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  • Review Article
  • Published:

Current and emerging therapies for PNETs in patients with or without MEN1

Nature Reviews Endocrinology volume 14, pages 216–227 (2018)Cite this article

Subjects

Key Points

  • Patients with multiple endocrine neoplasia type 1 (MEN1) can develop hormone-secreting and non-hormone-secreting tumours in endocrine organs, including in the pancreas, which decreases their life expectancy substantially

  • Pancreatic neuroendocrine tumours (PNETs) in patients with MEN1 are especially difficult to treat owing to differences in growth potential, concomitant development of other tumours and relative insensitivity to treatment

  • Current medical, surgical and radiological treatments for MEN1-related PNETs have not been formally assessed but instead have been used on the basis of their effects on PNETs in patients without MEN1

  • Therapies targeting MEN1-related tumours are required, and preclinical studies indicate that gene therapy, epigenetic modifiers, and wingless (WNT) pathway and vascular endothelial growth factor (VEGF)-signalling antagonists might be promising treatments

  • Chemoprevention aimed at reducing or delaying the occurrence of MEN1-related PNETs might be possible by chronic administration of somatostatin analogues, which have anti-proliferative and anti-secretory actions

Abstract

Pancreatic neuroendocrine tumours (PNETs) might occur as a non-familial isolated endocrinopathy or as part of a complex hereditary syndrome, such as multiple endocrine neoplasia type 1 (MEN1). MEN1 is an autosomal dominant disorder characterized by the combined occurrence of PNETs with tumours of the parathyroids and anterior pituitary. Treatments for primary PNETs include surgery. Treatments for non-resectable PNETs and metastases include biotherapy (for example, somatostatin analogues, inhibitors of receptors and monoclonal antibodies), chemotherapy and radiological therapy. All these treatments are effective for PNETs in patients without MEN1; however, there is a scarcity of clinical trials reporting the efficacy of the same treatments of PNETs in patients with MEN1. Treatment of PNETs in patients with MEN1 is challenging owing to the concomitant development of other tumours, which might have metastasized. In recent years, preclinical studies have identified potential new therapeutic targets for treating MEN1-associated neuroendocrine tumours (including PNETs), and these include epigenetic modification, the β-catenin–wingless (WNT) pathway, Hedgehog signalling, somatostatin receptors and MEN1 gene replacement therapy. This Review discusses these advances.

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Figure 1: Current treatments for PNETs.
Figure 2: Distribution of endocrine and non-endocrine tumours in patients with MEN1.
Figure 3: Menin-associated pathways with potential targeted therapies.

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References

  1. Dasari, A. et al. Trends in the incidence, prevalence, and survival outcomes in patients with neuroendocrine tumors in the United States. JAMA Oncol. 3, 1335–1342 (2017).

    PubMed  PubMed Central  Google Scholar 

  2. Halfdanarson, T. R., Rabe, K. G., Rubin, J. & Petersen, G. M. Pancreatic neuroendocrine tumors (PNETs): incidence, prognosis and recent trend toward improved survival. Ann. Oncol. 19, 1727–1733 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Lepage, C. et al. Incidence and management of malignant digestive endocrine tumours in a well defined French population. Gut 53, 549–553 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Anlauf, M. et al. Hereditary neuroendocrine tumors of the gastroenteropancreatic system. Virchows Arch. 451 (Suppl. 1), S29–S38 (2007).

    PubMed  Google Scholar 

  5. Falconi, M. et al. ENETS Consensus Guidelines Update for the management of patients with functional pancreatic neuroendocrine tumors and non-functional pancreatic neuroendocrine tumors. Neuroendocrinology 103, 153–171 (2016).

    CAS  PubMed  Google Scholar 

  6. Pea, A., Hruban, R. H. & Wood, L. D. Genetics of pancreatic neuroendocrine tumors: implications for the clinic. Expert Rev. Gastroenterol. Hepatol. 9, 1407–1419 (2015).

    PubMed  PubMed Central  Google Scholar 

  7. Marx, S. J. & Simonds, W. F. Hereditary hormone excess: genes, molecular pathways, and syndromes. Endocr. Rev. 26, 615–661 (2005).

    CAS  PubMed  Google Scholar 

  8. Lemos, M. C. & Thakker, R. V. Multiple endocrine neoplasia type 1 (MEN1): analysis of 1336 mutations reported in the first decade following identification of the gene. Hum. Mutat. 29, 22–32 (2008).

    CAS  PubMed  Google Scholar 

  9. Jiao, Y. et al. DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuro-endocrine tumors. Science 331, 1199–1203 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Scarpa, A. et al. Whole-genome landscape of pancreatic neuroendocrine tumours. Nature 543, 65–71 (2017).

    CAS  PubMed  Google Scholar 

  11. Thakker, R. V. Multiple endocrine neoplasia type 1 (MEN1) and type 4 (MEN4). Mol. Cell. Endocrinol. 386, 2–15 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Dreijerink, K. M., Goudet, P., Burgess, J. R. & Valk, G. D. Breast-cancer predisposition in multiple endocrine neoplasia type 1. N. Engl. J. Med. 371, 583–584 (2014).

