{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T02:43:53Z","timestamp":1785811433265,"version":"3.56.0"},"reference-count":32,"publisher":"Springer Science and Business Media LLC","issue":"2","license":[{"start":{"date-parts":[[2026,5,24]],"date-time":"2026-05-24T00:00:00Z","timestamp":1779580800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0"},{"start":{"date-parts":[[2026,5,24]],"date-time":"2026-05-24T00:00:00Z","timestamp":1779580800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0"}],"funder":[{"name":"GETNE","award":["GETNE1716"],"award-info":[{"award-number":["GETNE1716"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Drugs R D"],"published-print":{"date-parts":[[2026,6]]},"DOI":"10.1007\/s40268-026-00544-x","type":"journal-article","created":{"date-parts":[[2026,5,24]],"date-time":"2026-05-24T12:28:27Z","timestamp":1779625707000},"page":"155-167","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Combination of the Tryptophan Hydroxylase Inhibitor Telotristat with the mTOR Inhibitor Everolimus as an Effective Strategy Against Neuroendocrine Tumors"],"prefix":"10.1007","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4616-0598","authenticated-orcid":false,"given":"Javier","family":"Molina-Cerrillo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arantzazu","family":"Sierra-Ramirez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 L.","family":"L\u00f3pez-Aceituno","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marinela","family":"M\u00e9ndez-Pertuz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teresa","family":"Alonso-Gordoa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Linnebacher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matteo","family":"Santoni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pablo J.","family":"Fernandez-Marcos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enrique","family":"Grande","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,5,24]]},"reference":[{"key":"544_CR1","doi-asserted-by":"publisher","DOI":"10.3390\/IJMS20123049","author":"AK Stueven","year":"2019","unstructured":"Stueven AK, Kayser A, Wetz C, Amthauer H, Wree A, Tacke F, et al. Somatostatin analogues in the treatment of neuroendocrine tumors: past, present and future. Int J Mol Sci. 2019. https:\/\/doi.org\/10.3390\/IJMS20123049.","journal-title":"Int J Mol Sci"},{"key":"544_CR2","doi-asserted-by":"publisher","first-page":"6607","DOI":"10.2147\/CMAR.S261257","volume":"12","author":"MA Morse","year":"2020","unstructured":"Morse MA, Liu E, Joish VN, Huynh L, Cheng M, Duh MS, et al. Antiproliferative effects of telotristat ethyl in patients with neuroendocrine tumors: the TELEACE real-world chart review study. Cancer Manag Res. 2020;12:6607\u201314.","journal-title":"Cancer Manag Res"},{"key":"544_CR3","doi-asserted-by":"publisher","first-page":"365","DOI":"10.1007\/s11864-014-0294-4","volume":"15","author":"J Chan","year":"2014","unstructured":"Chan J, Kulke M. Targeting the mTOR signaling pathway in neuroendocrine tumors. Curr Treat Options Oncol. 2014;15:365\u201379.","journal-title":"Curr Treat Options Oncol"},{"key":"544_CR4","doi-asserted-by":"publisher","first-page":"1500","DOI":"10.1158\/0008-5472.CAN-05-2925","volume":"66","author":"KE O\u2019Reilly","year":"2006","unstructured":"O\u2019Reilly KE, Rojo F, She Q-B, Solit D, Mills GB, Smith D, et al. mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res. 2006;66:1500.","journal-title":"Cancer Res"},{"key":"544_CR5","doi-asserted-by":"publisher","first-page":"514","DOI":"10.1056\/NEJMoa1009290","volume":"364","author":"JC Yao","year":"2011","unstructured":"Yao JC, Shah MH, Ito T, Bohas CL, Wolin EM, van Cutsem E, et al. Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med. 2011;364:514\u201323.","journal-title":"N Engl J Med"},{"key":"544_CR6","doi-asserted-by":"publisher","first-page":"968","DOI":"10.1016\/S0140-6736(15)00817-X","volume":"387","author":"JC Yao","year":"2016","unstructured":"Yao JC, Fazio N, Singh S, Buzzoni R, Carnaghi C, Wolin E, et al. 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. 2016;387:968\u201377.","journal-title":"Lancet"},{"key":"544_CR7","doi-asserted-by":"publisher","first-page":"2005","DOI":"10.1016\/S0140-6736(11)61742-X","volume":"378","author":"ME Pavel","year":"2011","unstructured":"Pavel ME, Hainsworth JD, Baudin E, Peeters M, H\u00f6rsch D, Winkler RE, 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. 2011;378:2005\u201312.","journal-title":"Lancet"},{"key":"544_CR8","doi-asserted-by":"publisher","first-page":"1569","DOI":"10.1093\/annonc\/mdx193","volume":"28","author":"ME Pavel","year":"2017","unstructured":"Pavel ME, Baudin E, \u00d6berg KE, Hainsworth JD, Voi M, Rouyrre N, et al. Efficacy of everolimus plus octreotide LAR in patients with advanced neuroendocrine tumor and carcinoid syndrome: final overall survival from the randomized, placebo-controlled phase 3 RADIANT-2 study. Ann Oncol. 2017;28:1569\u201375.","journal-title":"Ann Oncol"},{"key":"544_CR9","first-page":"1461","volume":"17","author":"J Murakami","year":"2007","unstructured":"Murakami J, Lee YJ, Kokeguchi S, Tsujigiwa H, Asaumi JI, Nagatsuka H, et al. Depletion of O6-methylguanine-DNA methyltransferase by O 6-benzylguanine enhances 5-FU cytotoxicity in colon and oral cancer cell lines. Oncol Rep. 2007;17:1461\u20137.","journal-title":"Oncol Rep"},{"key":"544_CR10","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1007\/978-3-319-12048-5_2","volume":"163","author":"AL Cohen","year":"2015","unstructured":"Cohen AL, Colman H. Glioma biology and molecular markers. Cancer Treat Res. 2015;163:15\u201330.","journal-title":"Cancer Treat Res"},{"key":"544_CR11","doi-asserted-by":"publisher","first-page":"268","DOI":"10.1002\/cncr.25425","volume":"117","author":"JR Strosberg","year":"2011","unstructured":"Strosberg JR, Fine RL, Choi J, Nasir A, Coppola D, Chen DT, et al. First-line chemotherapy with capecitabine and temozolomide in patients with metastatic pancreatic endocrine carcinomas. Cancer. 2011;117:268\u201375.","journal-title":"Cancer"},{"key":"544_CR12","doi-asserted-by":"publisher","first-page":"741","DOI":"10.1080\/02841860601048388","volume":"46","author":"ML Fj\u00e4llskog","year":"2007","unstructured":"Fj\u00e4llskog ML, Hessman O, Eriksson B, Janson ET. Upregulated expression of PDGF receptor beta in endocrine pancreatic tumors and metastases compared to normal endocrine pancreas. Acta Oncol. 2007;46:741\u20136.","journal-title":"Acta Oncol"},{"key":"544_CR13","unstructured":"Fj\u00e4llskog M-LH, Lejonklou MH, Berg KEO\u00a8, Eriksson BK, Janson ET. Expression of Molecular Targets for Tyrosine Kinase Receptor Antagonists in Malignant Endocrine Pancreatic Tumors 1. http:\/\/aacrjournals.org\/clincancerres\/article-pdf\/9\/4\/1469\/2088157\/df0403001469.pdf. Accessed 29 Jul 2022."},{"key":"544_CR14","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1200\/JCO.2005.02.2194","volume":"24","author":"S Faivre","year":"2006","unstructured":"Faivre S, Delbaldo C, Vera K, Robert C, Lozahic S, Lassau N, et al. Safety, pharmacokinetic, and antitumor activity of SU11248, a novel oral multitarget tyrosine kinase inhibitor, in patients with cancer. J Clin Oncol. 2006;24:25\u201335.","journal-title":"J Clin Oncol"},{"key":"544_CR15","doi-asserted-by":"publisher","first-page":"3403","DOI":"10.1200\/JCO.2007.15.9020","volume":"26","author":"MH Kulke","year":"2008","unstructured":"Kulke MH, Lenz HJ, Meropol NJ, Posey J, Ryan DP, Picus J, et al. Activity of sunitinib in patients with advanced neuroendocrine tumors. J Clin Oncol. 