Abstract
Well differentiated neuroendocrine tumours (WDNET) are a diverse group of cancers that are often advanced at the time of diagnosis and generally do not respond significantly to traditional chemotherapy. A number of intriguing therapeutic targets have emerged, including somatostatin receptors, insulin-like growth factor-1 (IGF-1) and its receptor (IGF-1R), the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway, and vascular endothelial growth factor receptor. Functional somatostatin receptors and IGF-1R as well as dysregulated mTOR-a key pathway component for both growth factor signalling and protein synthesis — have been identified in human neuroendocrine tumour (NET) cell lines. Somatostatin analogues (SSA) and mTOR inhibitors have exhibited in vitro and in vivo antitumour activity against NET and have shown effects on the IGF-1 pathway in preclinical studies. SSA inhibit PI3K/Akt signalling upstream of mTOR, suggesting that the combination of an SSA and an mTOR inhibitor may have greater efficacy than either as single agents. Recent clinical trial experience has provided some encouraging findings and prompted the design of additional studies of this dual-targeted approach to treating advanced WDNET. Results of ongoing trials of dual-targeted therapy combinations will define future therapies for advanced WDNET.
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Yao JC, Hassan M, Phan A, et al. One hundred years after “carcinoid”: epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol 2008; 26: 3063–72
Modlin IM, Moss SF, Chung DC, et al. Priorities for improving the management of gastroenteropancreatic neuro-endocrine tumors. J Natl Cancer Inst 2008; 100: 1282–9
Grozinsky-Glasberg S, Shimon I, Korbonits M, et al. Somatostatin analogues in the control of neuroendocrine tumors: efficacy and mechanisms. Endocr Relat Cancer 2008; 15: 701–20
Öberg K, Jelic S, on behalf of the ESMO Guidelines Working Group. Neuroendocrine gastroenteropancreatic tumors: ESMO Clinical Recommendation for diagnosis, treatment and follow-up. Ann Oncol 2009; 20 Suppl. 4: iv150–3
Florio T. Molecular mechanisms of the antiproliferative activity of somatostatin receptors (sstrs) in neuroendocrine tumors. Front Biosci 2008; 13: 822–40
von Wichert G, Jehle PM, Hoeflich A, et al. Insulin-like growth factor-I is an autocrine regulator of chromagranin A secretion and growth in human neuroendocrine tumor cells. Cancer Res 2000; 60: 4573–81
Albanell J, Dalmases A, Rovira A, et al. mTOR signalling in human cancer. Clin Transl Oncol 2007; 9: 484–93
Nilsson O, Wängberg B, Theodorsson E, et al. Presence of IGF-I in human midgut carcinoid tumours: an autocrine regulator of carcinoid tumour growth? Int J Cancer 1992; 51: 195–203
Hörsch D, Tielke S, Schrader J. Expression and activation of mTOR in neuroendocrine tumors: effects of mTOR inhibition by RAD001 upon growth, cell cycle regulation, and signaling in neuroendocrine cell lines [abstract no. 10570]. J Clin Oncol 2007; 25(18S): 582s
Grozinsky-Glasberg S, Franchi G, Teng M, et al. Octreotide and the mTOR inhibitor RAD001 (everolimus) block proliferation and interact with the Akt-mTOR-p70S6K pathway in a neuro-endocrine tumour cell line. Neuro-endocrinology 2008; 87: 168–81
Hofland LJ, Lamberts SWJ. The pathophysiological consequences of somatostatin receptor internalization and resistance. Endocr Rev 2003; 24: 28–47
Lamberts SW, van der Lely AJ, de Herder WW, et al. Octreotide. N Engl J Med 1996; 334: 246–54
Öberg K, Kvols L, Caplin M, et al. Consensus report on the use of somatostatin analogs for the management of neuroendocrine tumors of the gastroenteropancreatic system. Ann Oncol 2004; 15: 966–73
