid tumour growth? Int J Cancer 1992; 51: 195-203
10. Zhang H, Yee D. The therapeutic potential of agents targeting the type I insulin-like growth factor receptor. Expert Opin Investig Drugs 2004; 13: 1569-1577
11. Jain RK, Duda DG, Clark JW, Loeffler JS. Lessons from phase III clinical trials on anti-VEGF therapy for cancer. Nat Clin Pract Oncol 2006; 3: 24-40
12. Morabito A, De Maio E, Di Maio M, Normanno N, Perrone F. Tyrosine kinase inhibitors of vascular endothelial growth factor receptors in clinical trials: current status and future directions. Oncologist 2006; 11: 753-764
13. Hopfner M, Sutter AP, Gerst B, Zeitz M, Scherubl H. A novel approach in the treatment of neuroendocrine gastrointestinal tumours. Targeting the epidermal growth factor receptor by gefitinib (ZD1839). Br J Cancer 2003; 89: 1766-1775
14. Hopfner M, Baradari V, Huether A, Schofl C, Scherubl H. The insulin-like growth factor receptor 1 is a promising target for novel treatment approaches in neuroendocrine gastrointestinal tumours. Endocr Relat Cancer 2006; 13: 135-149
15. Bjornsti MA, Houghton PJ. The TOR pathway: a target for cancer therapy. Nat Rev Cancer 2004; 4: 335-348
16. Wilhelm SM, Carter C, Tang L, Wilkie D, McNabola A, Rong H, Chen C, Zhang X, Vincent P, McHugh M, Cao Y, Shujath J, Gawlak S, Eveleigh D, Rowley B, Liu L, Adnane L, Lynch M, Auclair D, Taylor I, Gedrich R, Voznesensky A, Riedl B, Post LE, Bollag G, Trail PA. 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
17. Ciardiello F, Troiani T, Bianco R, Orditura M, Morgillo F, Martinelli E, Morelli MP, Cascone T, Tortora G. 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
18. Maione P, Gridelli C, Troiani T, Ciardiello F. Combining targeted therapies and drugs with multiple targets in the treatment of NSCLC. Oncologist 2006; 11: 274-284
19. Burgaud JL, Baserga R. Intracellular transactivation of the insulin-like growth factor I receptor by an epidermal growth factor receptor. Exp Cell Res 1996; 223: 412-419
20. Gilmore AP, Valentijn AJ, Wang P, Ranger AM, Bundred N, O'Hare MJ, Wakeling A, Korsmeyer SJ, Streuli CH. Activation of BAD by therapeutic inhibition of epidermal growth factor receptor and transactivation by insulin-like growth factor receptor. J Biol Chem 2002; 277: 27643-27650
21. Carmeliet P. Angiogenesis in health and disease. Nat Med 2003; 9: 653-660
22. Folkman J. Role of angiogenesis in tumor growth and metastasis. Semin Oncol 2002; 29: 15-18
23. Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med 1971; 285: 1182-1186
24. Shibuya M. Vascular endothelial growth factor receptor-1 (VEGFR-1/ Flt-1): a dual regulator for angiogenesis. Angiogenesis 2006; 9: 225-230; discussion 231
25. Terris B, Scoazec JY, Rubbia L, Bregeaud L, Pepper MS, Ruszniewski P, Belghiti J, Flejou J, Degott C. Expression of vascular endothelial growth factor in digestive neuroendocrine tumours. Histopathology 1998; 32: 133-138
26. La Rosa S, Uccella S, Finzi G, Albarello L, Sessa F, Capella C. Localization of vascular endothelial growth factor and its receptors in digestive endocrine tumors: correlation with microvessel density and clinicopathologic features. Hum Pathol 2003; 34: 18-27
27. Christofori G, Naik P, Hanahan D. Vascular endothelial growth factor and its receptors, flt-1 and flk-1, are expressed in normal pancreatic islets and throughout islet cell tumorigenesis. Mol Endocrinol 1995; 9: 1760-1770
28. Wiedenmann B, Pape UF. From basic to clinical research in gastroenteropancreatic neuroendocrine tumor disease - the clinician-scientist perspective. Neuroendocrinology 2004; 80 Suppl 1: 94-98
29. Pavel ME, Hassler G, Baum U, Hahn EG, Lohmann T, Schuppan D. Circulating levels of angiogenic cytokines can predict tumour progression and prognosis in neuroendocrine carcinomas. Clin Endocrinol (Oxf) 2005; 62: 434-443
30. Zhang J, Jia Z, Li Q, Wang L, Rashid A, Zhu Z, Evans DB, Vauthey JN, Xie K, Yao JC. Elevated expression of vascular endothelial growth factor correlates with increased angiogenesis and decreased progression-free survival among patients with low-grade neuroendocrine tumors. Cancer 2007; 109: 1478-1486
31. Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, Berlin J, Baron A, Griffing S, Holmgren E, Ferrara N, Fyfe G, Rogers B, Ross R, Kabbinavar F. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004; 350: 2335-2342
32. Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, Lilenbaum R, Johnson DH. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 2006; 355: 2542-2550
33. Yao JC, Ng C, Hoff P, Phan T, Hess K. Improved progression free survival (PFS) and rapid sustained decreased perfusion among patients with advanced carcinoid treated with bevacizumab. J Clin Oncol 2005; 23: 4007. Available from URL: http://meeting.ascopubs.org/ cgi/content/abstract/23/16_suppl/4007
34. Schumacher G, Hoffmann J, Cramer T, Spinelli A, Jacob D, Bahra M, Pratschke J, Pfitzmann R, Schmidt S, Lage H. Antineoplastic activity of 2-methoxyestradiol in human pancreatic and gastric cancer cells with different multidrug-resistant phenotypes. J Gastroenterol Hepatol 2007; 22: 1469-1473
35. Cicek M, Iwaniec UT, Goblirsch MJ, Vrabel A, Ruan M, Clohisy DR, Turner RR, Oursler MJ. 2-Methoxyestradiol suppresses osteolytic breast cancer tumor progression in vivo. Cancer Res 2007; 67: 10106-10111
36. Dahut WL, Lakhani NJ, Culley JL, Arlen PM, Kohn EC, Kotz H, McNally D, Parr A, Nguyen D, Yang SX, Steinberg SM, Venitz J, Sparreboom A, Figg WD. Phase I clinical trial of oral 2-methoxyestradiol, an antiangiogenic and apoptotic agent, in patients with solid tumors. Cancer Biol Ther 2006; 5: 22-27
37. Basu A, Castle VP, Bouziane M, Bhalla K, Haldar S. Crosstalk between extrinsic and intrinsic cell death pathways in pancreatic cancer: synergistic action of estrogen metabolite and ligands of death receptor family. Cancer Res 2006; 66: 4309-4318
38. Kulke MH, Stuart K, Enzinger PC, Ryan DP, Clark JW, Muzikansky A, Vincitore M, Michelini A, Fuchs CS. Phase II study of temozolomide and thalidomide in patients with metastatic neuroendocrine tumors. J Clin Oncol 2006; 24: 401-406
39. Boting J. The history of thalidomide. Drug News Perspect 2002; 15: 604-611. Available from: URL:http://journals.prous.com/ journals/servlet/xmlxsl/pk_journals.xml_toc_pr?p_JournalID= 3&p_IssueID=49
40. Fischer C, Jonckx B, Mazzone M, Zacchigna S, Loges S, Pattarini L, Chorianopoulos E, Liesenborghs L, Koch M, De Mol M, Autiero M, Wyns S, Plaisance S, Moons L, van Rooijen N, Giacca M, Stassen JM, Dewerchin M, Collen D, Carmeliet P. Anti-PIGF inhibits growth of VEGF(R)-inhibitor-resistant tumors without affecting healthy vessels. Cell 2007; 131: 463-475
41. Motzer RJ, Michaelson MD, Redman BC, Hudes CR, Wilding G, Figlin RA, Ginsberg MS, Kim ST. Baum CM, DePrimo SE, Li JZ, Bello CL, Theuer CP, George DJ, Rini BI. 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
42. Rosen LS, Kurzrock R, Mulay M, Van Vugt A, Purdom M, Ng C, Silverman J, Koutsoukos A, Sun YN, Bass MB, Xu RY, Polverino A, Wiezorek JS, Chang DD, Benjamin R, Herbst RS. Safety, pharmacokinetics, and efficacy of AMG 706, an oral multikinase inhibitor, in patients with advanced solid tumors. J Clin Oncol 2007; 25: 2369-2376
43. Willett CG, Boucher Y, Duda DG, di Tomaso E, Munn LL, Tong RT, Kozin SV, Petit L, Jain RK, Chung DC, Sahani DV, Kalva SP, Cohen KS, Scadden DT, Fischman AJ, Clark JW, Ryan DP, Zhu AX, Blaszkowsky LS, Shellito PC, Mino-Kenudson M, Lauwers GY. 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
44. Cabebe E, Wakelee H. Role of anti-angiogenesis agents in treating NSCLC: focus on bevacizumab and VEGFR tyrosine kinase inhibitors. Curr Treat Options Oncol 2007; 8: 15-27
45. Motzer RJ, Bukowski RM. Targeted therapy for metastatic renal cell carcinoma. J Clin Oncol 2006; 24: 5601-5608
46. Goodman VL, Rock EP, Dagher R, Ramchandani RP, Abraham S, Gobburu JV, Booth BP, Verbois SL, Morse DE, Liang CY, Chidambaram N, Jiang JX, Tang S, Mahjoob K, Justice R, Pazdur R. Approval summary: sunitinib for the treatment of imatinib refractory or intolerant gastrointestinal stromal tumors and advanced renal cell carcinoma. Clin Cancer Res 2007; 13: 1367-1373