    PubMed  PubMed Central  Google Scholar 

  13. Marx, S. et al. Multiple endocrine neoplasia type 1: clinical and genetic topics. Ann. Intern. Med. 129, 484–494 (1998).

    CAS  PubMed  Google Scholar 

  14. Schaaf, L. et al. Developing effective screening strategies in multiple endocrine neoplasia type 1 (MEN 1) on the basis of clinical and sequencing data of German patients with MEN 1. Exp. Clin. Endocrinol. Diabetes 115, 509–517 (2007).

    CAS  PubMed  Google Scholar 

  15. Yates, C. J., Newey, P. J. & Thakker, R. V. Challenges and controversies in management of pancreatic neuroendocrine tumours in patients with MEN1. Lancet Diabetes Endocrinol. 3, 895–905 (2015).

    PubMed  Google Scholar 

  16. Frilling, A. et al. Neuroendocrine tumor disease: an evolving landscape. Endocr. Relat. Cancer 19, R163–R185 (2012).

    CAS  PubMed  Google Scholar 

  17. Thakker, R. V. et al. Clinical practice guidelines for multiple endocrine neoplasia type 1 (MEN1). J. Clin. Endocrinol. Metab. 97, 2990–3011 (2012).

    CAS  PubMed  Google Scholar 

  18. Dean, P. G. et al. Are patients with multiple endocrine neoplasia type I prone to premature death? World J. Surg. 24, 1437–1441 (2000).

    CAS  PubMed  Google Scholar 

  19. Bassett, J. H. et al. Characterization of mutations in patients with multiple endocrine neoplasia type 1. Am. J. Hum. Genet. 62, 232–244 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Concolino, P., Costella, A. & Capoluongo, E. Multiple endocrine neoplasia type 1 (MEN1): an update of 208 new germline variants reported in the last nine years. Cancer Genet. 209, 36–41 (2016).

    PubMed  Google Scholar 

  21. Goudet, P. et al. Risk factors and causes of death in MEN1 disease. A GTE (Groupe d'Etude des Tumeurs Endocrines) cohort study among 758 patients. World J. Surg. 34, 249–255 (2010).

    PubMed  Google Scholar 

  22. Ito, T., Igarashi, H., Uehara, H., Berna, M. J. & Jensen, R. T. Causes of death and prognostic factors in multiple endocrine neoplasia type 1: a prospective study: comparison of 106 MEN1/Zollinger-Ellison syndrome patients with 1613 literature MEN1 patients with or without pancreatic endocrine tumors. Med. (Baltimore) 92, 135–181 (2013).

    CAS  Google Scholar 

  23. Pieterman, C. R. et al. Multiple endocrine neoplasia type 1 (MEN1): its manifestations and effect of genetic screening on clinical outcome. Clin. Endocrinol. (Oxf.) 70, 575–581 (2009).

    CAS  Google Scholar 

  24. Newey, P. J. et al. Asymptomatic children with multiple endocrine neoplasia type 1 mutations may harbor nonfunctioning pancreatic neuroendocrine tumors. J. Clin. Endocrinol. Metab. 94, 3640–3646 (2009).

    CAS  PubMed  Google Scholar 

  25. Jensen, R. T., Berna, M. J., Bingham, D. B. & Norton, J. A. Inherited pancreatic endocrine tumor syndromes: advances in molecular pathogenesis, diagnosis, management, and controversies. Cancer 113, 1807–1843 (2008).

    PubMed  Google Scholar 

  26. Conemans, E. B. et al. Prognostic factors for survival of MEN1 patients with duodenopancreatic tumours metastatic to the liver: results from the DMSG. Endocr. Pract. 23, 641–648 (2017).

    PubMed  Google Scholar 

  27. Akerstrom, G. & Hellman, P. Surgery on neuroendocrine tumours. Best Pract. Res. Clin. Endocrinol. Metab. 21, 87–109 (2007).

    PubMed  Google Scholar 

  28. Jensen, R. T. Management of the Zollinger–Ellison syndrome in patients with multiple endocrine neoplasia type 1. J. Intern. Med. 243, 477–488 (1998).

    CAS  PubMed  Google Scholar 

  29. Trouillas, J. et al. Pituitary tumors and hyperplasia in multiple endocrine neoplasia type 1 syndrome (MEN1): a case-control study in a series of 77 patients versus 2509 non-MEN1 patients. Am. J. Surg. Pathol. 32, 534–543 (2008).

    PubMed  Google Scholar 

  30. Fraenkel, M., Kim, M. K., Faggiano, A. & Valk, G. D. Epidemiology of gastroenteropancreatic neuroendocrine tumours. Best Pract. Res. Clin. Gastroenterol. 26, 691–703 (2012).

    CAS  PubMed  Google Scholar 

  31. Rindi, G. et al. TNM staging of neoplasms of the endocrine pancreas: results from a large international cohort study. J. Natl Cancer Institute 104, 764–777 (2012).

