The mTOR signalling pathways in the pathogenesis and treatment of neuroendocrine tumours Review article
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Published:
Mar 4, 2016
Keywords:
neuroendocrine tumors (NETs), mTOR signalling pathway, mTOR inhibitors
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Abstract
Neuroendocrine tumours (NET) are a rare and heterogeneous group of neoplasms. The majority of patients are diagnosed with locally advanced or metastatic disease, and curative surgery is rarely an option. Treatment approaches involving targeted therapy, including the use of agents inhibiting the mTOR signalling pathways involved in neuroendocrine tumourigenesis, provide new therapeutic options for patients with NETs.
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1.
Kolasińska-Ćwikła A. The mTOR signalling pathways in the pathogenesis and treatment of neuroendocrine tumours. OncoReview [Internet]. 2016Mar.4 [cited 2024Jun.22];6(1(21):37-2. Available from: https://journalsmededu.pl/index.php/OncoReview/article/view/476
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This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
Copyright: © Medical Education sp. z o.o. This is an Open Access article distributed under the terms of the Attribution-NonCommercial 4.0 International (CC BY-NC 4.0). License (https://creativecommons.org/licenses/by-nc/4.0/), allowing third parties to copy and redistribute the material in any medium or format and to remix, transform, and build upon the material, provided the original work is properly cited and states its license.
Address reprint requests to: Medical Education, Marcin Kuźma (marcin.kuzma@mededu.pl)
References
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8. Blume-Jensen P, Hunter T. Oncogenic kinase signalling. Nature 2001; 411: 355-365.
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11. Faivre S, Kroemer G, Raymond E. Current development of mTOR inhibitors as anticancer agents. Nat Rev Drug Discov 2006; 5: 671-688.
12. Kim DH, Sarbassov DD, Ali SM et al. mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell 2002; 110: 163-175.
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15. Sarbassov DD, Guertin DA, Ali SM, Sabatini DM. Phosphorylation and regulation of AKT/PKB by the rictor mTOR complex. Science 2005; 307: 1098-1101.
16. Guertin DA, Sabatini DM. An expanding role for mTOR in cancer. Trends Mol Med 2005; 11: 353-361.
17. Martin DE, Hall MN. The expanding TOR signaling network. Curr Opin Cell Biol 2005; 17: 158-166.
18. Garcia JA, Danielpour D. Mammalian target of rapamycin inhibtion as a therapeutic strategy in the management of urologic malignancies. Mol Cancer Ther 2008; 7(6): 1347-1354.
19. Manning BD, Cantley LC. United at last: the tuberous sclerosis complex gene products connect the phosphoinositide 3-kinase/AKT pathway to mammalian target of rapamycin (mTOR) signalling. Biochem Soc Trans 2003; 31(Pt 3): 573-578.
20. Jacinto E, Facchinetti V, Liu D. et al. SIN1/MIP1 maintains rictor-mTOR complex integrity and regulates Akt phosphorylation and substrate specificity. Cell 2006; 127: 125-137.
21. Toschi A, Lee E, Gadir N. Differential dependence of hypoxia-inducible factors 1{alpha} and 2{alpha} on mTORC1 and mTORC2. J Biol Chem 2008; 283: 34495-34499.
22. Jiao Y, Shi C, Edil BH et al. DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors. Science 2011; 331(6021): 1199-1203.
23. 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(2): 245-255.
24. Briest F, Grabowski P. PI3K-AKT-mTOR-Signaling and beyond: the Complex Network in Gastroenteropancreatic Neuroendocrine Neoplasms Theranostics 2014; 4(4): 336-365.
25. Qian ZR, Ter-Minassian M, Chan JA et al. Prognostic significance of MTOR pathway component expression in neuroendocrine tumors. J Clin Oncol 2013; 31(27): 3418-3425.
