Abstract
Recently molecular targeted drugs have been introduced in the management of neuroendocrine tumours (NETs). While in pancreatic NET the mammalian target of rapamycin (mTOR) inhibitor, everolimus, and the multiple tyrosine kinase inhibitor, sunitinib, have been approved in progressive disease based on prolongation of progression-free survival in large placebo-controlled trials, the role of targeted drugs is currently less clear for NET of other primary tumour origins. Many more targeted drugs, such as inhibitors of vascular endothelial growth factor (VEGF), insulin-like growth factor 1 (IGF-1) and epidermal growth factor (EGF) receptor signalling, have been explored as single drugs or in combination with other drugs, such as chemotherapeutics or somatostatin analogues. Since objective remissions are rare with targeted drugs and stabilisation of disease and minor tumour shrinkage is not an uncommon finding with best supportive care in patients with NET, the value of these targeted drugs needs to be elucidated in well-designed prospective comparative trials in distinct types of NET.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Banck MS, Kanwar R, Kulkarni AA, Boora GK, Metge F, Kipp BR, Zhang L, Thorland EC, Minn KT, Tentu R, Eckloff BW, Wieben ED, Wu Y, Cunningham JM, Nagorney DM, Gilbert JA, Ames MM, Beutler AS (2013) The genomic landscape of small intestine neuroendocrine tumors. J Clin Invest 123(6):2502–2508. doi:10.1172/JCI67963
Jiao Y, Shi C, Edil BH, de Wilde RF, Klimstra DS, Maitra A, Schulick RD, Tang LH, Wolfgang CL, Choti MA, Velculescu VE, Diaz LA Jr, Vogelstein B, Kinzler KW, Hruban RH, Papadopoulos N (2011) DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors. Science 331(6021):1199–1203. doi:10.1126/science.1200609
Chaudhry A, Funa K, Oberg K (1993) Expression of growth factor peptides and their receptors in neuroendocrine tumors of the digestive system. Acta Oncol 32(2):107–114
Welin S, Fjällskog ML, Saras J, Eriksson B, Janson ET (2006) Expression of tyrosine kinase receptors in malignant midgut carcinoid tumors. Neuroendocrinology 84(1):42–48
Pavel M, Wiedenmann B (2011) Novel Therapeutic Agents for the Treatment of Gastroenteropancreatic Neuroendocrine Tumors. Horm Metab Res 43(12):844–853
Szoazec JY (2013) Angiogenesis in neuroendocrine tumors: therapeutic applications. Neuroendocrinology 97(1):45–56. doi:10.1159/000338371
Kidd M, Schimmack S, Lawrence B, Alaimo D, Modlin IM (2013) EGFR/TGFα and TGFβ/CTGF signaling in neuroendocrine neoplasia: theoretical therapeutic targets. Neuroendocrinology 97(1):35–44. doi:10.1159/000334891
Wulbrand U, Wied M, Zöfel P, Göke B, Arnold R, Fehmann H (1998) Growth factor receptor expression in human gastroenteropancreatic neuroendocrine tumours. Eur J Clin Invest 28(12):1038–1049
von Wichert G, Jehle PM, Hoeflich A, Koschnick S, Dralle H, Wolf E, Wiedenmann B, Boehm BO, Adler G, Seufferlein T (2000) 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
Shaw RJ, Cantley LC (2006) Ras, PI(3)K and mTOR signalling controls tumour cell growth. Nature 441(7092):424–430
Shida T, Kishimoto T, Furuya M, Nikaido T, Koda K, Takano S, Kimura F, Shimizu H, Yoshidome H, Ohtsuka M, Tanizawa T, Nakatani Y, Miyazaki M (2010) Expression of an activated mammalian target of rapamycin (mTOR) in gastroenteropancreatic neuroendocrine tumors. Cancer Chemother Pharmacol 65(5):889–893. doi:10.1007/s00280-009-1094-6
Missiaglia E, Dalai I, Barbi S, Beghelli S, Falconi M, della Peruta M, Piemonti L, Capurso G, Di Florio A, delle Fave G, Pederzoli P, Croce CM, Scarpa A (2010) Pancreatic endocrine tumors: expression profiling evidences a role for AKT-mTOR pathway. J Clin Oncol 28:245–255
Duran I, Kortmansky J, Singh D, Hirte H, Kocha W, Goss G, Le L, Oza A, Nicklee T, Ho J, Birle D, Pond GR, Arboine D, Dancey J, Aviel-Ronen S, Tsao MS, Hedley D, Siu LL (2006) A phase II clinical and pharmacodynamic study of temsirolimus in advanced neuroendocrine carcinomas. Br J Cancer 95(9):1148–1154
Yao JC, Phan AT, Chang DZ, Wolff RA, Hess K, Gupta S, Jacobs C, Mares JE, Landgraf AN, Rashid A, Meric-Bernstam F (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 26:4311–4318
Yao JC, Lombard-Bohas C, Baudin E, Kvols LK, Rougier P, Ruszniewski P, Hoosen S, St Peter J, Haas T, Lebwohl D, Van Cutsem E, Kulke MH, Hobday TJ, O’Dorisio TM, Shah MH, Cadiot G, Luppi G, Posey JA, Wiedenmann B (2010) Daily oral everolimus activity in patients with metastatic pancreatic neuroendocrine tumours after failure of cytotoxic chemotherapy: a phase II trial. J Clin Oncol 28:69–76