    CAS  Google Scholar 

  32. Cakir, M., Dworakowska, D. & Grossman, A. Somatostatin receptor biology in neuroendocrine and pituitary tumours: part 1 — molecular pathways. J. Cell. Mol. Med. 14, 2570–2584 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Schmid, H. A. & Silva, A. P. Short- and long-term effects of octreotide and SOM230 on GH, IGF-I, ACTH, corticosterone and ghrelin in rats. J. Endocrinol. Invest. 28, 28–35 (2005).

    CAS  PubMed  Google Scholar 

  34. Walter, T., Brixi-Benmansour, H., Lombard-Bohas, C. & Cadiot, G. New treatment strategies in advanced neuroendocrine tumours. Dig. Liver Dis. 44, 95–105 (2012).

    CAS  PubMed  Google Scholar 

  35. Martin-Richard, M. et al. Antiproliferative effects of lanreotide autogel in patients with progressive, well-differentiated neuroendocrine tumours: a Spanish, multicentre, open-label, single arm phase II study. BMC Cancer 13, 427 (2013).

    PubMed  PubMed Central  Google Scholar 

  36. Palazzo, M. et al. Ki67 proliferation index, hepatic tumor load, and pretreatment tumor growth predict the antitumoral efficacy of lanreotide in patients with malignant digestive neuroendocrine tumors. Eur. J. Gastroenterol. Hepatol. 25, 232–238 (2013).

    CAS  PubMed  Google Scholar 

  37. Caplin, M. E. et al. Lanreotide in metastatic enteropancreatic neuroendocrine tumors. N. Engl. J. Med. 371, 224–233 (2014).

    PubMed  Google Scholar 

  38. Caplin, M. E. et al. Anti-tumour effects of lanreotide for pancreatic and intestinal neuroendocrine tumours: the CLARINET open-label extension study. Endocr. Relat. Cancer 23, 191–199 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Ramundo, V. et al. Impact of long-acting octreotide in patients with early-stage MEN1-related duodeno-pancreatic neuroendocrine tumours. Clin. Endocrinol. (Oxf.) 80, 850–855 (2014).

    CAS  Google Scholar 

  40. Yao, J. C. et al. Everolimus for advanced pancreatic neuroendocrine tumors. N. Engl. J. Med. 364, 514–523 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Lombard-Bohas, C. et al. Impact of prior chemotherapy use on the efficacy of everolimus in patients with advanced pancreatic neuroendocrine tumors: a subgroup analysis of the phase III RADIANT-3 trial. Pancreas 44, 181–189 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Yao, J. C. et al. Everolimus for the treatment of advanced pancreatic neuroendocrine tumors: overall survival and circulating biomarkers from the randomized, phase III RADIANT-3 study. J. Clin. Oncol. 34, 3906–3913 (2016).

    PubMed  PubMed Central  Google Scholar 

  43. Oh, D. Y. et al. Phase 2 study of everolimus monotherapy in patients with nonfunctioning neuroendocrine tumors or pheochromocytomas/paragangliomas. Cancer 118, 6162–6170 (2012).

    CAS  PubMed  Google Scholar 

  44. Hanahan, D., Christofori, G., Naik, P. & Arbeit, J. Transgenic mouse models of tumour angiogenesis: the angiogenic switch, its molecular controls, and prospects for preclinical therapeutic models. Eur. J. Cancer 32A, 2386–2393 (1996).

    CAS  PubMed  Google Scholar 

  45. Scoazec, J. Y. Angiogenesis in neuroendocrine tumors: therapeutic applications. Neuroendocrinology 97, 45–56 (2013).

    CAS  PubMed  Google Scholar 

  46. Raymond, E. et al. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N. Engl. J. Med. 364, 501–513 (2011).

    CAS  PubMed  Google Scholar 

  47. Ahn, H. K. et al. Phase II study of pazopanib monotherapy in metastatic gastroenteropancreatic neuroendocrine tumours. Br. J. Cancer 109, 1414–1419 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Pavel, M. E. et al. Everolimus plus octreotide long-acting repeatable for the treatment of advanced neuroendocrine tumours associated with carcinoid syndrome (RADIANT-2): a randomised, placebo-controlled, phase 3 study. Lancet 378, 2005–2012 (2011).

    CAS  PubMed  Google Scholar 

  49. Phan, A. T. et al. Pazopanib and depot octreotide in advanced, well-differentiated neuroendocrine tumours: a multicentre, single-group, phase 2 study. Lancet Oncol. 16, 695–703 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Hobday, T. J. et al. Multicenter phase II trial of temsirolimus and bevacizumab in pancreatic neuroendocrine tumors. J. Clin. Oncol. 33, 1551–1556 (2015).

    CAS  PubMed  Google Scholar 

  51. Kulke, M. Randomized phase II study of everolimus (E) versus everolimus plus bevacizumab (E + B) in patients (Pts) with locally advanced or metastatic pancreatic neuroendocrine tumors (pNET), CALGB 80701 (Alliance) [abstract]. J. Clin Oncol 33, 4005 (2015).