47. Kulke M, Bergsland E, Ryan D. A Phase II study to evaluate the safety and efficacy of SU11248 in patients with unresectable neuroendocrine tumors. Proc Am Soc Clin Oncol 2003; 22: 958
48. Kulke M, Lenz Hj, Meropol NJ, Posey J, Ryan DP, Picus J, Bergsland E, Stuart K, Baum CM, Fuchs CS. A phase two study to evaluate the efficacy and safety of SU11248 in patients (pts) with unresectable neuroendocrine tumors (NET). J Clin Oncol 2005; 23: 4008. Available from: URL: http://meeting.ascopubs.org/cgi/content/abstract/23/ 16_suppl/4008
49. Polverino A, Coxon A, Starnes C, Diaz Z, DeMelfi T, Wang L, Bready J, Estrada J, Cattley R, Kaufman S, Chen D, Gan Y, Kumar G, Meyer J, Neervannan S, Alva G, Talvenheimo J, Montestruque S, Tasker A, Patel V, Radinsky R, Kendall R. AMG 706, an oral, multikinase inhibitor that selectively targets vascular endothelial growth factor, platelet-derived growth factor, and kit receptors, potently inhibits angiogenesis and induces regression in tumor xenografts. Cancer Res 2006; 66: 8715-8721
50. von Mehren M. Beyond imatinib: second generation c-KIT inhibitors for the management of gastrointestinal stromal tumors. Clin Colorectal Cancer 2006; 6 Suppl 1: S30-S34
51. Kumar R, Knick VB, Rudolph SK, Johnson JH, Crosby RM, Crouthamel MC, Hopper TM, Miller CG, Harrington LE, Onori JA, Mullin RJ, Gilmer TM, Truesdale AT, Epperly AH, Boloor A, Stafford JA, Luttrell DK, Cheung M. Pharmacokinetic-pharmacodynamic correlation from mouse to human with pazopanib, a multikinase angiogenesis inhibitor with potent antitumor and antiangiogenic activity. Mol Cancer Ther 2007; 6: 2012-2021
52. Suttle AB, Hurwitz H, Dowlati A, Fernando N, Savage S, Coviello K, Dar M, Ertel P, Whitehead B, Pandite L. Pharmacokinetics (PK) and tolerability of GW786034, a VEGFR tyrosine kinase inhibitor, after daily oral administration to patients with solid tumors. J Clin Oncol 2004; 22: 3054. Available from: URL: http://meeting.ascopubs.org/ cgi/content/abstract/22/14_suppl/3054
53. Shah NP. Medical Management of CML. Hematology Am Soc Hematol Educ Program 2007; 2007: 371-375
54. Rubin BP, Heinrich MC, Corless CL. Gastrointestinal stromal tumour. Lancet 2007; 369: 1731-1741
55. Abrams TA, Schuetze SM. Targeted therapy for dermatofibrosarcoma protuberans. Curr Oncol Rep 2006; 8: 291-296
56. Welin S, Fjallskog ML, Saras J, Eriksson B, Janson ET. Expression of tyrosine kinase receptors in malignant midgut carcinoid tumors. Neuroendocrinology 2006; 84: 42-88
57. Chaudhry A, Funa K, Oberg K. Expression of growth factor peptides and their receptors in neuroendocrine tumors of the digestive system. Acta Oncol 1993; 32: 107-114
58. Yao JC, Zhang JX, Rashid A, Yeung SC, Szklaruk J, Hess K, Xie K, Ellis L, Abbruzzese JL, Ajani JA. Clinical and in vitro studies of imatinib in advanced carcinoid tumors. Clin Cancer Res 2007; 13: 234-240
59. Gross DJ, Munter G, Bitan M, Siegal T, Gabizon A, Weitzen R, Merimsky O, Ackerstein A, Salmon A, Sella A, Slavin S. The role of imatinib mesylate (Glivec) for treatment of patients with malignant endocrine tumors positive for c-kit or PDGF-R. Endocr Relat Cancer 2006; 13: 535-540
60. McAuliffe JC, Lazar AJ, Yang D, Steinert DM, Qiao W, Thall PF, Raymond AK, Benjamin RS, Trent JC. Association of intratumoral vascular endothelial growth factor expression and clinical outcome for patients with gastrointestinal stromal tumors treated with imatinib mesylate. Clin Cancer Res 2007; 13: 6727-6734
61. Wood JM, Bold G, Buchdunger E, Cozens R, Ferrari S, Frei J, Hofmann F, Mestan J, Mett H, O'Reilly T, Persohn E, Rosel J, Schnell C, Stover D, Theuer A, Towbin H, Wenger F, Woods-Cook K, Menrad A, Siemeister G, Schirner M, Thierauch KH, Schneider MR, Drevs J, Martiny-Baron G, Totzke F. PTK787/ZK 222584, a novel and potent inhibitor of vascular endothelial growth factor receptor tyrosine kinases, impairs vascular endothelial growth factor-induced responses and tumor growth after oral administration. Cancer Res 2000; 60: 2178-2189