2008;26:3403\u201310.","journal-title":"J Clin Oncol"},{"key":"544_CR16","doi-asserted-by":"publisher","first-page":"939","DOI":"10.1200\/JCO.2005.07.093","volume":"23","author":"K Pietras","year":"2005","unstructured":"Pietras K, Hanahan D. A multitargeted, metronomic, and maximum-tolerated dose \u2018chemo-switch\u2019 regimen is antiangiogenic, producing objective responses and survival benefit in a mouse model of cancer. J Clin Oncol. 2005;23:939\u201352.","journal-title":"J Clin Oncol"},{"key":"544_CR17","doi-asserted-by":"publisher","first-page":"501","DOI":"10.1056\/NEJMoa1003825","volume":"364","author":"E Raymond","year":"2011","unstructured":"Raymond E, Dahan L, Raoul J-L, Bang Y-J, Borbath I, Lombard-Bohas C, et al. Sunitinib Malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med. 2011;364:501\u201313.","journal-title":"N Engl J Med"},{"key":"544_CR18","doi-asserted-by":"publisher","first-page":"4934","DOI":"10.1002\/cncr.24533","volume":"115","author":"I Drozdov","year":"2009","unstructured":"Drozdov I, Kidd M, Gustafsson BI, Svejda B, Joseph R, Pfragner R, et al. Autoregulatory effects of serotonin on proliferation and signaling pathways in lung and small intestine neuroendocrine tumor cell lines. Cancer. 2009;115:4934\u201345.","journal-title":"Cancer"},{"key":"544_CR19","doi-asserted-by":"publisher","first-page":"173","DOI":"10.1159\/000338793","volume":"96","author":"S Grozinsky-Glasberg","year":"2012","unstructured":"Grozinsky-Glasberg S, Shimon I, Rubinfeld H. The role of cell lines in the study of neuroendocrine tumors. Neuroendocrinology. 2012;96:173\u201387.","journal-title":"Neuroendocrinology"},{"issue":"5","key":"544_CR20","doi-asserted-by":"publisher","first-page":"351","DOI":"10.1159\/000502200","volume":"110","author":"AD Herrera-Mart\u00ednez","year":"2020","unstructured":"Herrera-Mart\u00ednez AD, Feelders RA, Van den Dungen R, Dogan-Oruc F, van Koetsveld PM, Casta\u00f1o JP, et al. Effect of the Tryptophan Hydroxylase Inhibitor Telotristat on growth and Serotonin secretion in 2D and 3D cultured pancreatic neuroendocrine tumor cells. Neuroendocrinology. 2020;110(5):351\u201363.","journal-title":"Neuroendocrinology"},{"issue":"3","key":"544_CR21","doi-asserted-by":"publisher","first-page":"726","DOI":"10.1016\/j.surg.2023.09.018","volume":"175","author":"DH Tow","year":"2024","unstructured":"Tow DH, Chan CH, Howe JR, Ear PH. A luminescent sensor for investigating serotonin metabolism in neuroendocrine cancer. Surgery. 2024;175(3):726\u201334.","journal-title":"Surgery"},{"key":"544_CR22","doi-asserted-by":"publisher","DOI":"10.3390\/CANCERS12030691","author":"KB Luley","year":"2020","unstructured":"Luley KB, Biedermann SB, K\u00fcnstner A, Busch H, Franzenburg S, Schrader J, et al. A comprehensive molecular characterization of the pancreatic neuroendocrine tumor cell lines BON-1 and QGP-1. Cancers (Basel). 2020. https:\/\/doi.org\/10.3390\/CANCERS12030691.","journal-title":"Cancers (Basel)"},{"key":"544_CR23","doi-asserted-by":"publisher","first-page":"3749","DOI":"10.3748\/wjg.v24.i33.3749","volume":"24","author":"M Gock","year":"2018","unstructured":"Gock M, Mullins CS, Harnack C, Prall F, Ramer R, G\u00f6der A, et al. Establishment, functional and genetic characterization of a colon derived large cell neuroendocrine carcinoma cell line. World J Gastroenterol. 2018;24:3749\u201359.","journal-title":"World J Gastroenterol"},{"key":"544_CR24","doi-asserted-by":"publisher","first-page":"6","DOI":"10.3389\/fendo.2018.00146","volume":"9","author":"S Exner","year":"2018","unstructured":"Exner S, Prasad V, Wiedenmann B, Gr\u00f6tzinger C. Octreotide does not inhibit proliferation in five neuroendocrine tumor cell lines. Front Endocrinol (Lausanne). 2018;9:6.","journal-title":"Front Endocrinol (Lausanne)"},{"key":"544_CR25","doi-asserted-by":"publisher","first-page":"257","DOI":"10.1677\/ERC-07-0202","volume":"15","author":"A Moreno","year":"2008","unstructured":"Moreno A, Akcakanat A, Munsell MF, Soni A, Yao JC, Meric-Bernstam F. Antitumor activity of rapamycin and octreotide as single agents or in combination in neuroendocrine tumors. Endocr-Relat Cancer. 