    Google Scholar 

  52. Yao, J. C. et al. Perfusion computed tomography as functional biomarker in randomized run-in study of bevacizumab and everolimus in well-differentiated neuroendocrine tumors. Pancreas 44, 190–197 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Chan, J. A. et al. Phase I study of pasireotide (SOM 230) and everolimus (RAD001) in advanced neuroendocrine tumors. Endocr. Relat. Cancer 19, 615–623 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Cives, M. et al. Phase II clinical trial of pasireotide long-acting repeatable in patients with metastatic neuroendocrine tumors. Endocr. Relat. Cancer 22, 1–9 (2015).

    CAS  PubMed  Google Scholar 

  55. Yao, J. C. et al. Phase I dose-escalation study of long-acting pasireotide in patients with neuroendocrine tumors. OncoTargets Ther. 10, 3177–3186 (2017).

    Google Scholar 

  56. Faiss, S. et al. 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. J. Clin. Oncol. 21, 2689–2696 (2003).

    CAS  PubMed  Google Scholar 

  57. 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 13, 135–149 (2006).

    PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  59. Reidy-Lagunes, D. L. et al. A phase 2 study of the insulin-like growth factor-1 receptor inhibitor MK-0646 in patients with metastatic, well-differentiated neuroendocrine tumors. Cancer 118, 4795–4800 (2012).

    CAS  PubMed  Google Scholar 

  60. Strosberg, J. R. et al. A multi-institutional, phase II open-label study of ganitumab (AMG 479) in advanced carcinoid and pancreatic neuroendocrine tumors. Endocr. Relat. Cancer 20, 383–390 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Dasari, A. et al. Phase I study of the anti-IGF1R antibody cixutumumab with everolimus and octreotide in advanced well-differentiated neuroendocrine tumors. Endocr. Relat. Cancer 22, 431–441 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Bendell, J. C. et al. A phase II study of the combination of bevacizumab, pertuzumab, and octreotide lar for patients with advanced neuroendocrine cancers. Cancer Invest. 34, 213–219 (2016).

    CAS  PubMed  Google Scholar 

  63. Fazio, N. et al. A phase II study of BEZ235 in patients with everolimus-resistant, advanced pancreatic neuroendocrine tumours. Anticancer Res. 36, 713–719 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Pavel, M. et al. ENETS Consensus Guidelines for the management of patients with liver and other distant metastases from neuroendocrine neoplasms of foregut, midgut, hindgut, and unknown primary. Neuroendocrinology 95, 157–176 (2012).

    CAS  PubMed  Google Scholar 

  65. Strosberg, J. Advances in the treatment of pancreatic neuroendocrine tumors (pNETs). Gastrointest. Cancer Res. 6, S10–S12 (2013).

    PubMed  PubMed Central  Google Scholar 

  66. Hammel, P. et al. New treatment options with cytotoxic agents in neuroendocrine tumours. Target Oncol. 7, 169–172 (2012).

    PubMed  Google Scholar 

  67. Moertel, C. G., Hanley, J. A. & Johnson, L. A. Streptozocin alone compared with streptozocin plus fluorouracil in the treatment of advanced islet-cell carcinoma. N. Engl. J. Med. 303, 1189–1194 (1980).

    CAS  PubMed  Google Scholar 

  68. Moertel, C. G., Lefkopoulo, M., Lipsitz, S., Hahn, R. G. & Klaassen, D. Streptozocin-doxorubicin, streptozocin-fluorouracil or chlorozotocin in the treatment of advanced islet-cell carcinoma. N. Engl. J. Med. 326, 519–523 (1992).

    CAS  PubMed  Google Scholar 

  69. Kouvaraki, M. A. et al. Fluorouracil, doxorubicin, and streptozocin in the treatment of patients with locally advanced and metastatic pancreatic endocrine carcinomas. J. Clin. Oncol. 22, 4762–4771 (2004).

    CAS  PubMed  Google Scholar 

  70. Ekeblad, S. et al. Temozolomide as monotherapy is effective in treatment of advanced malignant neuroendocrine tumors. Clin. Cancer Res. 13, 2986–2991 (2007).

    CAS  PubMed  Google Scholar 

  71. Isacoff, W. H., Moss, R. A., Pecora, A. L. & Fine, R. L. Temozolomide/capecitabine therapy for metastatic neuroendocrine tumors of the pancreas. A retrospective review. J. Clin. Oncol. 24, 14023–14023 (2006).

    Google Scholar 

  72. Chan, J. A. et al. A prospective, phase 1/2 study of everolimus and temozolomide in patients with advanced pancreatic neuroendocrine tumor. Cancer 119, 3212–3218 (2013).

    CAS  PubMed  Google Scholar 

  73. Ducreux, M. et al. Bevacizumab combined with 5-FU/streptozocin in patients with progressive metastatic well-differentiated pancreatic endocrine tumours (BETTER trial) — a phase II non-randomised trial. Eur. J. Cancer 50, 3098–3106 (2014).

    CAS  PubMed  Google Scholar 

  74. Berruti, A. et al. Bevacizumab plus octreotide and metronomic capecitabine in patients with metastatic well-to-moderately differentiated neuroendocrine tumors: the XELBEVOCT study. BMC Cancer 14, 184 (2014).