62. Liu Y, Poon RT, Li Q, Kok TW, Lau C, Fan ST. Both antiangiogenesis- and angiogenesis-independent effects are responsible for hepatocellular carcinoma growth arrest by tyrosine kinase inhibitor PTK787/ZK222584. Cancer Res 2005; 65: 3691-3699
63. Steeghs N, Nortier JW, Gelderblom H. Small molecule tyrosine kinase inhibitors in the treatment of solid tumors: an update of recent developments. Ann Surg Oncol 2007; 14: 942-953
64. Anthony LB, McCall J, Nunez J, O'Dorisio T, O'Dorisio S. An open-label phase II clinical trial of PTK787 in patients with progressive neuroendocrine cancer. J Clin Oncol 2007. 25 (18S): 14127. Available from: URL: http://meeting.ascopubs.org/cgi/content/abstract/25/ 18_suppl/14127
65. Sangro B, Mazzollini G, Prieto J. Future therapies for hepatocellular carcinoma. Eur J Gastroenterol Hepatol 2005; 17: 515-521
66. Rocha-Lima CM, Soares HP, Raez LE, Singal R. EGFR targeting of solid tumors. Cancer Control 2007; 14: 295-304
67. Thatcher N, Chang A, Parikh P, Rodrigues Pereira J, Ciuleanu T, von Pawel J, Thongprasert S, Tan EH, Pemberton K, Archer V, Carroll K. Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet 2005; 366: 1527-1537
68. Wang W, Johansson HE, Bergholm UI, Westermark KM, Grimelius LE. Expression of c-Myc, TGF-alpha and EGF-receptor in sporadic medullary thyroid carcinoma. Acta Oncol 1997; 36: 407-411
69. Ezzat S. The role of hormones, growth factors and their receptors in pituitary tumorigenesis. Brain Pathol 2001; 11: 356-370
70. Peghini PL, Iwamoto M, Raffeld M, Chen YJ, Goebel SU, Serrano J, Jensen RT. Overexpression of epidermal growth factor and hepatocyte growth factor receptors in a proportion of gastrinomas correlates with aggressive growth and lower curability. Clin Cancer Res 2002; 8: 2273-2285
71. Back W, Rohr G, Bleyl U. Expression of TGF-alpha in neuroendocrine tumours of the distal colon and rectum. APMIS 2003; 111: 931-939
72. Shimizu T, Tanaka S, Haruma K, Kitadai Y, Yoshihara M, Sumii K, Kajiyama G, Shimamoto F. Growth characteristics of rectal carcinoid tumors. Oncology 2000; 59: 229-237
73. Oberg K, Expression of growth factors and their receptors in neuroendocrine gut and pancreatic tumors, and prognostic factors for survival. Ann N Y Acad Sci 1994; 733: 46-55
74. Nilsson O, Wangberg B, Kolby L, Schultz GS, Ahlman H. Expression of transforming growth factor alpha and its receptor in human neuroendocrine tumours. Int J Cancer 1995; 60: 645-651
75. Nilsson O, Wangberg B, McRae A, Dahlstrom A, Ahlman H. Growth factors and carcinoid tumours. Acta Oncol 1993; 32: 115-124
76. Wulbrand U, Wied M, Zofel P, Goke B, Arnold R, Fehmann H. Growth factor receptor expression in human gastroenteropancreatic neuroendocrine tumours. Eur J Clin Invest 1998; 28: 1038-1049
77. Papouchado B, Erickson LA, Rohlinger AL, Hobday TJ, Erlichman C, Ames MM, Lloyd RV. Epidermal growth factor receptor and activated epidermal growth factor receptor expression in gastrointestinal carcinoids and pancreatic endocrine carcinomas. Mod Pathol 2005; 18: 1329-1335
78. Shah T, Hochhauser D, Frow R, Quaglia A, Dhillon AP, Caplin ME. Epidermal growth factor receptor expression and activation in neuroendocrine tumours. J Neuroendocrinol 2006; 18: 355-360
79. Hobday TJ, Holen K, Donehower R, Camoriano J, Kim G, Picus J, Philip P, Lloyd R, Mahoney M, Erlichman C. A phase II trial of gefitinib in patients (pts) with progressive metastatic neuroendocrine tumors (NET): A Phase II Consortium (P2C) study. J Clin Oncol 2006; 24: 4043. Available from: URL: http://meeting.ascopubs.org/cgi/ content/abstract/24/18_suppl/4043
80. Sutter AP, Hopfner M, Huether A, Maaser K, Scherubl H. Targeting the epidermal growth factor receptor by erlotinib (Tarceva) for the treatment of esophageal cancer. Int J Cancer 2006; 118: 1814-1822
81. 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