2008;15:257\u201366.","journal-title":"Endocr-Relat Cancer"},{"key":"544_CR26","volume":"9","author":"X Wang","year":"2022","unstructured":"Wang X, Kuban-Johnston D, Lapuerta P, Lacerda CMR. Telotristat ethyl reverses myxomatous changes in mice mitral valves. Front Cardiovasc Med. 2022;9:2019.","journal-title":"Front Cardiovasc Med"},{"key":"544_CR27","doi-asserted-by":"publisher","first-page":"G455","DOI":"10.1152\/ajpgi.00299.2014","volume":"309","author":"JJ Kim","year":"2015","unstructured":"Kim JJ, Wang H, Terc JD, Zambrowicz B, Yang QM, Khan WI. Blocking peripheral serotonin synthesis by telotristat etiprate (LX1032\/LX1606) reduces severity of both chemical- and infection-induced intestinal inflammation. Am J Physiol Gastrointest Liver Physiol. 2015;309:G455\u201365.","journal-title":"Am J Physiol Gastrointest Liver Physiol"},{"key":"544_CR28","doi-asserted-by":"publisher","DOI":"10.1371\/JOURNAL.PONE.0091387","author":"CB Johnbeck","year":"2014","unstructured":"Johnbeck CB, Jensen MM, Nielsen CH, Hag AMF, Knigge U, Kjaer A. 18F-FDG and 18F-FLT-PET imaging for monitoring everolimus effect on tumor-growth in neuroendocrine tumors: studies in human tumor xenografts in mice. PLoS\u00a0One. 2014. https:\/\/doi.org\/10.1371\/JOURNAL.PONE.0091387.","journal-title":"PLoS\u00a0One"},{"key":"544_CR29","doi-asserted-by":"publisher","first-page":"e15602","DOI":"10.1200\/JCO.2020.38.15_suppl.e15602","volume":"38","author":"HJ Kliman","year":"2020","unstructured":"Kliman HJ, Ling IS, Milano KM. Efficacy of telotristat ethyl: a peripheral tryptophan hydroxylase inhibitor that blocks serotonin biosynthesis against cultured liposarcoma, colon cancer, and cholangiocarcinoma cell lines. J Clin Oncol. 2020;38:e15602\u2013e15602.","journal-title":"J Clin Oncol"},{"key":"544_CR30","doi-asserted-by":"publisher","first-page":"1240","DOI":"10.2967\/jnumed.118.224048","volume":"60","author":"XF Jin","year":"2019","unstructured":"Jin XF, Auernhammer CJ, Ilhan H, Lindner S, N\u00f6lting S, Maurer J, et al. Combination of 5-Fluorouracil with epigenetic modifiers induces radiosensitization, somatostatin receptor 2 expression, and radioligand binding in neuroendocrine tumor cells in vitro. J Nucl Med. 2019;60:1240\u20136.","journal-title":"J Nucl Med"},{"key":"544_CR31","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1530\/JME-14-0304","volume":"54","author":"T Vandamme","year":"2015","unstructured":"Vandamme T, Peeters M, Dogan F, Pauwels P, van Assche E, Beyens M, et al. Whole-exome characterization of pancreatic neuroendocrine tumor cell lines BON-1 and QGP-1. J Mol Endocrinol. 2015;54:137\u201347.","journal-title":"J Mol Endocrinol"},{"key":"544_CR32","doi-asserted-by":"publisher","first-page":"1148","DOI":"10.1016\/j.humpath.2004.04.015","volume":"35","author":"C Salon","year":"2004","unstructured":"Salon C, Moro D, Lantuejoul S, Brichon PY, Drabkin H, Brambilla C, et al. E-cadherin-\u03b2-catenin adhesion complex in neuroendocrine tumors of the lung: a suggested role upon local invasion and metastasis. Hum Pathol. 2004;35:1148\u201355.","journal-title":"Hum Pathol"}],"container-title":["Drugs in R&D"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s40268-026-00544-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s40268-026-00544-x","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s40268-026-00544-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T01:43:56Z","timestamp":1785807836000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s40268-026-00544-x"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,24]]},"references-count":32,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2026,6]]}},"alternative-id":["544"],"URL":"https:\/\/doi.org\/10.1007\/s40268-026-00544-x","relation":{},"ISSN":["1174-5886","1179-6901"],"issn-type":[{"value":"1174-5886","type":"print"},{"value":"1179-6901","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,24]]},"assertion":[{"value":"8 