Skip to main content

Advertisement

SpringerLink
Log in

Somatostatin analogs for the treatment of neuroendocrine tumors

  • Published:
Cancer and Metastasis Reviews Aims and scope Submit manuscript

Abstract

Somatostatin is an important regulator of endocrine and exocrine secretion, affecting the release of many hormones. The effects of somatostatin are mediated through its interaction with one of five somatostatin receptors. Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) express multiple somatostatin receptors, making them excellent potential therapeutic targets. Many trials have shown that treatment with somatostatin analogs is associated with disease stabilization and prolonged survival. More recently, somatostatin analogs have been shown to have antiproliferative effects, thus broadening the scope of their uses. In this review, we update the current data on the treatment of GEP-NETs with somatostatin analogs, with particular emphasis on the results of the PROMID study. In addition, we discuss the current state of knowledge of novel therapies against GEP-NETs, including the use of somatostatin analogs with broader receptor binding profiles, chimeric somatostatin–dopamine molecules, combinations of somatostatin analogs with other active chemotherapy agents, and peptide receptor-targeted radionuclide therapy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Brazeau, P., Vale, W., Burgus, R., et al. (1973). Hypothalamic polypeptide that inhibits the secretion of immunoreactive pituitary growth hormone. Science, 179(68), 77–79.

    Article  PubMed  CAS  Google Scholar 

  2. Reichlin, S. (1983). Somatostatin. The New England Journal of Medicine, 309(24), 1495–1501.

    Article  PubMed  CAS  Google Scholar 

  3. Serri, O., Brazeau, P., Kachra, Z., et al. (1992). Octreotide inhibits insulin-like growth factor-I hepatic gene expression in the hypophysectomized rat: Evidence for a direct and indirect mechanism of action. Endocrinology, 130(4), 1816–1821.

    Article  PubMed  CAS  Google Scholar 

  4. Epelbaum, J. (1986). Somatostatin in the central nervous system: Physiology and pathological modifications. Progress in Neurobiology, 27(1), 63–100.

    Article  PubMed  CAS  Google Scholar 

  5. Maurer, R., & Reubi, J. C. (1985). Somatostatin receptors. JAMA, 253(18), 2741.

    Article  PubMed  CAS  Google Scholar 

  6. Bruns, C., Raulf, F., Hoyer, D., et al. (1996). Binding properties of somatostatin receptor subtypes. Metabolism, 45(8 Suppl 1), 17–20.

    Article  PubMed  CAS  Google Scholar 

  7. Hoyer, D., Lubbert, H., & Bruns, C. (1994). Molecular pharmacology of somatostatin receptors. Naunyn Schmiedebergs Arch Pharmacol, 350(5), 441–453.

    Article  PubMed  CAS  Google Scholar 

  8. Oberg, K. E., Reubi, J. C., Kwekkeboom, D. J., et al. (2010). Role of somatostatins in gastroenteropancreatic neuroendocrine tumor development and therapy. Gastroenterology, 139(3), 742–753. 753 e1.

    Article  PubMed  Google Scholar 

  9. Bauer, W., Briner, U., Doepfner, W., et al. (1982). SMS 201-995: A very potent and selective octapeptide analogue of somatostatin with prolonged action. Life Sciences, 31(11), 1133–1140.

    Article  PubMed  CAS  Google Scholar 

  10. Murphy, W. A., Lance, V. A., Moreau, S., et al. (1987). Inhibition of rat prostate tumor growth by an octapeptide analog of somatostatin. Life Sciences, 40(26), 2515–2522.

    Article  PubMed  CAS  Google Scholar 

  11. Karashima, T., Cai, R. Z., & Schally, A. V. (1987). Effects of highly potent octapeptide analogs of somatostatin on growth hormone, insulin and glucagon release. Life Sciences, 41(8), 1011–1019.

    Article  PubMed  CAS  Google Scholar 

  12. Mazziotti, G., Floriani, I., Bonadonna, S., et al. (2009). Effects of somatostatin analogs on glucose homeostasis: A metaanalysis of acromegaly studies. The Journal of Clinical Endocrinology and Metabolism, 94(5), 1500–1508.

    Article  PubMed  CAS  Google Scholar 

  13. Strosberg, J., Gardner, N., & Kvols, L. (2009). Survival and prognostic factor analysis of 146 metastatic neuroendocrine tumors of the mid-gut. Neuroendocrinology, 89(4), 471–476.