82. Carter P. Improving the efficacy of antibody-based cancer therapies. Nat Rev Cancer 2001; 1: 118-129
83. Huether A, Hopfner M, Sutter AP, 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
84. Bourhis J, Rivera F, Mesia R, Awada A, Geoffrois L, Borel C, Humblet Y, Lopez-Pousa A, Hitt R, Vega Villegas ME, Duck L, Rosine D, Amellal N, Schueler A, Harstrick A. Phase I/II study of cetuximab in combination with cisplatin or carboplatin and fluorouracil in patients with recurrent or metastatic squamous cell carcinoma of the head and neck. J Clin Oncol 2006; 24: 2866-2872
85. Moore MJ, Goldstein D, Hamm J, Figer J, Hecht S, Gallinger S, Au HJ, K. Ding, J. Christy-Bittel, Parulekar W. Erlotinib plus gemcitabine compared to gemcitabine alone in patients with advanced pancreatic cancer. A phase III trial of the National Cancer Institute of Canada Clinical Trials Group [NCIC-CTG]. J Clin Oncol 2005; 23: 1. Available from: URL:http://meeting.ascopubs.org/cgi/content/abstract/23/ 16_suppl/1
86. Tortora G, Caputo R, Damiano V, Melisi D, Bianco R, Fontanini G, Veneziani BM, De Placido S, Bianco AR, Ciardiello F. 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
87. Sachdev D, Yee D. Disrupting insulin-like growth factor signaling as a potential cancer therapy. Mol Cancer Ther 2007; 6: 1-12
88. Hofmann F, Garcia-Echeverria C. Blocking the insulin-like growth factor-I receptor as a strategy for targeting cancer. Drug Discov Today 2005; 10: 1041-1047
89. Wang Y, Sun Y. Insulin-like growth factor receptor-1 as an anti-cancer target: blocking transformation and inducing apoptosis. Curr Cancer Drug Targets 2002; 2: 191-207
90. Wang Z, Ruan YB, Guan Y, Liu SH. Expression of IGF-II in early experimental hepatocellular carcinomas and its significance in early diagnosis. World J Gastroenterol 2003; 9: 267-270
91. Vitale L, Lenzi L, Huntsman SA, Canaider S, Frabetti F, Casadei R, Facchin F, Carinci P, Zannotti M, Coppola D, Strippoli P. Differential expression of alternatively spliced mRNA forms of the insulin-like growth factor 1 receptor in human neuroendocrine tumors. Oncol Rep 2006; 15: 1249-1256
92. Scharf JG, Braulke T. The role of the IGF axis in hepatocarcinogenesis. Harm Metab Res 2003; 35: 685-693
93. Yao X, Hu JF, Daniels M, Yien H, Lu H, Sharan H, Zhou X, Zeng Z, Li T, Yang Y, Hoffman AR. A novel orthotopic tumor model to study growth factors and oncogenes in hepatocarcinogenesis. Clin Cancer Res 2003; 9: 2719-2726
94. Fottner Ch, Hoeflich A, Wolf E, Weber MM. Role of the insulin-like growth factor system in adrenocortical growth control and carcinogenesis. Horm Metab Res 2004; 36: 397-405
95. von Wichert G, Haeussler U, Greten FR, Kliche S, Dralle H, Bohm BO, Adler G, Seufferlein T. Regulation of cyclin D1 expression by autocrine IGF-I in human BON neuroendocrine tumour cells. Oncogene 2005; 24: 1284-1289
96. Corleto VD, Delle Fave G, Jensen RT. Molecular insights into gastrointestinal neuroendocrine tumours: importance and recent advances. Dig Liver Dis 2002; 34: 668-680
97. Furukawa M, Raffeld M, Mateo C, Sakamoto A, Moody TW, Ito T, Venzon DJ, Serrano J, Jensen RT. Increased expression of insulin-like growth factor I and/or its receptor in gastrinomas is associated with low curability, increased growth, and development of metastases. Clin Cancer Res 2005; 11: 3233-3242
98. Scotlandi K, Benini S, Nanni P, Lollini PL, Nicoletti G, Landuzzi L, Serra M, Manara MC, Picci P, Baldini N. Blockage of insulin-like growth factor-I receptor inhibits the growth of Ewing's sarcoma in athymic mice. Cancer Res 1998; 58: 4127-4131
99. Shapiro DN, Jones BG, Shapiro LH, Dias P, Houghton PJ. Antisense-mediated reduction in insulin-like growth factor-I receptor expression suppresses the malignant phenotype of a human alveolar rhabdomyosarcoma. J Clin Invest 1994; 94: 1235-1242
100. Salisbury AJ, Macaulay VM. Development of molecular agents for IGF receptor targeting. Horm Metab Res 2003; 35: 843-849