    PubMed  PubMed Central  Google Scholar 

  75. Chan, J. A. et al. Prospective study of bevacizumab plus temozolomide in patients with advanced neuroendocrine tumors. J. Clin. Oncol. 30, 2963–2968 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Anlauf, M. et al. Microadenomatosis of the endocrine pancreas in patients with and without the multiple endocrine neoplasia type 1 syndrome. Am. J. Surg. Pathol. 30, 560–574 (2006).

    PubMed  Google Scholar 

  77. Trump, D. et al. Clinical studies of multiple endocrine neoplasia type 1 (MEN1). QJM 89, 653–669 (1996).

    CAS  PubMed  Google Scholar 

  78. Anlauf, M. et al. Primary lymph node gastrinoma or occult duodenal microgastrinoma with lymph node metastases in a MEN1 patient: the need for a systematic search for the primary tumor. Am. J. Surg. Pathol. 32, 1101–1105 (2008).

    PubMed  Google Scholar 

  79. Lowney, J. K., Frisella, M. M., Lairmore, T. C. & Doherty, G. M. Pancreatic islet cell tumor metastasis in multiple endocrine neoplasia type 1: correlation with primary tumor size. Surgery 124, 1043–1048 (1998).

    CAS  PubMed  Google Scholar 

  80. Triponez, F. et al. Is surgery beneficial for MEN1 patients with small (≤2 cm), nonfunctioning pancreaticoduodenal endocrine tumor? An analysis of 65 patients from the GTE. World J. Surg. 30, 654–662 (2006).

    PubMed  Google Scholar 

  81. Sakurai, A. et al. Long-term follow-up of patients with multiple endocrine neoplasia type 1. Endocr. J. 54, 295–302 (2007).

    PubMed  Google Scholar 

  82. Norton, J. A. Surgical treatment and prognosis of gastrinoma. Best Pract. Res. Clin. Gastroenterol. 19, 799–805 (2005).

    PubMed  Google Scholar 

  83. Norton, J. A. et al. Surgery to cure the Zollinger–Ellison syndrome. N. Engl. J. Med. 341, 635–644 (1999).

    CAS  PubMed  Google Scholar 

  84. Cadiot, G. et al. Prognostic factors in patients with Zollinger-Ellison syndrome and multiple endocrine neoplasia type 1. Groupe d'Etude des Neoplasies Endocriniennes Multiples (GENEM and groupe de Recherche et d'Etude du Syndrome de Zollinger-Ellison (GRESZE). Gastroenterology 116, 286–293 (1999).

    CAS  PubMed  Google Scholar 

  85. Wells, S. A., Norton, J. A., Thompson, N. W. & Friesen, S. R. Comparison of surgical results in patients with advanced and limited disease with multiple endocrine neoplasia type 1 and Zollinger-Ellison syndrome — Discussion. Ann. Surg. 234, 505–506 (2001).

    Google Scholar 

  86. van Essen, M. et al. Peptide-receptor radionuclide therapy for endocrine tumors. Nat. Rev. Endocrinology 5, 382–393 (2009).

    CAS  PubMed  Google Scholar 

  87. Bodei, L. et al. Peptide receptor radionuclide therapy with 177Lu-DOTATATE: the IEO phase I-II study. Eur. J. Nucl. Med. Mol. Imaging 38, 2125–2135 (2011).

    CAS  PubMed  Google Scholar 

  88. Claringbold, P. G., Price, R. A. & Turner, J. H. Phase I-II study of radiopeptide 177Lu-octreotate in combination with capecitabine and temozolomide in advanced low-grade neuroendocrine tumors. Cancer Biother. Radiopharm. 27, 561–569 (2012).

    CAS  PubMed  Google Scholar 

  89. Ezziddin, S. et al. Outcome of peptide receptor radionuclide therapy with 177Lu-octreotate in advanced grade 1/2 pancreatic neuroendocrine tumours. Eur. J. Nucl. Med. Mol. Imag. 41, 925–933 (2014).

    CAS  Google Scholar 

  90. Imhof, A. et al. Response, survival, and long-term toxicity after therapy with the radiolabeled somatostatin analogue [90Y-DOTA]-TOC in metastasized neuroendocrine cancers. J. Clin. Oncol. 29, 2416–2423 (2011).

    CAS  PubMed  Google Scholar 

  91. Sansovini, M. et al. Treatment with the radiolabelled somatostatin analog Lu-DOTATATE for advanced pancreatic neuroendocrine tumors. Neuroendocrinology 97, 347–354 (2013).

    CAS  PubMed  Google Scholar 

  92. Villard, L. et al. Cohort study of somatostatin-based radiopeptide therapy with [90Y-DOTA]-TOC versus [90Y-DOTA]-TOC plus [177Lu-DOTA]-TOC in neuroendocrine cancers. J. Clin. Oncol. 30, 1100–1106 (2012).

    CAS  PubMed  Google Scholar 

  93. Bhagat, N. et al. Phase II study of chemoembolization with drug-eluting beads in patients with hepatic neuroendocrine metastases: high incidence of biliary injury. Cardiovasc. Intervent Radiol 36, 449–459 (2013).

