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Therapy innovations: tyrosine kinase inhibitors for the treatment of pancreatic neuroendocrine tumors

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Abstract

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) show limited sensitivity to cytotoxic agents, requiring the search for novel therapies. Recently, data from a phase III trial demonstrated that sunitinib produces a clinically significant improvement in progression-free survival in patients with unresectable, advanced, or metastatic GEP-NETs. Based on this finding, sunitinib became the first targeted drug approved for the treatment of GEP-NETs, paving the way for the approval of other anticancer agents in this drug-orphan disease. To date, results of trials involving other multitargeted tyrosine kinase inhibitors, such as sorafenib, the monoclonal antibody bevacizumab, and insulin-like growth factor 1 receptor inhibitors, have also shown promising results, and some are already being studied in phase III trials. This review updates the results of ongoing trials using inhibitors of growth factors and tyrosine kinase receptors involved in the carcinogenesis of GEP-NETs.

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References

  1. Modlin, I. M., Pavel, M., Kidd, M., et al. (2010). Review article: somatostatin analogues in the treatment of gastroenteropancreatic neuroendocrine (carcinoid) tumours. Alimentary Pharmacology & Therapeutics, 31(2), 169–188.

    CAS  Google Scholar 

  2. Rinke, A., Muller, H. H., Schade-Brittinger, C., et al. (2009). Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group. Journal of Clinical Oncology, 27(28), 4656–4663.

    Article  PubMed  CAS  Google Scholar 

  3. Eriksson, B. (2010). New drugs in neuroendocrine tumors: rising of new therapeutic philosophies? Current Opinion in Oncology, 22(4), 381–386.

    Article  PubMed  CAS  Google Scholar 

  4. Hansel, D. E., Rahman, A., Hermans, J., et al. (2003). Liver metastases arising from well-differentiated pancreatic endocrine neoplasms demonstrate increased VEGF-C expression. Modern Pathology, 16(7), 652–659.

    Article  PubMed  Google Scholar 

  5. Fjällskog, M. L., Hessman, O., Eriksson, B., et al. (2007). Upregulated expression of PDGF receptor beta in endocrine pancreatic tumors and metastases compared to normal endocrine pancreas. Acta Oncológica, 46(6), 741–746.

    Article  PubMed  Google Scholar 

  6. Fjällskog, M. L., Lejonklou, M. H., Oberg, K. E., et al. (2003). Expression of molecular targets for tyrosine kinase receptor antagonists in malignant endocrine pancreatic tumors. Clinical Cancer Research, 9(4), 1469–1473.

    PubMed  Google Scholar 

  7. Pugh, C. W., & Ratcliffe, P. J. (2003). Regulation of angiogenesis by hypoxia: role of the HIF system. Natural Medicines, 9(6), 677–684.

    Article  CAS  Google Scholar 

  8. Stuttfeld, E., & Ballmer-Hofer, K. (2009). Structure and function of VEGF receptors. IUBMB Life, 61(9), 915–922.

    Article  PubMed  CAS  Google Scholar 

  9. Ferrara, N. (2002). Role of vascular endothelial growth factor in physiologic and pathologic angiogenesis: therapeutic implications. Seminars in Oncology, 29(6 Suppl 16), 10–14.

    PubMed  CAS  Google Scholar 

  10. Rouhi, P., Lee, S. L., Cao, Z., et al. (2010). Pathological angiogenesis facilitates tumor cell dissemination and metastasis. Cell Cycle, 9(5), 913–917.

    Article  PubMed  CAS  Google Scholar 

  11. Zhang, J., Jia, Z., Li, Q., et al. (2007). Elevated expression of vascular endothelial growth factor correlates with increased angiogenesis and decreased progression-free survival among patients with low-grade neuroendocrine tumors. Cancer, 109(8), 1478–1486.

    Article  PubMed  CAS  Google Scholar 

  12. Mendel, D. B., Laird, A. D., 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. Clinical Cancer Research, 9(1), 327–337.

    PubMed  CAS  Google Scholar 

  13. O’Farrell, A. M., Abrams, T. J., Yuen, H. A., et al. (2003). SU11248 is a novel FLT3 tyrosine kinase inhibitor with potent activity in vitro and in vivo. Blood, 101(9), 3597–3605.

    Article  PubMed  Google Scholar 

  14. Faivre, S., Demetri, G., Sargent, W., et al. (2007). Molecular basis for sunitinib efficacy and future clinical development. Nature Reviews. Drug Discovery, 6(9), 734–745.