Modlin IM, Pavel M, Kidd M, et al. Review articles: somatostatin analogues in the treatment of gastroenteropancreatic neuroendocrine (carcinoid) tumours. Aliment Pharmacol Ther 2010; 31: 169–88
Kurosaki M, Saeger W, Abe T, et al. Expression of vascular endothelial growth factor in growth hormone-secreting pituitary adenomas: special reference to the octreotide treatment. Neurol Res 2008; 30: 518–22
Anthony LB, Martin W, Delbeke D, et al. Somatostatin receptor imaging: predictive and prognostic considerations. Digestion 1996; 57: 50–3
Townsend A, Price T, Yeend S, et al. Metastatic carcinoid tumor: changing patterns of care over two decades. J Clin Gastroenterol 2010; 44: 195–9
Aparicio T, Ducreux M, Baudin E, et al. Antitumor activity of somatostatin analogues in progressive metastatic neuro-endocrine tumors. Eur J Cancer 2001; 37: 1014–9
Panzuto F, Di Fonzo M, Iannicelli E, et al. Long-term clinical outcome of somatostatin analogues for treatment of progressive, metastatic, well-differentiated entero-pancreatic endocrine carcinoma. Ann Oncol 2006; 17: 461–6
Rinke A, Müller HH, Schade-Brittinger C, 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 2009; 27: 4656–63
Kvols L, Wiedenmann B, Öberg K, et al. Efficacy and safety results from a phase II study of pasireotide (SOM230) in the treatment of patients with metastatic NET refractory or resistant to octreotide LAR [poster presentation C57]. Conference of the European Neuroendocrine Tumour Society; 2010 Mar 11–12; Berlin
Novartis Pharmaceuticals. An open label, multicenter, single arm study of pasireotide LAR in patients with rare tumors of neuroendocrine origin [ClinicalTrials.gov identifier NCT00958841]. US National Institutes of Health, Clinical Trials.gov [online]. Available from URL: http://www.clinicaltrials.gov [Accessed 2009 Jul 21]
Novartis Pharmaceuticals. A multicenter, randomized, blinded efficacy and safety study of pasireotide LAR vs octreotide LAR in patients with metastatic carcinoid tumors whose disease-related symptoms are inadequately controlled by somatostatin analogues [ClinicalTrials.gov identifier NCT00690430]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://www.clinicaltrials.gov [Accessed 2009 Jul 21]
LeRoith D, Yakar S. Mechanisms of disease: metabolic effects of growth hormone and insulin-like growth factor 1. Nat Clin Pract Endocrinol Metab 2007; 3: 302–10
Pollak MN, Polychronakos C, Guyda H. Somatostatin analogue SMS 201-995 reduces serum IGF-I levels in patients with neoplasms potentially dependent on IGF-I. Anticancer Res 1989; 9: 889–92
Schmid HA, Stumm M, McSheehy P, et al. Inhibitory effect of pasireotide in a rat pancreatic tumor model (CA20948) alone and in combination with everolimus (RAD001) [poster]. Annual Meeting of the American Association for Cancer Research; 2009 Apr 18–22; Denver (CO)
Friedlander T, Weinberg V, Sharib J, et al. Effect of the somatostatin analog octreotide acetate on circulating IGF-1 and on PSA in patients with castration-resistant prostate cancer (CRPC): results of a phase II study [abstract no. 99 plus poster]. Genitourinary Cancers Symposium; 2010 Mar 5–7; San Francisco (CA)
Pokrajac A, Frystyk J, Flyvbjerg A, et al. Pituitary-independent effect of octreotide on IGF1 generation. Eur J Endocrinol 2009; 160: 543–8
Reidy DL, Hollywood E, Segal M, et al. 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) [abstract no. 4163]. J Clin Oncol 2010; 28 Suppl.: 15s
Faivre S, Kroemer G, Raymond E. Current development of mTOR inhibitors as anticancer agents. Nat Rev Drug Discov 2006; 5(8): 671–88
Meric-Bernstam F, Gonzalez-Angulo AM. Targeting the mTOR signaling network for cancer therapy. J Clin Oncol 2009; 27(13): 2278–87
Shida T, Kishimoto T, Furuya M, et al. Expression of an activated mammalian target of rapamycin (mTOR) in gastroenteropancreatic neuroendocrine tumors. Cancer Chemother Pharmacol 2010; 65: 889–93