    Article  PubMed  CAS  Google Scholar 

  14. Arnold, R., Trautmann, M. E., Creutzfeldt, W., et al. (1996). Somatostatin analogue octreotide and inhibition of tumour growth in metastatic endocrine gastroenteropancreatic tumours. Gut, 38(3), 430–438.

    Article  PubMed  CAS  Google Scholar 

  15. Saltz, L., Trochanowski, B., Buckley, M., et al. (1993). Octreotide as an antineoplastic agent in the treatment of functional and nonfunctional neuroendocrine tumors. Cancer, 72(1), 244–248.

    Article  PubMed  CAS  Google Scholar 

  16. Ducreux, M., Ruszniewski, P., Chayvialle, J. A., et al. (2000). The antitumoral effect of the long-acting somatostatin analog lanreotide in neuroendocrine tumors. The American Journal of Gastroenterology, 95(11), 3276–3281.

    Article  PubMed  CAS  Google Scholar 

  17. Wymenga, A. N., Eriksson, B., Salmela, P. I., et al. (1999). Efficacy and safety of prolonged-release lanreotide in patients with gastrointestinal neuroendocrine tumors and hormone-related symptoms. Journal of Clinical Oncology, 17(4), 1111.

    PubMed  CAS  Google Scholar 

  18. Susini, C., & Buscail, L. (2006). Rationale for the use of somatostatin analogs as antitumor agents. Annals of Oncology, 17(12), 1733–1742.

    Article  PubMed  CAS  Google Scholar 

  19. Weckbecker, G., Lewis, I., Albert, R., et al. (2003). Opportunities in somatostatin research: Biological, chemical and therapeutic aspects. Nature Reviews. Drug Discovery, 2(12), 999–1017.

    Article  PubMed  CAS  Google Scholar 

  20. Lattuada, D., Casnici, C., Venuto, A., et al. (2002). The apoptotic effect of somatostatin analogue SMS 201-995 on human lymphocytes. Journal of Neuroimmunology, 133(1–2), 211–216.

    Article  PubMed  CAS  Google Scholar 

  21. Florio, T. (2008). Somatostatin/somatostatin receptor signalling: Phosphotyrosine phosphatases. Molecular and Cellular Endocrinology, 286(1–2), 40–48.

    Article  PubMed  CAS  Google Scholar 

  22. Florio, T., Morini, M., Villa, V., et al. (2003). Somatostatin inhibits tumor angiogenesis and growth via somatostatin receptor-3-mediated regulation of endothelial nitric oxide synthase and mitogen-activated protein kinase activities. Endocrinology, 144(4), 1574–1584.

    Article  PubMed  CAS  Google Scholar 

  23. Hofland, L. J., & Lamberts, S. W. (2003). The pathophysiological consequences of somatostatin receptor internalization and resistance. Endocrine Reviews, 24(1), 28–47.

    Article  PubMed  CAS  Google Scholar 

  24. Bruns, C., Lewis, I., Briner, U., et al. (2002). SOM230: A novel somatostatin peptidomimetic with broad somatotropin release inhibiting factor (SRIF) receptor binding and a unique antisecretory profile. European Journal of Endocrinology, 146(5), 707–716.

    Article  PubMed  CAS  Google Scholar 

  25. Imtiaz, K. E., Monteith, P., & Khaleeli, A. (2000). Complete histological regression of metastatic carcinoid tumour after treatment with octreotide. Clinical Endocrinology (Oxford), 53(6), 755–758.

    Article  CAS  Google Scholar 

  26. Joensuu, H., Katka, K., & Kujari, H. (1992). Dramatic response of a metastatic carcinoid tumour to a combination of interferon and octreotide. Acta Endocrinologica (Copenhagen), 126(2), 184–185.

    CAS  Google Scholar 

  27. Arnold, R., Rinke, A., Klose, K. J., et al. (2005). Octreotide versus octreotide plus interferon-alpha in endocrine gastroenteropancreatic tumors: A randomized trial. Clinical Gastroenterology and Hepatology, 3(8), 761–771.

    Article  PubMed  CAS  Google Scholar 

  28. Faiss, S., Pape, U. F., Bohmig, M., et al. (2003). Prospective, randomized, multicenter trial on the antiproliferative effect of lanreotide, interferon alfa, and their combination for therapy of metastatic neuroendocrine gastroenteropancreatic tumors—the International Lanreotide and Interferon Alfa Study Group. Journal of Clinical Oncology, 21(14), 2689–2696.