    PubMed  Google Scholar 

  94. Fiore, F. et al. Transarterial embolization (TAE) is equally effective and slightly safer than transarterial chemoembolization (TACE) to manage liver metastases in neuroendocrine tumors. Endocr 47, 177–182 (2014).

    CAS  Google Scholar 

  95. Gamblin, T. C., Christians, K. & Pappas, S. G. Radiofrequency ablation of neuroendocrine hepatic metastasis. Surg. Oncol. Clin. N. Am. 20, 273–279 (2011).

    PubMed  Google Scholar 

  96. Gaur, S. K. et al. Hepatic arterial chemoembolization using drug-eluting beads in gastrointestinal neuroendocrine tumor metastatic to the liver. Cardiovasc. Intervent Radiol 34, 566–572 (2011).

    PubMed  Google Scholar 

  97. Orgera, G. et al. Current status of interventional radiology in the management of gastro-entero-pancreatic neuroendocrine tumours (GEP-NETs). Cardiovasc. Intervent Radiol 38, 13–24 (2015).

    PubMed  Google Scholar 

  98. Peppa, M. et al. Embolization as an alternative treatment of insulinoma in a patient with multiple endocrine neoplasia type 1 syndrome. Cardiovasc. Intervent Radiol 32, 807–811 (2009).

    PubMed  Google Scholar 

  99. Rossi, S. et al. Radiofrequency ablation of pancreatic neuroendocrine tumors: a pilot study of feasibility, efficacy, and safety. Pancreas 43, 938–945 (2014).

    PubMed  Google Scholar 

  100. Strosberg, J. R. et al. A phase II clinical trial of sunitinib following hepatic transarterial embolization for metastatic neuroendocrine tumors. Ann. Oncol. 23, 2335–2341 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Barbier, C. E., Garske-Roman, U., Sandstrom, M., Nyman, R. & Granberg, D. Selective internal radiation therapy in patients with progressive neuroendocrine liver metastases. Eur. J. Nucl. Med. Mol. Imag. 43, 1425–1431 (2016).

    CAS  Google Scholar 

  102. Wiedemann, T. & Pellegata, N. S. Animal models of multiple endocrine neoplasia. Mol. Cell. Endocrinol. 421, 49–59 (2016).

    CAS  PubMed  Google Scholar 

  103. Bertolino, P., Tong, W. M., Galendo, D., Wang, Z. Q. & Zhang, C. X. Heterozygous Men1 mutant mice develop a range of endocrine tumors mimicking multiple endocrine neoplasia type 1. Mol. Endocrinol. 17, 1880–1892 (2003).

    CAS  PubMed  Google Scholar 

  104. Bertolino, P. et al. Pancreatic beta-cell-specific ablation of the multiple endocrine neoplasia type 1 (MEN1) gene causes full penetrance of insulinoma development in mice. Cancer Res. 63, 4836–4841 (2003).

    CAS  PubMed  Google Scholar 

  105. Biondi, C. A. et al. Conditional inactivation of the MEN1 gene leads to pancreatic and pituitary tumorigenesis but does not affect normal development of these tissues. Mol. Cell. Biol. 24, 3125–3131 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Crabtree, J. S. et al. A mouse model of multiple endocrine neoplasia, type 1, develops multiple endocrine tumors. Proc. Natl Acad. Sci. USA 98, 1118–1123 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Crabtree, J. S. et al. Of mice and MEN1: insulinomas in a conditional mouse knockout. Mol. Cell. Biol. 23, 6075–6085 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Gannon, M., Shiota, C., Postic, C., Wright, C. V. & Magnuson, M. Analysis of the Cre-mediated recombination driven by rat insulin promoter in embryonic and adult mouse pancreas. Genesis 26, 139–142 (2000).

    CAS  PubMed  Google Scholar 

  109. Harding, B. et al. Multiple endocrine neoplasia type 1 knockout mice develop parathyroid, pancreatic, pituitary and adrenal tumours with hypercalcaemia, hypophosphataemia and hypercorticosteronaemia. Endocr. Relat. Cancer 16, 1313–1327 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Li, F. et al. Conditional deletion of Men1 in the pancreatic beta-cell leads to glucagon-expressing tumor development. Endocrinology 156, 48–57 (2015).

    PubMed  Google Scholar 

  111. Loffler, K. A. et al. Broad tumor spectrum in a mouse model of multiple endocrine neoplasia type 1. Int. J. Cancer 120, 259–267 (2007).

    CAS  PubMed  Google Scholar 

  112. Cao, Y. et al. Nuclear-cytoplasmic shuttling of menin regulates nuclear translocation of β-catenin. Mol. Cell. Biol. 29, 5477–5487 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Huang, J. et al. The same pocket in menin binds both MLL and JUND but has opposite effects on transcription. Nature 482, 542–546 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Matkar, S., Thiel, A. & Hua, X. Menin: a scaffold protein that controls gene expression and cell signaling. Trends Biochem. Sci. 38, 394–402 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Klaus, A. & Birchmeier, W. Wnt signalling and its impact on development and cancer. Nat. Rev. Cancer 8, 387–398 (2008).