Samlowski WE, Vogelzang NJ. Emerging drugs for the treatment of metastatic renal cancer. Expert Opin Emerg Drugs 2007; 12: 605–18
Missiaglia E, Dalai I, Barbi S, et al. Pancreatic endocrine tumors: expression profiling evidences a role for Akt-mTOR pathway. J Clin Oncol 2010; 28: 245–55
Ter-Minassian M, Wang Z, Asomaning K, et al. Association of a TSC2 SNP with sporadic neuroendocrine tumor risk [abstract no. 3050]. Proceedings of the Annual Meeting of the American Association for Cancer Research; 2009 Apr 18–22; Denver (CO)
Moreno A, Akcakanat A, Munsell MF, et al. Antitumor activity of rapamycin and octreotide as single agents or in combination in neuroendocrine tumors. Endocr Relat Cancer 2008; 15: 257–66
Neshat MS, Mellinghoff IK, Tran C, et al. Enhanced sensitivity of PTEN-deficient tumors to inhibition of FRAP/mTOR. Proc Natl Acad Sci USA 2001; 98: 10314–9
Artime MC, Blackman S, Ebbinghaus S, et al. PI3K suppression by the mTOR inhibitor ridaforolimus and the AKT inhibitor MK-2206 is associated with enhanced anti-tumor activity and hyperglycemia in preclinical models [abstract no. 3478]. Annual Meeting of the American Association for Cancer Research; 2010 Apr 17–21; Washington (DC)
Zitzmann K, De Toni EN, Brand S, et al. The novel mTOR inhibitor RAD001 (everolimus) induces antiproliferative effects in human pancreatic neuroendocrine tumor cells. Neuroendocrinology 2007; 85: 54–60
Duran I, Kortmansky J, Singh D, et al. A phase II clinical and pharmacodynamic study of temsirolimus in advanced neuroendocrine carcinomas. Br J Cancer 2006; 95: 1148–54
Yao JC, Lombard-Bohas C, Baudin E, et al. Daily oral everolimus activity in patients with metastatic pancreatic neuroendocrine tumors after failure of cytotoxic chemotherapy: a phase II trial. J Clin Oncol 2010; 28: 69–76
Yao JC, Shah MH, Ito T, et al. Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med 2011; 364: 514–23
Folkman J, Shing Y. Angiogenesis. J Biol Chem 1992; 267: 10931–4
Holash J, Wiegand SJ, Yancopoulos GD. New model of tumor angiogenesis: dynamic balance between vessel regression and growth mediated by angiopoietin and VEGF. Oncogene 1999; 18: 5356–62
Casanovas O, Hicklin DJ, Bergers G, et al. Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors. Cancer Cell 2005; 8: 299–309
Inoue M, Hager JH, Ferrara N, et al. VEGF-A has a critical, nonredundant role in angiogenic switching and pancreatic beta cell carcinogenesis. Cancer Cell 2002; 1: 193–202
La Rosa S, Uccella S, Finzi G, et al. Localization of vascular endothelial growth factor and its receptors in digestive endocrine tumors: correlation with microvessel density and clinicopathologic features. Hum Pathol 2003; 34: 18–27
Zhang J, Jia Z, Li Q, et al. Elevated expression of vascular endothelial growth factor correlates with increased angiogenesis and decreased progression-free survival among patients with low-grade neuroendocrine tumors. Cancer 2007; 109: 1478–86
Hansel DE, Rahman A, Hermans J, et al. Liver metastases arising from well-differentiated pancreatic endocrine neoplasms demonstrate increased VEGF-C expression. Mod Pathol 2003; 16: 652–9
Pietras K, Hanahan D. A multitargeted, metronomic, and maximum-tolerated dose “chemo-switch” regimen is antiangiogenic, producing objective responses and survival benefit in a mouse model of cancer. J Clin Oncol 2005; 23: 939–52
Yao VJ, Sennino B, Davis RB, et al. Combined anti-VEGFR and anti-PDGFR actions of sunitinib on blood vessels in preclinical tumor models [abstract]. Eur J Cancer 2006; 4 Suppl.: 27–8
Faivre S, Delbaldo C, Vera K, et al. Safety, pharmaco-kinetic, and antitumor activity of SU11248, a novel oral multitarget tyrosine kinase inhibitor, in patients with cancer. J Clin Oncol 2006; 24: 25–35