    Article  PubMed  CAS  Google Scholar 

  29. Aparicio, T., Ducreux, M., Baudin, E., et al. (2001). Antitumour activity of somatostatin analogues in progressive metastatic neuroendocrine tumours. European Journal of Cancer, 37(8), 1014–1019.

    Article  PubMed  CAS  Google Scholar 

  30. di Bartolomeo, M., Bajetta, E., Buzzoni, R., et al. (1996). Clinical efficacy of octreotide in the treatment of metastatic neuroendocrine tumors. A study by the Italian trials in medical oncology group. Cancer, 77(2), 402–408.

    Article  PubMed  Google Scholar 

  31. Rinke, A., Müller, 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 

  32. Blumberg J, Gómez-Panzani E, Latapie-Martínez S, et al. Somatuline® Autogel® 120 mg (lanreotide) evaluation of tumor progression-free survival in patients with non-functioning entero-pancreatic endocrine tumors: An ongoing, double-blind, randomized, placebo-controlled, multicenter study (the CLARINET Study). NANETS—2010 Neuroendocrine Tumor Symposium (abstr. 726).

  33. Rocheville, M., Lange, D. C., Kumar, U., et al. (2000). Receptors for dopamine and somatostatin: Formation of hetero-oligomers with enhanced functional activity. Science, 288(5463), 154–157.

    Article  PubMed  CAS  Google Scholar 

  34. Schmid, H. A. (2008). Pasireotide (SOM230): Development, mechanism of action and potential applications. Molecular and Cellular Endocrinology, 286(1–2), 69–74.

    Article  PubMed  CAS  Google Scholar 

  35. Van Vugt, H. H., Schmid, H. A., Sailer, A. W. (2008) Ligand-dependent internalization of somatostatin receptors. In: Endocrine abstract. p. 654.

  36. Kvols, L., Wiedenmann, B., Oberg, K., et al. (2006). Safety and efficacy of pasireotide (SOM230) in patients with metastatic carcinoid tumors refractory or resistant to octreotide LAR: Results of a phase II study. Journal of Clinical Oncology (Meeting Abstracts), 24(18_suppl), 4082-.

    Google Scholar 

  37. Lamberts, S. W., van der Lely, A. J., de Herder, W. W., et al. (1996). Octreotide. The New England Journal of Medicine, 334(4), 246–254.

    Article  PubMed  CAS  Google Scholar 

  38. Rocheville, M., Lange, D. C., Kumar, U., et al. (2000). Subtypes of the somatostatin receptor assemble as functional homo- and heterodimers. The Journal of Biological Chemistry, 275(11), 7862–7869.

    Article  PubMed  CAS  Google Scholar 

  39. Saveanu, A., Gunz, G., Dufour, H., et al. (2001). Bim-23244, a somatostatin receptor subtype 2- and 5-selective analog with enhanced efficacy in suppressing growth hormone (GH) from octreotide-resistant human GH-secreting adenomas. The Journal of Clinical Endocrinology and Metabolism, 86(1), 140–145.

    Article  PubMed  CAS  Google Scholar 

  40. Minniti, G., Jaffrain-Rea, M. L., Baldelli, R., et al. (1997). Acute effects of octreotide, cabergoline and a combination of both drugs on GH secretion in acromegalic patients. La Clinica Terapeutica, 148(12), 601–607.

    PubMed  CAS  Google Scholar 

  41. Flogstad, A. K., Halse, J., Grass, P., et al. (1994). A comparison of octreotide, bromocriptine, or a combination of both drugs in acromegaly. The Journal of Clinical Endocrinology and Metabolism, 79(2), 461–465.

    Article  PubMed  CAS  Google Scholar 

  42. Saveanu, A., Lavaque, E., Gunz, G., et al. (2002). Demonstration of enhanced potency of a chimeric somatostatin–dopamine molecule, BIM-23A387, in suppressing growth hormone and prolactin secretion from human pituitary somatotroph adenoma cells. The Journal of Clinical Endocrinology and Metabolism, 87(12), 5545–5552.

    Article  PubMed  CAS  Google Scholar 

  43. Kidd, M., Modlin, I. M., Black, J. W., et al. (2007). A comparison of the effects of gastrin, somatostatin and dopamine receptor ligands on rat gastric enterochromaffin-like cell secretion and proliferation. Regulatory Peptides, 143(1–3), 109–117.

