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Molecular targeted therapies in the treatment of gastroenteropancreatic neuroendocrine tumors

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Abstract

Gastroenteropancreatic neuroendocrine tumors (GEPNETs) are rare neoplasms that require a multidisciplinary approach for an optimal management. The traditional cytotoxic agents are of limited efficacy in the treatment of these tumors. A better understanding of the molecular pathways that characterize tumor growth has provided novel targets in cancer treatment. Several proteins have been implicated as having a crucial role in GEPNETs. Several proangiogenic molecules are overexpressed in GEPNETs including vascular endothelial growth factor (VEGF) and its receptors, and related signaling pathway components such as epidermal growth factor receptor (EGFR), insulin growth factor-I receptor (IGF-IR) and PI3K-AKT-mTOR pathway. In this article we aim to review the recent development of the main molecules that target these proteins and have showed promising activity in the treatment of GEPNETs.

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References

  1. Oberg K, Astrup L, Eriksson B et al (2004) Guidelines for the management of gastroenteropancreatic neuroendocrine tumours (including bronchopulmonary and thymic neoplasms). Part I-general overview. Acta Oncol 43(7):617–625

    Article  PubMed  Google Scholar 

  2. Tomassetti P, Migliori M, Lalli S, Campana D, Tomassetti V, Corinaldesi R (2001) Epidemiology, clinical features and diagnosis of gastroenteropancreatic endocrine tumours. Acta Oncol 12(Suppl 2):S95–99

    Google Scholar 

  3. Oberg K, Norheim I, Lundqvist G, Wide L (1987) Cytotoxic treatment in patients with malignant carcinoid tumors. Response to streptozocin–alone or in combination with 5-FU. Acta Oncol 26(6):429–432

    Article  CAS  PubMed  Google Scholar 

  4. Sun W, Lipsitz S, Catalano P, Mailliard JA, Haller DG (2005) Phase II/III Study of Doxorubicin With Fluorouracil Compared With Streptozocin With Fluorouracil or Dacarbazine in the Treatment of Advanced Carcinoid Tumors: Eastern Cooperative Oncology Group Study E1281. J Clin Oncol 23(22):4897–4904

    Article  CAS  PubMed  Google Scholar 

  5. Fjällskog ML, Granberg DP, Welin SL et al (2001) Treatment with cisplatin and etoposide in patients with neuroendocrine tumors. Cancer 92(5):1101–1107

    Article  PubMed  Google Scholar 

  6. Vilar E, Salazar R, Pérez-García J, Cortes J, Oberg K, Tabernero J (2007) Chemotherapy and role of the proliferation marker Ki-67 in digestive neuroendocrine tumors. Endocr Relat Cancer 14(2):221–232

    Article  CAS  PubMed  Google Scholar 

  7. Kouvaraki MA, Ajani JA, Hoff P et al (2004) Fluorouracil, doxorubicin, and streptozocin in the treatment of patients with locally advanced and metastatic pancreatic endocrine carcinomas. J Clin Oncol 22(23):4762–4771

    Article  CAS  PubMed  Google Scholar 

  8. Moertel CG, Hanley JA (1979) Combination chemotherapy trials in metastatic carcinoid tumor and the malignant carcinoid syndrome. Cancer Clin Trials 2(4):327–334

    CAS  PubMed  Google Scholar 

  9. Falconi M, Plockinger U, Kwekkeboom DJ et al (2006) Well-differentiated pancreatic nonfunctioning tumors/carcinoma. Neuroendocrinology 84(3):196–192

    Article  CAS  PubMed  Google Scholar 

  10. Eriksson B, Klöppel G, Krenning E et al (2008) Consensus guidelines for the management of patients with digestive neuroendocrine tumors–well-differentiated jejunal-ileal tumor/carcinoma. Neuroendocrinology 87(1):8–19

    Article  CAS  PubMed  Google Scholar 

  11. Modlin IM, Oberg K, Chung DC et al (2008) Gastroenteropancreatic neuroendocrine tumours. Lancet Oncol 9(1):61–72

    Article  CAS  PubMed  Google Scholar 

  12. Terris B, Scoazec JY, Rubbia L et al (1998) Expression of vascular endothelial growth factor in digestive neuroendocrine tumours. Histopathology 32(2):133–138

    Article  CAS  PubMed  Google Scholar 

  13. Casanovas O, Hicklin DJ, Bergers G, Hanahan D (2005) Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors. Cancer Cell 8(4):299–309