26. Di Florio A, Sancho V, Moreno P. Gastrointestinal hormones stimulate growth of Foregut Neuroendocrine Tumors by transactivating the EGF receptor. Biochim Biophys Acta 2013; 1833: 573-582.
27. Krausch M, Raffel A, Anlauf M et al. Loss of PTEN expression in neuroendocrine pancreatic tumors. Horm Metab Res 2011; 43: 865-871.
28. Chung DC, Brown SB, Graeme-Cook F et al. Localization of putative tumor suppressor loci by genome-wide allelotyping in human pancreatic endocrine tumors. Cancer Res 1998; 58(16): 3706-3711.
29. Perren A, Komminoth P, Saremaslani P et al. Mutation and expression analyses reveal differential subcellular compartmentalization of PTEN in endocrine pancreatic tumors compared to normal islet cells. Am J Pathol 2000; 157(4): 1097-1103.
30. Kasajima A, Pavel M, Darb-Esfahani S et al. mTOR expression and activity patterns in gastroenteropancreatic neuroendocrine tumours. Endocr Relat Cancer 2011; 18(1): 181-192.
31. Chan J, Kulke M. Targeting the mTOR Signaling Pathway in Neuroendocrine Tumors. Curr Treat Options Oncol 2014; 15: 365-379.
32. Lodish MB, Stratakis CA. Endocrine tumours in neurofibromatosis type 1, tuberous sclerosis and related syndromes. Best Pract Res Clin Endocrinol Metab 2010; 24(3): 439-449.
33. Regulska K, Stanisz B, Regulski M. Indywidualizacja terapii przeciwnowotworowej; molekularne uwarunkowania mechanizmów działania nowoczesnych leków onkologicznych. Post Hig Med Dosw 2012; 66: 855-867.
34. Ghobrial IM, Witzig TE, Adjei AA. Targeting apoptosis pathways in cancer therapy. CA Cancer J Clin 2005; 55: 178-194.
35. 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: 4311-4318.
36. 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.
37. Yao JC, Shah MH, Ito T et al.; RAD001 in Advanced Neuroendocrine Tumors, Third Trial (RADIANT-3) Study Group: Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med 2011; 364: 514-523.
38. Yao J, Pavel M, Kunz T. Everolimus (EVE) for the treatment of advanced pancreatic neuroendocrine tumors (pNET): Final overall survival (OS) results of a randomized, double-blind, placebo (PBO)-controlled, multicenter Phase III trial (RADIANT-3), ESMO 2014: abstr. 1132O.
39. Pavel ME, Hainsworth JD, Baudin E; RADIANT-2 Study Group. 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 2011; 378(9808): 2005-2012.
40. Fazio N, Granberg D, Grossman A et al. Everolimus plus octreotide long-acting repeatable in patients with advanced lung neuroendocrine tumors: analysis of the phase 3, randomized, placebo-controlled RADIANT2-study. Chest 2013; 143: 955-962.
41. Castellano D, Bajetta E, Panneerselvam A et al. Everolimus plus octreotide long-acting repeatable in patients with colorectal neuroendocrine tumors: a subgroup analysis of the phase III RADIANT-2 study. Oncologist 2013; 18(1): 46-53.
42. Yao JC, Fazio N, Singh S et al.; RAD001 in Advanced Neuroendocrine Tumours, Fourth Trial (RADIANT-4) Study Group. Everolimus for the treatment of advanced, non-functional neuroendocrine tumours of the lung or gastrointestinal tract (RADIANT-4): a randomised, placebo-controlled, phase 3 study. Lancet 2015 [pii: S0140-6736(15)00817-X].
43. Singh S, Carnaghi C, Buzzoni R et al. Efficacy and safety of everolimus in advanced, progressive, nonfunctional neuroendocrine tumors (NET) of the gastrointestinal (GI) tract and unknown primary: A subgroup analysis of the phase III RADIANT-4 trial. American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium w San Francisco (2016; abstr. 315).