    Article  PubMed  CAS  Google Scholar 

  44. O’Toole, D., Saveanu, A., Couvelard, A., et al. (2006). The analysis of quantitative expression of somatostatin and dopamine receptors in gastro-entero-pancreatic tumours opens new therapeutic strategies. European Journal of Endocrinology, 155(6), 849–857.

    Article  PubMed  Google Scholar 

  45. Hebert, T. E., & Bouvier, M. (1998). Structural and functional aspects of G protein-coupled receptor oligomerization. Biochemistry and Cell Biology, 76(1), 1–11.

    Article  PubMed  CAS  Google Scholar 

  46. Tiensuu Janson, E. M., Ahlstrom, H., Andersson, T., et al. (1992). Octreotide and interferon alfa: A new combination for the treatment of malignant carcinoid tumours. European Journal of Cancer, 28A(10), 1647–1650.

    Article  PubMed  CAS  Google Scholar 

  47. Kolby, L., Persson, G., Franzen, S., et al. (2003). Randomized clinical trial of the effect of interferon alpha on survival in patients with disseminated midgut carcinoid tumours. The British Journal of Surgery, 90(6), 687–693.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  49. Konno, H., Arai, T., Tanaka, T., et al. (1998). Antitumor effect of a neutralizing antibody to vascular endothelial growth factor on liver metastasis of endocrine neoplasm. Japanese Journal of Cancer Research, 89(9), 933–939.

    PubMed  CAS  Google Scholar 

  50. 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 

  51. Yuan, R., Kay, A., Berg, W. J., et al. (2009). Targeting tumorigenesis: Development and use of mTOR inhibitors in cancer therapy. J Hematol Oncol, 2, 45.

    Article  PubMed  Google Scholar 

  52. 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 

  53. Moreno, A., Akcakanat, A., Munsell, M. F., et al. (2008). Antitumor activity of rapamycin and octreotide as single agents or in combination in neuroendocrine tumors. Endocrine-Related Cancer, 15(1), 257–266.

    Article  PubMed  CAS  Google Scholar 

  54. Yao, J. C., Phan, A. T., Chang, D. Z., et al. (2008). Efficacy of RAD001 (everolimus) and octreotide LAR in advanced low- to intermediate-grade neuroendocrine tumors: Results of a phase II study. Journal of Clinical Oncology, 26(26), 4311–4318.

    Article  PubMed  Google Scholar 

  55. Yao, J. C., Lombard-Bohas, C., Baudin, E., et al. (2010). Daily oral everolimus activity in patients with metastatic pancreatic neuroendocrine tumors after failure of cytotoxic chemotherapy: A phase II trial. Journal of Clinical Oncology, 28(1), 69–76.

    Article  PubMed  CAS  Google Scholar 

  56. Behr, T. M., Memtsoudis, S., Sharkey, R. M., et al. (1998). Experimental studies on the role of antibody fragments in cancer radio-immunotherapy: Influence of radiation dose and dose rate on toxicity and anti-tumor efficacy. International Journal of Cancer, 77(5), 787–795.

    Article  CAS  Google Scholar 

  57. Krenning, E. P., Bakker, W. H., Breeman, W. A., et al. (1989). Localisation of endocrine-related tumours with radioiodinated analogue of somatostatin. Lancet, 1(8632), 242–244.

    Article  PubMed  CAS  Google Scholar 

  58. Waldherr, C., Pless, M., Maecke, H. R., et al. (2002). Tumor response and clinical benefit in neuroendocrine tumors after 7.4 GBq (90)Y-DOTATOC. Journal of Nuclear Medicine, 43(5), 610–616.

    PubMed  CAS  Google Scholar 

  59. Appetecchia, M., & Baldelli, R. (2010). Somatostatin analogues in the treatment of gastroenteropancreatic neuroendocrine tumours, current aspects and new perspectives. Journal of Experimental & Clinical Cancer Research, 29, 19.

    Article  Google Scholar 

  60. Heppeler, A., Froidevaux, S., Eberle, A. N., et al. (2000). Receptor targeting for tumor localisation and therapy with radiopeptides. Current Medicinal Chemistry, 7(9), 971–994.