    CAS  PubMed  Google Scholar 

  116. Agarwal, S. K. et al. Menin interacts with the AP1 transcription factor JunD and represses JunD-activated transcription. Cell 96, 143–152 (1999).

    CAS  PubMed  Google Scholar 

  117. Agarwal, S. K. et al. Transcription factor JunD, deprived of menin, switches from growth suppressor to growth promoter. Proc. Natl Acad. Sci. USA 100, 10770–10775 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Gurung, B. et al. Menin epigenetically represses Hedgehog signaling in MEN1 tumor syndrome. Cancer Res. 73, 2650–2658 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Hughes, C. M. et al. Menin associates with a trithorax family histone methyltransferase complex and with the hoxc8 locus. Mol. Cell 13, 587–597 (2004).

    CAS  PubMed  Google Scholar 

  120. Milne, T. A. et al. Menin and MLL cooperatively regulate expression of cyclin-dependent kinase inhibitors. Proc. Natl Acad. Sci. USA 102, 749–754 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Attisano, L. & Wrana, J. L. Signal transduction by the TGF-β superfamily. Science 296, 1646–1647 (2002).

    CAS  PubMed  Google Scholar 

  122. Hendy, G. N., Kaji, H., Sowa, H., Lebrun, J. J. & Canaff, L. Menin and TGF-beta superfamily member signaling via the Smad pathway in pituitary, parathyroid and osteoblast. Horm. Metab. Res. 37, 375–379 (2005).

    CAS  PubMed  Google Scholar 

  123. Canaff, L., Vanbellinghen, J. F., Kaji, H., Goltzman, D. & Hendy, G. N. Impaired transforming growth factor-beta (TGF-β) transcriptional activity and cell proliferation control of a menin in-frame deletion mutant associated with multiple endocrine neoplasia type 1 (MEN1). J. Biol. Chem. 287, 8584–8597 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Heppner, C. et al. The tumor suppressor protein menin interacts with NF-kappaB proteins and inhibits NF-kappaB-mediated transactivation. Oncogene 20, 4917–4925 (2001).

    CAS  PubMed  Google Scholar 

  125. Wu, Y. et al. Interplay between menin and K-Ras in regulating lung adenocarcinoma. J. Biol. Chem. 287, 40003–40011 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Chamberlain, C. E. et al. Menin determines K-RAS proliferative outputs in endocrine cells. J. Clin. Invest. 124, 4093–4101 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Patel, Y. C. Somatostatin and its receptor family. Front. Neuroendocrinol. 20, 157–198 (1999).

    CAS  PubMed  Google Scholar 

  128. Gallo, A. et al. Menin uncouples Elk-1, JunD and c-Jun phosphorylation from MAP kinase activation. Oncogene 21, 6434–6445 (2002).

    CAS  PubMed  Google Scholar 

  129. Wang, Y. et al. The tumor suppressor protein menin inhibits AKT activation by regulating its cellular localization. Cancer Res. 71, 371–382 (2011).

    CAS  PubMed  Google Scholar 

  130. Bill, R. et al. Nintedanib is a highly effective therapeutic for neuroendocrine carcinoma of the pancreas (PNET) in the Rip1Tag2 transgenic mouse model. Clin. Cancer Res. 21, 4856–4867 (2015).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  132. Jiang, X. et al. Targeting beta-catenin signaling for therapeutic intervention in MEN1-deficient pancreatic neuroendocrine tumours. Nat. Commun. 5, 5809 (2014).

    CAS  PubMed  Google Scholar 

  133. Lines, K. E. et al. A MEN1 pancreatic neuroendocrine tumour mouse model under temporal control. Endocr. Connect. 6, 232–242 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Quinn, T. J. et al. Pasireotide (SOM230) is effective for the treatment of pancreatic neuroendocrine tumors (PNETs) in a multiple endocrine neoplasia type 1 (MEN1) conditional knockout mouse model. Surgery 152, 1068–1077 (2012).

    PubMed  Google Scholar 

  135. Smith, T. L. et al. AAVP displaying octreotide for ligand-directed therapeutic transgene delivery in neuroendocrine tumors of the pancreas. Proc. Natl Acad. Sci. USA 113, 2466–2471 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Walls, G. V. et al. MEN1 gene replacement therapy reduces proliferation rates in a mouse model of pituitary adenomas. Cancer Res. 72, 5060–5068 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. Walls, G. V. et al. Pasireotide therapy of multiple endocrine neoplasia type 1-associated neuroendocrine tumors in female mice deleted for an Men1 allele improves survival and reduces tumor progression. Endocrinology 157, 1789–1798 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. Kim, Y. S. et al. Stable overexpression of MEN1 suppresses tumorigenicity of RAS. Oncogene 18, 5936–5942 (1999).

    CAS  PubMed  Google Scholar 

  139. Sayo, Y. et al. The multiple endocrine neoplasia type 1 gene product, menin, inhibits insulin production in rat insulinoma cells. Endocrinology 143, 2437–2440 (2002).

    CAS  PubMed  Google Scholar 

  140. Schnepp, R. W. et al. Menin induces apoptosis in murine embryonic fibroblasts. J. Biol. Chem. 279, 10685–10691 (2004).