Yao JC, Shah MH, Ito T, Bohas CL, Wolin EM, Van Cutsem E, Hobday TJ, Okusaka T, Capdevila J, de Vries EG, Tomassetti P, Pavel ME, Hoosen S, Haas T, Lincy J, Lebwohl D, Öberg K (2011) Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med 364:514–523
Danesi R, Del Tacca M (1996) The effects of the somatostatin analog octreotide on angiogenesis in vitro. Metabolism 45(8 Suppl 1):49–50
Kulke MH, Lenz HJ, Meropol NJ, Posey J, Ryan DP, Picus J, Bergsland E, Stuart K, Tye L, Huang X, Li JZ, Baum CM, Fuchs CS (2008) Activity of sunitinib in patients with advanced neuroendocrine tumors. J Clin Oncol 26:3403–3410
Hobday T, Rubin J, Holen K, Picus J, Donehower R, Marschke R, Maples W, Lloyd R, Mahoney M, Erlichman C (2007) MC044h, a phase II trial of sorafenib in patients (pts) with metastatic neuroendocrine tumors (NET): a Phase II Consortium (P2C) study. J Clin Oncol; ASCO Annual Meeting Proceedings 2007; Part I 25 (18S (Suppl)):4504
Ahn HK, Choi JY, Kim KM, Kim H, Choi SH, Park SH, Park JO, Lim HY, Kang WK, Lee J, Park YS (2013) Phase II study of pazopanib monotherapy in metastatic gastroenteropancreatic neuroendocrine tumours. Br J Cancer 109(6):1414–1419. doi:10.1038/bjc.2013.470
Raymond E, Dahan L, Raoul JL, Bang YJ, Borbath I, Lombard-Bohas C, Valle J, Metrakos P, Smith D, Vinik A, Chen JS, Hörsch D, Hammel P, Wiedenmann B, Van Cutsem E, Patyna S, Lu DR, Blanckmeister C, Chao R, Ruszniewski P (2011) Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med 364(6):501–513. doi:10.1056/NEJMoa1003825
Abdel-Rahman O, Fouad M (2015) Bevacizumab-based combination therapy for advanced gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs): a systematic review of the literature. J Cancer Res Clin Oncol 141(2):295–305. doi:10.1007/s00432-014-1757-5
Chan JA, Stuart K, Earle CC, Clark JW, Bhargava P, Miksad R, Blaszkowsky L, Enzinger PC, Meyerhardt JA, Zheng H, Fuchs CS, Kulke MH (2012) Prospective study of bevacizumab plus temozolomide in patients with advanced neuroendocrine tumors. J Clin Oncol 30:2963–2968
Berruti A, Fazio N, Ferrero A, Brizzi MP, Volante M, Nobili E, Tozzi L, Bodei L, Torta M, D’Avolio A, Priola AM, Birocco N, Amoroso V, Biasco G, Papotti M, Dogliotti L (2014) Bevacizumab plus octreotide and metronomic capecitabine in patients with metastatic well-to-moderately differentiated neuroendocrine tumors: the XELBEVOCT study. BMC Cancer 14:184. doi:10.1186/1471-2407-14-184
Castellano D, Capdevila J, Sastre J, Alonso V, Llanos M, García-Carbonero R, Manzano Mozo JL, Sevilla I, Durán I, Salazar R (2013) Sorafenib and bevacizumab combination targeted therapy in advanced neuroendocrine tumour: a phase II study of Spanish Neuroendocrine Tumour Group (GETNE0801). Eur J Cancer 49(18):3780–3787
Pavel ME, Hainsworth JD, Baudin E, Peeters M, Hörsch D, Winkler RE, Klimovsky J, Lebwohl D, Jehl V, Wolin EM, Oberg K, Van Cutsem E, Yao JC, RADIANT-2 Study Group (2011) 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(9808):2005–2012. doi:10.1016/S0140-6736(11)61742-X
Yao JC, Phan A, Hoff PM, Chen HX, Charnsangavej C, Yeung SC, Hess K, Ng C, Abbruzzese JL, Ajani JA (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. J Clin Oncol 26:1316–1323
Reidy-Lagunes DL, Vakiani E, Segal MF, Hollywood EM, Tang LH, Solit DB, Pietanza MC, Capanu M, Saltz LB (2012) 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(19):4795–4800. doi:10.1002/cncr.27459
Strosberg JR, Chan JA, Ryan DP, Meyerhardt JA, Fuchs CS, Abrams T, Regan E, Brady R, Weber J, Campos T, Kvols LK, Kulke MH (2013) A multi-institutional, phase II open-label study of ganitumab (AMG 479) in advanced carcinoid and pancreatic neuroendocrine tumors. Endocr Relat Cancer 20(3):383–390. doi:10.1530/ERC-12-0390
Pavel M (2013) Translation of molecular pathways into clinical trials of neuroendocrine tumors. Neuroendocrinology 97:99–112
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2015 Springer-Verlag Berlin Heidelberg
About this chapter
Cite this chapter
Pavel, M.E. (2015). Targeted Therapies. In: Yalcin, S., Öberg, K. (eds) Neuroendocrine Tumours. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-662-45215-8_32
Download citation
DOI: https://doi.org/10.1007/978-3-662-45215-8_32
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-662-45214-1
Online ISBN: 978-3-662-45215-8
eBook Packages: MedicineMedicine (R0)