    PubMed  CAS  Google Scholar 

  61. Reubi, J. C. (2003). Peptide receptors as molecular targets for cancer diagnosis and therapy. Endocrine Reviews, 24(4), 389–427.

    Article  PubMed  CAS  Google Scholar 

  62. Valkema, R., De Jong, M., Bakker, W. H., et al. (2002). Phase I study of peptide receptor radionuclide therapy with [In-DTPA]octreotide: The Rotterdam experience. Seminars in Nuclear Medicine, 32(2), 110–122.

    Article  PubMed  Google Scholar 

  63. Henze, M., Schuhmacher, J., Hipp, P., et al. (2001). PET imaging of somatostatin receptors using [68GA]DOTA-D-Phe1-Tyr3-octreotide: First results in patients with meningiomas. Journal of Nuclear Medicine, 42(7), 1053–1056.

    PubMed  CAS  Google Scholar 

  64. Kwekkeboom, D. J., de Herder, W. W., Kam, B. L., et al. (2008). Treatment with the radiolabeled somatostatin analog [177 Lu-DOTA 0, Tyr3]octreotate: Toxicity, efficacy, and survival. Journal of Clinical Oncology, 26(13), 2124–2130.

    Article  PubMed  CAS  Google Scholar 

  65. Teunissen, J. J., Kwekkeboom, D. J., & Krenning, E. P. (2004). Quality of life in patients with gastroenteropancreatic tumors treated with [177Lu-DOTA0, Tyr3]octreotate. Journal of Clinical Oncology, 22(13), 2724–2729.

    Article  PubMed  CAS  Google Scholar 

  66. van Essen, M., Krenning, E. P., Kam, B. L., et al. (2008). Report on short-term side effects of treatments with 177Lu-octreotate in combination with capecitabine in seven patients with gastroenteropancreatic neuroendocrine tumours. European Journal of Nuclear Medicine and Molecular Imaging, 35(4), 743–748.

    Article  PubMed  Google Scholar 

  67. Arnold, R., Benning, R., Neuhaus, C., et al. (1993). Gastroenteropancreatic endocrine tumours: Effect of Sandostatin® on tumour growth. Digestion, 54(Suppl. 1), 72.

    Article  PubMed  Google Scholar 

  68. Eriksson, B., Renstrup, J., Imam, H., et al. (1997). High-dose treatment with lanreotide of patients with advanced neuroendocrine gastrointestinal tumors: Clinical and biological effects. Annals of Oncology, 8(10), 1041–1044.

    Article  PubMed  CAS  Google Scholar 

  69. Ricci, S., Antonuzzo, A., Galli, L., et al. (2000). Long-acting depot lanreotide in the treatment of patients with advanced neuroendocrine tumors. American Journal of Clinical Oncology, 23(4), 412–415.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors acknowledge Dr. Fernando Sánchez-Barbero from HealthCo SL (Madrid, Spain) for his assistance in the preparation of this manuscript and Pfizer Spain for the financial support of medical writing services.

Conflicts of interest

The authors declare that they do not have any conflict of interest that may inappropriately influence this work. Michael Culler is an employee of IPSEN.

Author information

Authors and Affiliations

  1. Endocrinology Research, IPSEN, 27 Maple Street, Milford, MA, 01757, USA

    Michael D. Culler

  2. Oncology and Endocrinology Department, Uppsala University Hospital, Uppsala, Sweden

    Kjell Öberg

  3. Philipps University, Marburg, Munich, Germany

    Rudolf Arnold

  4. Nuclear Medicine and Internal Medicine Department, University Hospital and Erasmus University, Rotterdam, The Netherlands

    Eric P. Krenning

  5. Medical Oncology Department, University Hospital Vírgen de la Victoria, Málaga, Spain

    Isabel Sevilla

  6. Endocrinology and Nutrition Department, University Hospital San Carlos, Madrid, Spain

    José Ángel Díaz

Authors
  1. Michael D. Culler
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kjell Öberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Rudolf Arnold
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Eric P. Krenning
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Isabel Sevilla
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. José Ángel Díaz
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michael D. Culler.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Culler, M.D., Öberg, K., Arnold, R. et al. Somatostatin analogs for the treatment of neuroendocrine tumors. Cancer Metastasis Rev 30 (Suppl 1), 9–17 (2011). https://doi.org/10.1007/s10555-011-9293-0

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10555-011-9293-0

Keywords

Search

Navigation