101. Ellouk-Achard S, Djenabi S, De Oliveira GA, Desauty G, Duc HT, Zohair M, Trojan J, Claude JR, Sarasin A, Lafarge-Frayssinet C. Induction of apoptosis in rat hepatocarcinoma cells by expression of IGF-I antisense c-DNA. J Hepatol 1998; 29: 807-818
102. Tanno B, Mancini C, Vitali R, Mancuso M, McDowell HP, Dominici C, Raschella G. Down-regulation of insulin-like growth factor I receptor activity by NVP-AEW541 has an antitumor effect on neuroblastoma cells in vitro and in vivo. Clin Cancer Res 2006; 12: 6772-6780
103. Hopfner M, Sutter AP, Huether A, Baradari V, Scherubl H. Tyrosine kinase of insulin-like growth factor receptor as target for novel treatment and prevention strategies of colorectal cancer. World J Gastroenterol 2006; 12: 5635-5643
104. Hopfner M, Huether A, Sutter AP, 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
105. Warshamana-Greene GS, Litz J, Buchdunger E, Garcia-Echeverria C, Hofmann F, Krystal GW. The insulin-like growth factor-I receptor kinase inhibitor, NVP-ADW742, sensitizes small cell lung cancer cell lines to the effects of chemotherapy. Clin Cancer Res 2005; 11: 1563-1571
106. Manara MC, Landuzzi L, Nanni P, Nicoletti G, Zambelli D, Lollini PL, Nanni C, Hofmann F, Garcia-Echeverria C, Picci P, Scotlandi K. 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. Arteaga CL, Kitten LJ, Coronado EB, Jacobs S, Kull FC Jr. Allred DC, Osborne CK. Blockade of the type I somatomedin receptor inhibits growth of human breast cancer cells in athymic mice. J Clin Invest 1989; 84: 1418-1423
108. Garcia-Echeverria C, Pearson MA, Marti A, Meyer T, Mestan J, Zimmermann J, Gao J, Brueggen J, Capraro HG, Cozens R, Evans DB, Fabbro D, Furet P, Porta DG, Liebetanz J, Martiny-Baron G, Ruetz S, Hofmann F. In vivo antitumor activity of NVP-AEW541-A novel, potent, and selective inhibitor of the IGF-IR kinase. Cancer Cell 2004; 5: 231-239
109. Scotlandi K, Manara MC, Nicoletti G, Lollini PL, Lukas S, Benini S, Croci S, Perdichizzi S, Zambelli D, Serra M, Garcia-Echeverria C, Hofmann F, Picci P. Antitumor activity of the insulin-like growth factor-I receptor kinase inhibitor NVPA-EW541 in musculoskeletal tumors. Cancer Res 2005; 65: 3868-3876
110. Feng Y, Zhu Z, Xiao X, Choudhry V, Barrett JC, Dimitrov DS. Novel human monoclonal antibodies to insulin-like growth factor (IGF)-II that potently inhibit the IGF receptor type I signal transduction function. Mol Cancer Ther 2006; 5: 114-120
111. Hofmann F, Brueggen J, Capraro HG, Cozens R, Evans DB, Fabbro D, Ferrari S, Furet P, Garcia-Echeverria C, Geiger T, Porta DG, Liebetanz J, Maira SM, Marti A, Martiny-Baron G, Mestan J, Meyer T, Ruetz S, Stoltz B, Zimmermann J, Peterson MA. In vitro and in vivo profiling of selective and potent IGF-IR kinase inhibitors. Proc AACR 2003; 44: 37985
112. Burtrum D, Zhu Z, Lu D, Anderson DM, Prewett M, Pereira DS, Bassi R, Abdullah R, Hooper AT, Koo H, Jimenez X, Johnson D, Apblett R, Kussie P, Bohlen P, Witte L, Hicklin DJ, Ludwig DL. 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
113. Garber K. IGF-1: old growth factor shines as new drug target. J Natl Cancer Inst 2005; 97: 790-792
114. Leary A, Johnston SR. Small molecule signal transduction inhibitors for the treatment of solid tumors. Cancer Invest 2007; 25: 347-365
115. Desbois-Mouthon C, Cacheux W, Blivet-Van Eggelpoel MJ, Barbu V, Fartoux L, Poupon R, Housset C, Rosmorduc O. Impact of IGF-1R/EGFR cross-talks on hepatoma cell sensitivity to gefitinib. Int J Cancer 2006; 119: 2557-2566
116. Tao Y, Pinzi V, Bourhis J, Deutsch E. Mechanisms of disease: signaling of the insulin-like growth factor 1 receptor pathway - therapeutic perspectives in cancer. Nat Clin Pract Oncol 2007; 4: 591-602
117. Wiedmann M, Feisthammel J, Bluthner T, Tannapfel A, Kamenz T, Kluge A, Mossner J, Caca K. Novel targeted approaches to treating biliary tract cancer: the dual epidermal growth factor receptor and ErbB-2 tyrosine kinase inhibitor NVP-AEE788 is more efficient than the epidermal growth factor receptor inhibitors gefitinib and erlotinib. Anticancer Drugs 2006; 17: 783-795