    Article  CAS  PubMed  Google Scholar 

  14. Papouchado B, Erickson LA, Rohlinger AL et al (2005) Epidermal growth factor receptor and activated epidermal growth factor receptor expression in gastrointestinal carcinoids and pancreatic endocrine carcinomas. Mod Pathol 18(10):1329–1335

    Article  CAS  PubMed  Google Scholar 

  15. Höpfner M, Sutter AP, Gerst B, Zeitz M, Scherübl H (2003) A novel approach in the treatment of neuroendocrine gastrointestinal tumours. Targeting the epidermal growth factor receptor by gefitinib (ZD1839). Br J Cancer 89(9):1766–1775

    Article  PubMed  Google Scholar 

  16. von Wichert G, Jehle PM, Hoeflich A et al (2000) Insulin-like growth factor-I is an autocrine regulator of chromogranin A secretion and growth in human neuroendocrine tumor cells. Cancer Res 60(16):4573–4581

    Google Scholar 

  17. Vignot S, Faivre S, Aguirre D, Raymond E (2005) mTOR-targeted therapy of cancer with rapamycin derivatives. Ann Oncol 16(4):525–537

    Article  CAS  PubMed  Google Scholar 

  18. Wang L, Ignat A, Axiotis CA (2002) 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 10(2):139–146

    Article  CAS  PubMed  Google Scholar 

  19. Ferrara N (2002) VEGF and the quest for tumour angiogenesis factors. Nat Rev Cancer 2(10):795–803

    Article  CAS  PubMed  Google Scholar 

  20. Jain RK (2003) Molecular regulation of vessel maturation. Nat Med 9(6):685–693

    Article  CAS  PubMed  Google Scholar 

  21. Hicklin DJ, Ellis LM (2005) Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol 23(5):1011–1027

    Article  CAS  PubMed  Google Scholar 

  22. Dvorak HF (2002) Vascular permeability factor/vascular endothelial growth factor: a critical cytokine in tumor angiogenesis and a potential target for diagnosis and therapy. J Clin Oncol 20(21):4368–4380

    Article  CAS  PubMed  Google Scholar 

  23. Gray MJ, Wey JS, Belcheva A et al (2005) Neuropilin-1 suppresses tumorigenic properties in a human pancreatic adenocarcinoma cell line lacking neuropilin-1 coreceptors. Cancer Res 65(9):3664–3670

    Article  CAS  PubMed  Google Scholar 

  24. Kim KJ, Li B, Winer J et al (1993) Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo. Nature 362(6423):841–844

    Article  CAS  PubMed  Google Scholar 

  25. Dvorak HF, Brown LF, Detmar M, Dvorak AM (1995) Vascular permeability factor/vascular endothelial growth factor, microvascular hyperpermeability, and angiogenesis. Am J Pathol 146(5):1029–1039

    CAS  PubMed  Google Scholar 

  26. Manley PW, Martiny-Baron G, Schlaeppi JM, Wood JM (2002) Therapies directed at vascular endothelial growth factor. Expert Opin Investig Drugs 11(12):1715–1736

    Article  CAS  PubMed  Google Scholar 

  27. Ferrara N, Hillan KJ, Gerber HP, Novotny W (2004) Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nat Rev Drug Discov 3:391–400

    Article  CAS  PubMed  Google Scholar 

  28. Hurwitz H, Fehrenbacher L, Novotny W et al (2004) Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350(23):2335–2342

    Article  CAS  PubMed  Google Scholar 

  29. Yao JC, Phan A, Hoff PM et al (2008) Targeting vascular endothelial growth factor in advanced carcinoid tumor: a random assignment phase II study of depot octreotide with bevacizumab and pegylated interferon alfa-2b. J Clin Oncol 26(8):1316–1323

    Article  CAS  PubMed  Google Scholar 

  30. Kunz PL, Kuo T, Kaiser HL et al (2008) A phase II study of capecitabine, oxaliplatin, and bevacizumab for metastatic or unresectable neuroendocrine tumors: Preliminary results. Proc Am Soc Clin Oncol 26:15502

    Google Scholar 

  31. Venook AP, Ko AH, Tempero MA et al (2008) Phase II trial of FOLFOX plus bevacizumab in advanced, progressive neuroendocrine tumors. Proc Am Soc Clin Oncol 26:15545

    Google Scholar 

  32. Kulke MH, Stuart K, Earle CC et al (2006) A phase II study of temozolomide and bevacizumab in patients with advanced neuroendocrine tumors. Proc Am Soc Clin Oncol 24(18S):4044