2. Modlin IM, Lye KD, Kidd M. A 5-decade analysis of 13,715 carcinoid tumors. Cancer 2003; 97: 934-959.
3. Basu B, Sirohi B, Corrie P. Systemic therapy for neuroendocrine tumours of gastroenteropancreatic origin. Endocr Relat Cancer 2010; 17: 75-90.
4. Plöckinger U, Rindi R, Arnold R. Guidelines for the Diagnosis and Treatment of Neuroendocrine Gastrointestinal Tumours. Neuroendocrinology 2004; 80: 394-424.
5. De Martino MC, van Koetsveld PM, Pivonello R et al. Role of the mTOR Pathway in Normal and Tumoral Adrenal Cells. Neuroendocrinology 2010; 92(suppl. 1): 28-34.
6. Vivanco I, Sawyers CL. The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer 2002; 2: 489-501.
7. White MF. The IRS-signalling system: a network of docking proteins that mediate insulin action. Mol Cell Biochem 1998; 182: 3-11.
8. Blume-Jensen P, Hunter T. Oncogenic kinase signalling. Nature 2001; 411: 355-365.
9. Schmelzle T, Hall MN. TOR, a central controller of cell growth. Cell 2000; 103: 253-262.
10. Thomas G, Hall MN. TOR signalling and control of cell growth. Curr Opin Cell Biol 1997; 9: 782-787.
11. Faivre S, Kroemer G, Raymond E. Current development of mTOR inhibitors as anticancer agents. Nat Rev Drug Discov 2006; 5: 671-688.
12. Kim DH, Sarbassov DD, Ali SM et al. mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell 2002; 110: 163-175.
13. Kim DH, Sarbassov DD, Ali SM et al. GbetaL, a positive regulator of the rapamycin-sensitive pathway required for the nutrient-sensitive interaction between raptor and mTOR. Mol Cell 2003; 11: 895-904.
14. Sarbassov DD, Ali SM, Kim DH et al. Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr Biol 2004; 14: 1296-1302.
15. Sarbassov DD, Guertin DA, Ali SM, Sabatini DM. Phosphorylation and regulation of AKT/PKB by the rictor mTOR complex. Science 2005; 307: 1098-1101.
16. Guertin DA, Sabatini DM. An expanding role for mTOR in cancer. Trends Mol Med 2005; 11: 353-361.
17. Martin DE, Hall MN. The expanding TOR signaling network. Curr Opin Cell Biol 2005; 17: 158-166.
18. Garcia JA, Danielpour D. Mammalian target of rapamycin inhibtion as a therapeutic strategy in the management of urologic malignancies. Mol Cancer Ther 2008; 7(6): 1347-1354.
19. Manning BD, Cantley LC. United at last: the tuberous sclerosis complex gene products connect the phosphoinositide 3-kinase/AKT pathway to mammalian target of rapamycin (mTOR) signalling. Biochem Soc Trans 2003; 31(Pt 3): 573-578.
20. Jacinto E, Facchinetti V, Liu D. et al. SIN1/MIP1 maintains rictor-mTOR complex integrity and regulates Akt phosphorylation and substrate specificity. Cell 2006; 127: 125-137.
21. Toschi A, Lee E, Gadir N. Differential dependence of hypoxia-inducible factors 1{alpha} and 2{alpha} on mTORC1 and mTORC2. J Biol Chem 2008; 283: 34495-34499.
22. Jiao Y, Shi C, Edil BH et al. DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors. Science 2011; 331(6021): 1199-1203.
23. 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(2): 245-255.
24. Briest F, Grabowski P. PI3K-AKT-mTOR-Signaling and beyond: the Complex Network in Gastroenteropancreatic Neuroendocrine Neoplasms Theranostics 2014; 4(4): 336-365.
25. Qian ZR, Ter-Minassian M, Chan JA et al. Prognostic significance of MTOR pathway component expression in neuroendocrine tumors. J Clin Oncol 2013; 31(27): 3418-3425.