December 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"22 April 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 May 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"AS-R planned, performed, and analyzed all the experiments and helped in writing the article. JM-C designed the project, gathered funding, and helped in writing the article. JLL-A helped in many of the experiments. MM-P helped in the project design and in writing the article. TA-G helped in writing the article. ML generated and shared the HROC57 cells and helped in the design of experiments with them. MS helped in writing manuscript. PJF-M planned and analyzed all the experiments, gathered funding, wrote the article and coordinated the project. EG designed the project, gathered funding and critical reagents, and helped in writing the article. All authors have read and approved the final version.","order":1,"name":"Ethics","label":"Author contributions","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"EG has received honoraria for speaker engagements, advisory roles or funding of continuous medical education from Adacap, AMGEN, Angelini, Astellas, Astra Zeneca, Bayer, Blueprint, Bristol Myers Squibb, Caris Life Sciences, Celgene, Clovis-Oncology, Eisai, Eusa Pharma, Genetracer, Guardant Health, HRA-Pharma, IPSEN, ITM-Radiopharma, Janssen, Lexicon, Lilly, Merck KGaA, MSD, Nanostring Technologies, Natera, Novartis, ONCODNA (Biosequence), Palex, Pharmamar, Pierre Fabre, Pfizer, Roche, Sanofi-Genzyme, Servier, Taiho, Thermo Fisher Scientific, and Zodiac. EG has received research grants from Pfizer, Merck, Astra Zeneca, Astellas, and Lexicon Pharmaceuticals. JMC declares consultant, advisory or speaker roles for IPSEN, Roche, Pfizer, Sanofi, Janssen, and BMS. JMC has received research grants from Pfizer, IPSEN and Roche. TAG declares consultant, advisory or speaker roles for Ipsen, Pfizer, Roche, Bayer, Sanofi-Genzyme, Adacap, Janssen, Eisai, Bristol-Myers Squibb. TAG has received research grants from Pfizer, IPSEN and Roche. The other authors declare no conflicts of interest or state.","order":2,"name":"Ethics","label":"Conflict of interest","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"All data generated or analyzed during this study are included in this article and its supplementary material files. Further enquiries can be directed to the corresponding author.","order":3,"name":"Ethics","label":"Data availability","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"This study protocol was reviewed and approved by \u201c\u00c1rea de Protecci\u00f3n Animal de la Subdirecci\u00f3n General de Producci\u00f3n Agroalimentaria, Comunidad de Madrid, Spain\u201d, with approval number: PROEX 340.3\/21.","order":4,"name":"Ethics","label":"Statement of ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"This study did not involve human participants. Therefore, informed consent to participate was not required. All applicable international, national, and\/or institutional guidelines for the care and use of animals were followed. The study protocol was approved by the appropriate institutional ethics committee.","order":5,"name":"Ethics","label":"Consent to participate","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"No custom code or software was used in this study. Data analysis was performed using standard, commercially available software as described in the Methods section.","order":6,"name":"Ethics","label":"Code availability","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Not applicable.","order":7,"name":"Ethics","label":"Consent for publication","group":{"name":"EthicsHeading","label":"Declarations"}}]}}