    CAS  PubMed  Google Scholar 

  141. La, P. et al. Menin-mediated caspase 8 expression in suppressing multiple endocrine neoplasia type 1. J. Biol. Chem. 282, 31332–31340 2007).

    CAS  PubMed  Google Scholar 

  142. Kumar, R., Li, D. Q., Muller, S. & Knapp, S. Epigenomic regulation of oncogenesis by chromatin remodeling. Oncogene 35, 4423–4436 (2016).

    CAS  PubMed  Google Scholar 

  143. Lines, K. E. et al. Epigenetic pathway inhibitors represent potential drugs for treating pancreatic and bronchial neuroendocrine tumors. Oncogenesis 6, e332 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  144. Wong, C. et al. The bromodomain and extra-terminal inhibitor CPI203 enhances the antiproliferative effects of rapamycin on human neuroendocrine tumors. Cell Death Dis. 5, e1450 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  145. Mitry, E. et al. Bevacizumab plus capecitabine in patients with progressive advanced well-differentiated neuroendocrine tumors of the gastro-intestinal (GI-NETs) tract (BETTER trial) — a phase II non-randomised trial. Eur. J. Cancer 50, 3107–3115 (2014).

    CAS  PubMed  Google Scholar 

  146. Paez-Ribes, M. et al. Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell 15, 220–231 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  147. Sennino, B. et al. Suppression of tumor invasion and metastasis by concurrent inhibition of c-Met and VEGF signaling in pancreatic neuroendocrine tumors. Cancer Discov. 2, 270–287 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. Chu, X. et al. Multiple microvascular alterations in pancreatic islets and neuroendocrine tumors of a Men1 mouse model. Am. J. Pathol. 182, 2355–2367 (2013).

    CAS  PubMed  Google Scholar 

  149. Xie, L. et al. Counterbalancing angiogenic regulatory factors control the rate of cancer progression and survival in a stage-specific manner. Proc. Natl Acad. Sci. USA 108, 9939–9944 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  150. Kaji, H., Canaff, L., Lebrun, J. J., Goltzman, D. & Hendy, G. N. Inactivation of menin, a Smad3-interacting protein, blocks transforming growth factor type β signaling. Proc. Natl Acad. Sci. USA 98, 3837–3842 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  151. Padamsee, T. J., Wills, C. E., Yee, L. D. & Paskett, E. D. Decision making for breast cancer prevention among women at elevated risk. Breast Cacncer Res. 19, 34 (2017).

    Google Scholar 

  152. Cuzick, J. et al. Tamoxifen for prevention of breast cancer: extended long-term follow-up of the IBIS-I breast cancer prevention trial. Lancet Oncol. 16, 67–75 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  153. Lazzeroni, M. & DeCensi, A. Alternate dosing schedules for cancer chemopreventive agents. Seminars Oncol. 43, 116–122 (2016).

    CAS  Google Scholar 

  154. Ricciardiello, L., Ahnen, D. J. & Lynch, P. M. Chemoprevention of hereditary colon cancers: time for new strategies. Nat. Rev. Gastroenterol. Hepatol. 13, 352–361 (2016).

    CAS  PubMed  Google Scholar 

  155. Rinke, A. et al. 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. J. Clin. Oncol. 27, 4656–4663 (2009).

    CAS  PubMed  Google Scholar 

  156. Rinke, A. et al. 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 (PROMID): results of long-term survival. Neuroendocrinology 104, 26–32 (2017).

    CAS  PubMed  Google Scholar 

  157. Cioppi, F., Cianferotti, L., Masi, L., Giusti, F. & Brandi, M. L. The LARO-MEN1 study: a longitudinal clinical experience with octreotide long-acting release in patients with multiple endocrine neoplasia type 1 syndrome. Clin. Cases Miner. Bone Metab. 14, 123–130 (2017).

    PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was funded by the UK Medical Research Council (MRC) programme grants G9825289 and G1000467 (K.E.L., and R.V.T.), Danish Council for Independent Research (M.F.) and UK National Institute for Health Research (NIHR)–Oxford Biomedical Research Centre programme. R.V.T. is a Wellcome Trust investigator and an NIHR senior investigator.

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  1. Morten Frost and Kate E. Lines: These authors contributed equally to this work.

Authors and Affiliations

  1. Radcliffe Department of Medicine, Academic Endocrine Unit, Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford, OX3 7LJ, UK

    Morten Frost, Kate E. Lines & Rajesh V. Thakker

  2. Endocrine Research Unit, University of Southern Denmark, Sdr. Boulevard 29, 5000 Odense C, Denmark

    Morten Frost

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M.F. and K.E.L. researched data for the article. M.F., K.E.L. and R.V.T. provided substantial contributions to discussion of the content and to writing, review and/or editing of the manuscript before submission. M.F. and K.E.L. contributed equally to the article.

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Correspondence to Rajesh V. Thakker.

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Frost, M., Lines, K. & Thakker, R. Current and emerging therapies for PNETs in patients with or without MEN1. Nat Rev Endocrinol 14, 216–227 (2018). https://doi.org/10.1038/nrendo.2018.3

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