Kulke MH, Lenz HJ, Meropol NJ, et al. Activity of sunitinib in patients with advanced neuroendocrine tumors. J Clin Oncol 2008; 26: 3403–10
Raymond E, Dahan L, Raoul J-L, et al. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med 2011; 364: 501–13
Yao JC, Phan A, Hoff PM, et al. 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 2008; 26: 1316–23
Yao JC, Phan AT, Fogelman D, et al. Randomized run-in study of bevacizumab (B) and everolimus (E) in low- to intermediate-grade neuroendocrine tumors (LGNETs) using perfusion CT as functional biomarker [abstract no. 4002]. J Clin Oncol 2010; 28 Suppl.: 15s
Kwak EL, Clark JW, Chabner B. Targeted agents: the rules of combination. Clin Cancer Res 2007; 13: 5232–7
O'Reilly KE, Rojo F, She QB, et al. mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res 2006; 66: 1500–8
Van Gompel JJ, Chen H. Insulin-like growth factor 1 signaling in human gastrointestinal carcinoid tumor cells. Surgery 2004; 136: 1297–302
Charland S, Boucher M-J, Houde M, et al. Somatostatin inhibits Akt phosphorylation and cell cycle entry, but not p42/p44 mitogen-activated protein (MAP) kinase activation in normal and tumoral pancreatic acinar cells. Endocrinology 2001; 142: 121–8
Cerovac V, Monteserin-Garcia J, Rubinfeld H, et al. The somatostatin analogue octreotide confers sensitivity to rapamycin treatment on pituitary tumor cells. Cancer Res 2010; 70: 666–74
Yao JC, Phan AT, Chang DZ, et al. Efficacy of RAD001 (everolimus) and octreotide LAR in advanced low- to intermediate-grade neuroendocrine tumors: results of a phase II study. J Clin Oncol 2008; 26: 4311–8
Pavel M, Hainsworth JD, Baudin E, et al. A randomized, double blind, placebo-controlled, multicenter phase III trial of everolimus 1 octreotide lar vs placebo 1 octreotide in patients with advanced neuroendocrine tumors (NET) (RADIANT-2) [abstract]. Ann Oncol 2010; 21: 4
Sathyanarayanan S, Jha S, Klinghoffer R, et al. Combination treatment with the anti-IGF1R antibody MK-0646 and the mTOR inhibitor deforolimus leads to more effective PI3K pathway targeting and anti-tumor activity [poster]. Annual Meeting of the American Association for Cancer Research; 2009 Apr 18–22; Denver (CO)
Merck. A phase I study of ridaforolimus (MK8669) and MK0646 in patients with advanced cancer [ClinicalTrials. gov identifier NCT00730379]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://www.clinicaltrials.gov [Accessed 2009 Jul 21]
Hoffmann-La Roche. A multiple ascending dose study of the mTOR inhibitor (RAD001) in combination with R1 507 in patients with advanced solid tumors [ClinicalTrials.gov identifier NCT00985374]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://www.clinicaltrials.gov [Accessed 2010 Aug 17]
M.D. Anderson Cancer Center. Phase I study of anti-IGF1R monoclonal antibody, IMC-A12, and mTOR inhibitor, everolimus, in advanced low to intermediate grade neuro-endocrine carcinoma [ClinicalTrials.gov identifier NCT01204476]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://www.clinicaltrials.gov [Accessed 2011 Feb 20]
Montagut C, Settleman J. Targeting the RAF-MEK-ERK pathway in cancer therapy. Cancer Lett 2009; 283: 125–34
Hobday TJ, Rubin J, Holen K, et al. MCO44h, a phase II trial of sorafenib in patients (pts) with metastatic neuroendocrine tumors (NET): a phase II consortium (P2C) study, [abstract no. 4504] J Clin Oncol 2007; 25 Suppl. 18: 4504
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Salazar, R., Reidy-Lagunes, D. & Yao, J. Potential Synergies for Combined Targeted Therapy in the Treatment of Neuroendocrine Cancer. Drugs 71, 841–852 (2011). https://doi.org/10.2165/11585500-000000000-00000
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DOI: https://doi.org/10.2165/11585500-000000000-00000