118. Younes MN, Park YW, Yazici YD, Gu M, Santillan AA, Nong X, Kim S, Jasser SA, El-Naggar AK, Myers JN. Concomitant inhibition of epidermal growth factor and vascular endothelial growth factor receptor tyrosine kinases reduces growth and metastasis of human salivary adenoid cystic carcinoma in an orthotopic nude mouse model. Mol Cancer Ther 2006; 5: 2696-2705
119. Busby JE, Kim SJ, Yazici S, Nakamura T, Kim JS, He J, Maya M, Wang X, Do KA, Fan D, Fidler IJ. Therapy of multidrug resistant human prostate tumors in the prostate of nude mice by simultaneous targeting of the epidermal growth factor receptor and vascular endothelial growth factor receptor on tumor-associated endothelial cells. Prostate 2006; 66: 1788-1798
120. Heymach JV. ZD6474 - clinical experience to date. Br J Cancer 2005; 92 Suppl 1: S14-S20
121. Lakhani VT, You YN, Wells SA. The multiple endocrine neoplasia syndromes. Annu Rev Med 2007; 58: 253-265
122. Natale RB, Bodkin D, Govindan R, Sleckman B, Rizvi. N, Capo A, Germonpré P, Stockman P, Kennedy S, Ranson M. ZD6474 versus gefitinib in patients with advanced NSCLC: Final results from a two-part, double-blind, randomized phase II trial. J Clin Oncol 2006; 24: 7000. Available from: URL: http://meeting.ascopubs.org/cgi/ content/abstract/24/18_suppl/7000
123. Wells S, You YN, Lakhani V, Hou J, Langmuir P, Headley D, Skinner M, Morse M, Burch W, Schlumberger M. A phase II trial of ZD6474 in patients with hereditary metastatic medullary thyroid cancer. J Clin Oncol 2006; 24: 5533
124. Duran I, Salazar R, Casanovas O, Arrazubi V, Vilar E, Siu LL, Yao J, Tabernero J. New drug development in digestive neuroendocrine tumors. Ann Oncol 2007; 18: 1307-1313
125. Wang L, Ignat A, Axiotis CA. Differential expression of the PTEN tumor suppressor protein in fetal and adult neuroendocrine tissues and tumors: progressive loss of PTEN expression in poorly differentiated neuroendocrine neoplasms. Appl Immunohistochem Mol Morphol 2002; 10: 139-146
126. Perren A, Komminoth P, Saremaslani P, Matter C, Feurer S, Lees JA, Heitz PU, Eng C. Mutation and expression analyses reveal differential subcellular compartmentalization of PTEN in endocrine pancreatic tumors compared to normal islet cells. Am J Pathol 2000; 157: 1097-1103
127. Yao JC. Neuroendocrine tumors. Molecular targeted therapy for carcinoid and islet-cell carcinoma. Best Pract Res Clin Endocrinol Metab 2007; 21: 163-172
128. Avila MA, Berasain C, Sangro B, Prieto J. New therapies for hepatocellular carcinoma. Oncogene 2006; 25: 3866-3884
129. Zitzmann K, De Toni EN, Brand S, Coke B, Meinecke J, Spottl G, Meyer HH, Auernhammer CJ. The novel mTOR inhibitor RAD001 (everolimus) induces antiproliferative effects in human pancreatic neuroendocrine tumor cells. Neuroendocrinology 2007; 85: 54-60
130. Tsang CK, Qi H, Liu LF, Zheng XE. Targeting mammalian target of rapamycin (mTOR) for health and diseases. Drug Discov Today 2007; 12: 112-124
131. Dudkin L, Dilling MB, Cheshire PJ, Harwood FC, Hollingshead M, Arbuck SG, Travis R, Sausville EA, Houghton PJ. Biochemical correlates of mTOR inhibition by the rapamycin ester CCI-779 and tumor growth inhibition. Clin Cancer Res 2001; 7: 1758-1764
132. Easton JB, Houghton PJ. mTOR and cancer therapy. Oncogene 2006; 25: 6436-6446
133. Wullschleger S, Loewith R, Hall MN. TOR signaling in growth and metabolism. Cell 2006; 124: 471-484
134. Okuno S. Mammalian target of rapamycin inhibitors in sarcomas. Curr Opin Oncol 2006; 18: 360-362
135. Smolewski P. Recent developments in targeting the mammalian target of rapamycin (mTOR) kinase pathway. Anticancer Drugs 2006; 17: 487-494
136. Yao JC, Phan AT, Chang DZ, Jacobs C, Mares JE, Rashid A, Meric-Bernstam F. Phase II study of RAD001 (everolimus) and depot octreotide (Sandostatin LAR) in patients with advanced low grade neuroendocrine carcinoma (LGEP NET). J Clin Oncol 2006; 24 (18S): 4042