    Article  PubMed  CAS  Google Scholar 

  15. Sablin, M. P., Dreyer, C., Colichi, C., et al. (2010). Benefits from pharmacological and pharmacokinetic properties of sunitinib for clinical development. Expert Opinion on Drug Metabolism & Toxicology, 6(8), 1005–1015.

    Article  CAS  Google Scholar 

  16. Pietras, K., & Hanahan, D. (2005). A multitargeted, metronomic, and maximum-tolerated dose “chemo-switch” regimen is antiangiogenic, producing objective responses and survival benefit in a mouse model of cancer. Journal of Clinical Oncology, 23(5), 939–952.

    Article  PubMed  CAS  Google Scholar 

  17. Faivre, S., Delbaldo, C., Vera, K., et al. (2006). Safety, pharmacokinetic, and antitumor activity of SU11248, a novel oral multitarget tyrosine kinase inhibitor, in patients with cancer. Journal of Clinical Oncology, 24(1), 25–35.

    Article  PubMed  CAS  Google Scholar 

  18. Raymond, E., Faivre, S., Hammel, P., et al. (2009). Sunitinib paves the way for targeted therapies in neuroendocrine tumors. Target Oncol, 4(4), 253–254.

    Article  PubMed  Google Scholar 

  19. Kulke, M. H., Lenz, H. J., Meropol, N. J., et al. (2008). Activity of sunitinib in patients with advanced neuroendocrine tumors. Journal of Clinical Oncology, 26(20), 3403–3410.

    Article  PubMed  CAS  Google Scholar 

  20. Raymond, E., Dahan, L., Raoul, J. L., et al. (2011). Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. New England Journal of Medicine, in press.

  21. Wilhelm, S. M., Carter, C., Tang, L., et al. (2004). 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 Research, 64(19), 7099–7109.

    Article  PubMed  CAS  Google Scholar 

  22. Hobday, T. J., 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. Journal of Clinical Oncology (Meeting Abstracts), 25(18_suppl), 4504.

    Google Scholar 

  23. Azad, N. S., Posadas, E. M., Kwitkowski, V. E., et al. (2008). Combination targeted therapy with sorafenib and bevacizumab results in enhanced toxicity and antitumor activity. Journal of Clinical Oncology, 26(22), 3709–3714.

    Article  PubMed  CAS  Google Scholar 

  24. Castellano, D., Capdevila, J., Salazar, R., et al. (2010). Neuroendocrine tumors. Annals of Oncology, 21(suppl 8), Abstract 850P.

    Google Scholar 

  25. Ranieri, G., Patruno, R., Ruggieri, E., et al. (2006). Vascular endothelial growth factor (VEGF) as a target of bevacizumab in cancer: from the biology to the clinic. Current Medicinal Chemistry, 13(16), 1845–1857.

    Article  PubMed  CAS  Google Scholar 

  26. Avastin® (2010). Avastin® (bevacizumab)—summary of product characteristics. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000582/WC500029271.pdf (downloaded on September 24, 2010).

  27. Yao, J. C., Phan, A., Hoff, P. M., 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 alpha-2b. Journal of Clinical Oncology, 26(8), 1316–1323.

    Article  PubMed  CAS  Google Scholar 

  28. Yao, J. C., Phan, A. T., & Fogleman, D. (2010). Randomized run-in study of bevacizumab (B) and everolimus (E) in low- to intermediate-grade neuroendocrine tumors (LGNETs) using perfusion CT as functional biomarker. Journal of Clinical Oncology, 28(15), 4002.

    Google Scholar 

  29. Kunz, P. L., Kuo, T., & Zahn, J. M. (2010). A phase II study of capecitabine, oxaliplatin, and bevacizumab for metastatic or unresectable neuroendocrine tumors. J Clin Oncol, 28(15), 4104.

    Google Scholar 

  30. Gilbert, J. A., Adhikari, L. J., Lloyd, R. V., et al. (2010). Molecular markers for novel therapies in neuroendocrine (carcinoid) tumors. Endocrine Related Cancer, 17(3), 623–636.

    Article  PubMed  CAS  Google Scholar 

  31. Donovan, E. A., & Kummar, S. (2008). Role of insulin-like growth factor-1R system in colorectal carcinogenesis. Critical Reviews in Oncology/Hematology, 66(2), 91–98.

    Article  PubMed  Google Scholar 

  32. Dziadziuszko, R., Camidge, D. R., & Hirsch, F. R. (2008). The insulin-like growth factor pathway in lung cancer. Journal of Thoracic Oncology, 3(8), 815–818.