26. Di Florio A, Sancho V, Moreno P. Gastrointestinal hormones stimulate growth of Foregut Neuroendocrine Tumors by transactivating the EGF receptor. Biochim Biophys Acta 2013; 1833: 573-582.
27. Krausch M, Raffel A, Anlauf M et al. Loss of PTEN expression in neuroendocrine pancreatic tumors. Horm Metab Res 2011; 43: 865-871.
28. Chung DC, Brown SB, Graeme-Cook F et al. Localization of putative tumor suppressor loci by genome-wide allelotyping in human pancreatic endocrine tumors. Cancer Res 1998; 58(16): 3706-3711.
29. Perren A, Komminoth P, Saremaslani P et al. Mutation and expression analyses reveal differential subcellular compartmentalization of PTEN in endocrine pancreatic tumors compared to normal islet cells. Am J Pathol 2000; 157(4): 1097-1103.
30. Kasajima A, Pavel M, Darb-Esfahani S et al. mTOR expression and activity patterns in gastroenteropancreatic neuroendocrine tumours. Endocr Relat Cancer 2011; 18(1): 181-192.
31. Chan J, Kulke M. Targeting the mTOR Signaling Pathway in Neuroendocrine Tumors. Curr Treat Options Oncol 2014; 15: 365-379.
32. Lodish MB, Stratakis CA. Endocrine tumours in neurofibromatosis type 1, tuberous sclerosis and related syndromes. Best Pract Res Clin Endocrinol Metab 2010; 24(3): 439-449.
33. Regulska K, Stanisz B, Regulski M. Indywidualizacja terapii przeciwnowotworowej; molekularne uwarunkowania mechanizmów działania nowoczesnych leków onkologicznych. Post Hig Med Dosw 2012; 66: 855-867.
34. Ghobrial IM, Witzig TE, Adjei AA. Targeting apoptosis pathways in cancer therapy. CA Cancer J Clin 2005; 55: 178-194.
35. 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: 4311-4318.
36. 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.
37. Yao JC, Shah MH, Ito T et al.; RAD001 in Advanced Neuroendocrine Tumors, Third Trial (RADIANT-3) Study Group: Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med 2011; 364: 514-523.
38. Yao J, Pavel M, Kunz T. Everolimus (EVE) for the treatment of advanced pancreatic neuroendocrine tumors (pNET): Final overall survival (OS) results of a randomized, double-blind, placebo (PBO)-controlled, multicenter Phase III trial (RADIANT-3), ESMO 2014: abstr. 1132O.
39. Pavel ME, Hainsworth JD, Baudin E; RADIANT-2 Study Group. 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 2011; 378(9808): 2005-2012.
40. Fazio N, Granberg D, Grossman A et al. Everolimus plus octreotide long-acting repeatable in patients with advanced lung neuroendocrine tumors: analysis of the phase 3, randomized, placebo-controlled RADIANT2-study. Chest 2013; 143: 955-962.
41. Castellano D, Bajetta E, Panneerselvam A et al. Everolimus plus octreotide long-acting repeatable in patients with colorectal neuroendocrine tumors: a subgroup analysis of the phase III RADIANT-2 study. Oncologist 2013; 18(1): 46-53.
42. Yao JC, Fazio N, Singh S et al.; RAD001 in Advanced Neuroendocrine Tumours, Fourth Trial (RADIANT-4) Study Group. Everolimus for the treatment of advanced, non-functional neuroendocrine tumours of the lung or gastrointestinal tract (RADIANT-4): a randomised, placebo-controlled, phase 3 study. Lancet 2015 [pii: S0140-6736(15)00817-X].
43. Singh S, Carnaghi C, Buzzoni R et al. Efficacy and safety of everolimus in advanced, progressive, nonfunctional neuroendocrine tumors (NET) of the gastrointestinal (GI) tract and unknown primary: A subgroup analysis of the phase III RADIANT-4 trial. American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium w San Francisco (2016; abstr. 315).