    Google Scholar 

  33. Mendel DB, Laird AD, Xin X et al (2003) 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 9(1):327–337

    CAS  PubMed  Google Scholar 

  34. Kulke MH, Lenz H-J, Meropol NJ et al (2008) Activity of sunitinib in patients with advanced neuroendocrine tumors. J Clin Oncol 26(20):3403–3410

    Article  CAS  PubMed  Google Scholar 

  35. Bello CJ, Deprimo SE, Friece C et al (2006) Analysis of circulating biomarkers of sunitinib malate in patients with unresectable neuroendocrine tumors (NET): VEGF, IL-8, and soluble VEGF receptors 2 and 3. Proc Am Soc Clin Oncol 24(18S):4045

    Google Scholar 

  36. Raymond E, Raoul JL, Niccoli P et al (2009) Phase III, randomized, double-blind trial of sunitinib vs placebo in patients with progressive, well-differentiated, malignant pancreatic islet cell tumors. World Congress on Gastrointestinal Cancer 2009:0013

  37. Strosberg JR, Campos T, Kvols L (2009) Phase II study of sunitinib malate following hepatic artery embolization for metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Proc Am Soc Clin Oncol 2009:272

    Google Scholar 

  38. Hobday TJ, Rubin J, Holen K et al (2007) MC044h, a phase II trial of sorafenib in patients (pts) with metastatic neuroendocrine tumors (NET): A Phase II Consortium (P2C) study. Proc Am Soc Clin Oncol 25(18S):4504

    Google Scholar 

  39. Anthony L, Chester M, Michael S, O'Dorisio TM, O'Dorisio MS (2008) Phase II open-label clinical trial of vatalanib (PTK/ZK) in patients with progressive neuroendocrine cancer. Proc Am Soc Clin Oncol 26(20S):14624

    Google Scholar 

  40. Pavel ME, Bartel C, Heuck F et al (2008) Open-label, non-randomized, multicenter phase II study evaluating the angiogenesis inhibitor PTK787/ ZK222584 (PTK/ZK) in patients with advanced neuroendocrine carcinomas (NEC). Proc Am Soc Clin Oncol 26:14684

    Google Scholar 

  41. Gross DJ, Munter G, Bitan M et al (2006) The role of imatinib mesylate (Glivec) for treatment of patients with malignant endocrine tumors positive for c-kit or PDGF-R. Endocr Relat Cancer 13(2):535–540

    Article  CAS  PubMed  Google Scholar 

  42. Yao JC, Zhang JX, Rashid A et al (2007) Clinical and In vitro Studies of Imatinib in Advanced Carcinoid Tumors. Clin Cancer Res 13(1):234–240

    Article  CAS  PubMed  Google Scholar 

  43. D'Amato RJ, Loughnan MS, Flynn E, Folkman J (1994) Thalidomide is an inhibitor of angiogenesis. Proc Natl Acad Sci USA 91(9):4082–4085

    Article  PubMed  Google Scholar 

  44. Varker KA, Campbell J, Shah MH (2008) Phase II study of thalidomide in patients with metastatic carcinoid and islet cell tumors. Cancer Chemother Pharmacol 61(4):661–668

    Article  CAS  PubMed  Google Scholar 

  45. Kulke MH, Stuart K, Enzinger PC et al (2006) Phase II study of temozolomide and thalidomide in patients with metastatic neuroendocrine tumors. J Clin Oncol 24(3):401–406

    Article  CAS  PubMed  Google Scholar 

  46. Kulke MH, Bergsland EK, Ryan DP et al (2006) Phase II study of recombinant human endostatin in patients with advanced neuroendocrine tumors. J Clin Oncol 24(22):3555–3561

    Article  CAS  PubMed  Google Scholar 

  47. Shah T, Hochhauser D, Frow R, Quaglia A, Dhillon AP, Caplin ME (2006) Epidermal growth factor receptor expression and activation in neuroendocrine tumours. J Neuroendocrinol 18(5):355–360

    Article  CAS  PubMed  Google Scholar 

  48. Srivastava A, Alexander J, Lomakin I, Dayal Y (2001) Immunohistochemical expression of transforming growth factor alpha and epidermal growth factor receptor in pancreatic endocrine tumors. Hum Pathol 32(11):1184–1189

    Article  CAS  PubMed  Google Scholar 

  49. Hobday TJ, Holen K, Donehower R et al (2006) A phase II trial of gefitinib in patients (pts) with progressive metastatic neuroendocrine tumors (NET): A Phase II Consortium (P2C) study. Proc Am Soc Clin Oncol 24(18S):4043