    Article  PubMed  Google Scholar 

  33. Fürstenberger, G., Morant, R., & Senn, H. J. (2003). Insulin-like growth factors and breast cancer. Onkologie, 26(3), 290–294.

    Article  PubMed  Google Scholar 

  34. Byron, S. A., Horwitz, K. B., Richer, J. K., et al. (2006). Insulin receptor substrates mediate distinct biological responses to insulin-like growth factor receptor activation in breast cancer cells. British Journal of Cancer, 95(9), 1220–1228.

    Article  PubMed  CAS  Google Scholar 

  35. Grimberg, A. (2003). Mechanisms by which IGF-I may promote cancer. Cancer Biology & Therapy, 2(6), 630–635.

    Article  CAS  Google Scholar 

  36. Wulbrand, U., Remmert, G., Zofel, P., et al. (2000). mRNA expression patterns of insulin-like growth factor system components in human neuroendocrine tumours. European Journal of Clinical Investigation, 30(8), 729–739.

    Article  PubMed  CAS  Google Scholar 

  37. Furukawa, M., Raffeld, M., Mateo, C., et al. (2005). 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. Clinical Cancer Research, 11(9), 3233–3242.

    Article  PubMed  CAS  Google Scholar 

  38. von Wichert, G., Jehle, P. M., 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 Research, 60(16), 4573–4581.

    Google Scholar 

  39. Tanno, B., Mancini, C., Vitali, R., et al. (2006). 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. Clinical Cancer Research, 12(22), 6772–6780.

    Article  PubMed  CAS  Google Scholar 

  40. Höpfner, M., Baradari, V., Huether, A., et al. (2006). The insulin-like growth factor receptor 1 is a promising target for novel treatment approaches in neuroendocrine gastrointestinal tumours. Endocrine Related Cancer, 13(1), 135–149.

    Article  PubMed  Google Scholar 

  41. Atzori, F., Tabernero, J., & Cervantes, A. (2008). A phase I, pharmacokinetic (PK) and pharmacodynamic (PD) study of weekly (qW) MK-0646, an insulin-like growth factor-1 receptor (IGF1R) monoclonal antibody (MAb) in patients (pts) with advanced solid tumors. Journal of Clinical Oncology, 26(15), 3519.

    Google Scholar 

  42. Scartozzi, M., Bianconi, M., Maccaroni, E., et al. (2010). Dalotuzumab, a recombinant humanized mAb targeted against IGFR1 for the treatment of cancer. Current Opinion in Molecular Therapeutics, 12(3), 361–371.

    PubMed  CAS  Google Scholar 

  43. Reidy, D. L., Hollywood, E., & Segal, M. (2010). A phase II clinical trial of MK-0646, an insulin-like growth factor-1 receptor inhibitor (IGF-1R), in patients with metastatic well-differentiated neuroendocrine tumors (NETs). Journal of Clinical Oncology, 28(15), 4163.

    Google Scholar 

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Acknowledgments

The author acknowledges Dr. Ximena Alvira from HealthCo SL (Madrid, Spain) for her assistance in the preparation of this manuscript and Pfizer Spain for the financial support of medical writing services.

Conflicts of interest

Eric Raymond was consultant for Pfizer Inc. and Bayer Pharma. Alfredo Carrato has been consultant for Pfizer Inc. The authors declare that they do not have any conflict of interest that may inappropriately influence this work.

Author information

Authors and Affiliations

  1. Medical Oncology Department, Beaujon University Hospital, INSERM U728, APHP, Paris 7 University, 100 bd du Général Leclerc, 92880, Clichy, France

    Eric Raymond

  2. Oncology Department, College of Medicine, Mayo Clinic, Rochester, MN, USA

    Timothy Hobday

  3. Medical Oncology Department, University Hospital 12 de Octubre, Madrid, Spain

    Daniel Castellano

  4. Gastrointestinal Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    Diane Reidy-Lagunes

  5. Medical Oncology Department, Instituto de Biomedicina de Sevilla (IBIS), Virgen del Rocío University Hospital, Sevilla, Spain

    Rocío García-Carbonero

  6. Medical Oncology Department, Ramón y Cajal University Hospital, Madrid, Spain

    Alfredo Carrato

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  1. Eric Raymond
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Correspondence to Eric Raymond.

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Raymond, E., Hobday, T., Castellano, D. et al. Therapy innovations: tyrosine kinase inhibitors for the treatment of pancreatic neuroendocrine tumors. Cancer Metastasis Rev 30 (Suppl 1), 19–26 (2011). https://doi.org/10.1007/s10555-011-9291-2

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