137. Duran I, Kortmansky J, Singh D, Hirte H, Kocha W, Goss G, Le L, Oza A, Nicklee T, Ho J, Birle D, Pond GR, Arboine D, Dancey J, Aviel-Ronen S, Tsao MS, Hedley D, Siu LL. A phase II clinical and pharmacodynamic study of temsirolimus in advanced neuroendocrine carcinomas. Br J Cancer 2006; 95: 1148-1154
138. Sridhar SS, Hedley D, Siu LL. Raf kinase as a target for anticancer therapeutics. Mol Cancer Ther 2005; 4: 677-685
139. Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W, Davis N, Dicks E, Ewing R, Floyd Y, Gray K, Hall S, Hawes R, Hughes J, Kosmidou V, Menzies A, Mould C, Parker A, Stevens C, Watt S, Hooper S, Wilson R, Jayatilake H, Gusterson BA, Cooper C, Shipley J, Hargrave D, Pritchard-Jones K, Maitland N, Chenevix-Trench G, Riggins GJ, Bigner DD, Palmieri G, Cossu A, Flanagan A, Nicholson A, Ho JW, Leung SY, Yuen ST, Weber BL, Seigler HF, Darrow TL, Paterson H, Marais R, Marshall CJ, Wooster R, Stratton MR, Futreal PA. Mutations of the BRAF gene in human cancer. Nature
140. Fukushima T, Suzuki S, Mashiko M, Ohtake T, Endo Y, Takebayashi Y, Sekikawa K, Hagiwara K, Takenoshita S. BRAF mutations in papillary carcinomas of the thyroid. Oncogene 2003; 22: 6455-6457
141. Tannapfel A, Vomschloss S, Karhoff D, Markwarth A, Hengge UR, Wittekind C, Arnold R, Hersch D. BRAF gene mutations are rare events in gastroenteropancreatic neuroendocrine tumors. Am J Clin Pathol 2005; 123: 256-260
142. Karhoff D, Sauer S, Schrader J, Arnold R, Fendrich V, Bartsch DK, Horsch D. Rap1/B-Raf signaling is activated in neuroendocrine tumors of the digestive tract and Raf kinase inhibition constitutes a putative therapeutic target. Neuroendocrinology 2007; 85: 45-53
143. Wilhelm S, Chien DS. BAY 43-9006: preclinical data. Curr Pharm Des 2002; 8: 2255-2257
144. Gollob JA, Wilhelm S, Carter C, Kelley SL. Role of Raf kinase in cancer: therapeutic potential of targeting the Raf/MEK/ERK signal transduction pathway. Semin Oncol 2006; 33: 392-406
145. Liu L, Cao Y, Chen C, Zhang X, McNabola A, Wilkie D, Wilhelm S, Lynch M, Carter C. Sorafenib blocks the RAF/MEK/ERK pathway, inhibits tumor angiogenesis, and induces tumor cell apoptosis in hepatocellular carcinoma model PLC/FRF/5. Cancer Res 2006; 66: 11851-11858
146. Roccaro AM, Hideshima T, Richardson PG, Russo D, Ribatti D, Vacca A, Dammacco F, Anderson KC. Bortezomib as an antitumor agent. Curr Pharm Biotechnol 2006; 7: 441-448
147. Mitsiades CS, Mitsiades N, Hideshima T, Richardson PG, Anderson KC. Proteasome inhibitors as therapeutics. Essays Biochem 2005; 41: 205-218
148. Baradari V, Hopfner M, Huether A, Schuppan D, Scherubl H. Histone deacetylase inhibitor MS-275 alone or combined with bortezomib or sorafenib exhibits strong antiproliferative action in human cholangiocarcinoma cells. World J Gastroenterol 2007; 13: 4458-4466
149. Schwartz R, Davidson T. Pharmacology, pharmacokinetics, and practical applications of bortezomib. Oncology (Williston Park) 2004; 18: 14-21
150. Brignole C, Marimpietri D, Pastorino F, Nico B, Di Paolo D, Cioni M, Piccardi F, Cilli M, Pezzolo A, Corrias MV, Pistoia V, Ribatti D, Pagnan G, Ponzoni M. Effect of bortezomib on human neuroblastoma cell growth, apoptosis, and angiogenesis. J Natl Cancer Inst 2006; 98: 1142-1157
151. Larsson DE, Lovborg H, Rickardson L, Larsson R, Oberg K, Granberg D. Identification and evaluation of potential anticancer drugs on human neuroendocrine tumor cell lines. Anticancer Res 2006; 26: 4125-4129
152. Kane RC, Dagher R, Farrell A, Ko CW, Sridhara R, Justice R, Pazdur R. Bortezomib for the treatment of mantle cell lymphoma. Clin Cancer Res 2007; 13: 5291-5294
153. Shah MH, Young D, Kindler HL, Webb I, Kleiber B, Wright J, Grever M. Phase II study of the proteasome inhibitor bortezomib (PS-341) in patients with metastatic neuroendocrine tumors. Clin Cancer Res 2004; 10: 6111-6118
154. Baradari V, Huether A, Hopfner M, Schuppan D, Scherubl H. Antiproliferative and proapoptotic effects of histone deacetylase inhibitors on gastrointestinal neuroendocrine tumor cells. Endocr Relat Cancer 2006; 13: 1237-1250