    Google Scholar 

  50. Aoki M, Blazek E, Vogt PK (2001) A role of the kinase mTOR in cellular transformation induced by the oncoproteins P3k and Akt. Proc Natl Acad Sci USA 98:136–141

    Article  CAS  PubMed  Google Scholar 

  51. Vivanco I, Sawyers CL (2002) The phosphatidylinositol 3-kinase-Akt pathway in human cancer. Nat Rev Cancer 2:489–501

    Article  CAS  PubMed  Google Scholar 

  52. Guba M, von Breitenbuch P, Steinbauer M et al (2002) Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: involvement of vascular endothelial growth factor. Nat Med 8(2):128–135

    Article  CAS  PubMed  Google Scholar 

  53. Kim D, Sarbassov D, Ali S et al (2002) mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell 110(2):163–175

    Article  CAS  PubMed  Google Scholar 

  54. Sarbassov D, Guertin D, Ali S, Sabatini D (2005) Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 307(5712):1098–1101

    Article  CAS  PubMed  Google Scholar 

  55. Sabatini DM (2006) MTOR and cancer: Insights into a complex relationship. Nat Rev Cancer 6:729–734

    Article  CAS  PubMed  Google Scholar 

  56. Duran I, Kortmansky J, Singh D et al (2007) A phase II clinical and pharmacodynamic study of temsirolimus in advanced neuroendocrine carcinomas. Br J Cancer 95(9):1148–1154

    Article  Google Scholar 

  57. Yao JC, Phan AT, Chang DZ et al (2008) Efficacy of RAD001 (everolimus) and octreotide LAR in advanced low- to intermediate-grade neuroendocrine tumors: results of a phase II study. J Clin Oncol 26(26):4311–4318

    Article  PubMed  Google Scholar 

  58. Tabernero J, Rojo F, Calvo E et al (2008) Dose- and schedule-dependent inhibition of the mammalian target of rapamycin pathway with everolimus: a phase I tumor pharmacodynamic study in patients with advanced solid tumors. J Clin Oncol 26(10):1603–1610

    Article  CAS  PubMed  Google Scholar 

  59. Yao JC, Lombard-Bohas C, Baudin E et al (2009) A phase II trial of daily oral RAD001 (everolimus) in patients with metastatic pancreatic neuroendocrine tumors (NET) after failure of cytotoxic chemotherapy. ASCO Gastrointestinal Cancers Symposium 2009:122

  60. Raz I, Rubinger D, Popovtzer M, Grønbaek H, Weiss O, Flyvbjerg A (1998) Octreotide prevents the early increase in renal insulin-like growth factor binding protein 1 in streptozotocin diabetic rats. Diabetes 47(6):924–930

    Article  CAS  PubMed  Google Scholar 

  61. Di Cosimo S, Seoane J, Guzman M et al (2005) Combination of the mammalian target of rapamycin (mTOR) inhibitor everolimus (E) with the Insulin like Growth Factor-1-Receptor (IGF-1-R) inhibitor NVP-AEW-541: a mechanistic based anti-tumor strategy. Proc Am Soc Clin Oncol 23(16S):3112

    Google Scholar 

  62. Yeatman TJ (2004) A renaissance for SRC. Nat Rev Cancer 4(6):470–480

    Article  CAS  PubMed  Google Scholar 

  63. Gaur P, Samuel S, Bose D et al (2009) Blockade of in vivo tumor growth of newly established human midgut carcinoid tumors by Src inhibition. ASCO Gastrointestinal Cancers Symposium 2009:146

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The authors indicate no potential conflict of interest and no financial interests relating to the manuscript.

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Authors and Affiliations

  1. Department of Medical Oncology, Vall d’Hebron University Hospital, Barcelona, Spain

    Jaume Capdevila

  2. Early Clinical Research Unit, G-I Unit, Department of Medical Oncology, Institut Català d´Oncologia, Idibell., Av. Gran Via, 199-203, 08907, L´Hospitalet-Barcelona, Spain

    Ramon Salazar

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  1. Jaume Capdevila
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Correspondence to Ramon Salazar.

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Capdevila, J., Salazar, R. Molecular targeted therapies in the treatment of gastroenteropancreatic neuroendocrine tumors. Targ Oncol 4, 287–296 (2009). https://doi.org/10.1007/s11523-009-0128-7

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