{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T14:20:42Z","timestamp":1784557242789,"version":"3.55.0"},"reference-count":24,"publisher":"Bioscientifica","issue":"12","license":[{"start":{"date-parts":[[2023,9,15]],"date-time":"2023-09-15T00:00:00Z","timestamp":1694736000000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["erc.bioscientifica.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2023,9,15]]},"abstract":"<jats:p>\n                    Neuroendocrine tumors (NETs) are highly vascularized malignancies in which angiogenesis may entail cell proliferation and survival. Among the emerging compounds with antivascular properties, cabozantinib (CAB) appeared promising. We analyzed the antitumor activity of CAB against NETs utilizing\n                    <jats:italic>in vitro<\/jats:italic>\n                    and\n                    <jats:italic>in vivo<\/jats:italic>\n                    models. For cell cultures, we used BON-1, NCI-H727 and NCI-H720 cell lines. Cell viability was assessed by manual count coupled with quantification of cell death, performed through fluorescence-activated cell sorting analysis as propidium iodide exclusion assay. In addition, we investigated the modulation of the antiapoptotic myeloid cell leukemia 1 protein under CAB exposure, as a putative adaptive pro-survival mechanism, and compared the responses with sunitinib. The activity of CAB was also tested in mouse and zebrafish xenograft tumor models. Cabozantinib showed a dose-dependent and time-dependent effect on cell viability and proliferation in human NET cultures, besides a halting of cell cycle progression for endoduplication, never reported for other tyrosine kinase inhibitors. In a transplantable zebrafish model, CAB drastically inhibited NET-induced angiogenesis and migration of implanted cells through the embryo body. CAB showed encouraging activity in NETs, both\n                    <jats:italic>in vitro<\/jats:italic>\n                    and\n                    <jats:italic>in vivo<\/jats:italic>\n                    models. On this basis, we envisage future research to further investigate along these promising lines.\n                  <\/jats:p>","DOI":"10.1530\/erc-23-0232","type":"journal-article","created":{"date-parts":[[2023,9,15]],"date-time":"2023-09-15T12:08:39Z","timestamp":1694779719000},"update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-8","source":"Crossref","is-referenced-by-count":6,"title":["Cabozantinib in neuroendocrine tumors: tackling drug activity and resistance mechanisms"],"prefix":"10.1530","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7297-9110","authenticated-orcid":true,"given":"Chiara Alessandra","family":"Cella","sequence":"first","affiliation":[{"name":"Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IEO, IRCCS, Milan, Italy"},{"name":"Department of Molecular and Translational Medicine, Division of Biology and Genetics, University of Brescia, Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Riccardo","family":"Cazzoli","sequence":"additional","affiliation":[{"name":"Department of Experimental Oncology, European Institute of Oncology, IEO, IRCCS, Milan, Italy"},{"name":"Metal Targeted Therapy & Immunology lab, Childrens\u2019 cancer institute, Sydney, NSW, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6869-0704","authenticated-orcid":true,"given":"Nicola","family":"Fazio","sequence":"additional","affiliation":[{"name":"Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IEO, IRCCS, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppina","family":"De Petro","sequence":"additional","affiliation":[{"name":"Department of Molecular and Translational Medicine, Division of Biology and Genetics, University of Brescia, Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Germano","family":"Gaudenzi","sequence":"additional","affiliation":[{"name":"Laboratory of Geriatric and Oncologic Neuroendocrinology Research, IRCCS, Istituto Auxologico Italiano, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Carra","sequence":"additional","affiliation":[{"name":"Laboratory of Endocrine and Metabolic Research, IRCCS, Istituto Auxologico Italiano, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mauro","family":"Romanenghi","sequence":"additional","affiliation":[{"name":"Department of Experimental Oncology, European Institute of Oncology, IEO, IRCCS, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Spada","sequence":"additional","affiliation":[{"name":"Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IEO, IRCCS, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilaria","family":"Grossi","sequence":"additional","affiliation":[{"name":"Department of Molecular and Translational Medicine, Division of Biology and Genetics, University of Brescia, Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabella","family":"Pallavicini","sequence":"additional","affiliation":[{"name":"Department of Experimental Oncology, European Institute of Oncology, IEO, IRCCS, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saverio","family":"Minucci","sequence":"additional","affiliation":[{"name":"Department of Experimental Oncology, European Institute of Oncology, IEO, IRCCS, Milan, Italy"},{"name":"Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2478-683X","authenticated-orcid":true,"given":"Giovanni","family":"Vitale","sequence":"additional","affiliation":[{"name":"Laboratory of Geriatric and Oncologic Neuroendocrinology Research, IRCCS, Istituto Auxologico Italiano, Milan, Italy"},{"name":"Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"416","reference":[{"key":"bib1","series-title":"Journal of Clinical Oncology","first-page":"2304","article-title":"Lenvatinib in patients with advanced Grade 1\/2 pancreatic and gastrointestinal neuroendocrine tumors: results of the Phase II Talent trial (GETNE1509)","volume":"39","author":"Capdevila","year":"2021","unstructured":"Capdevila JFazio NLopez CTeul\u00e9 AValle JWTafuto SCustodio AReed NRaderer MGrande E, 2021Lenvatinib in patients with advanced Grade 1\/2 pancreatic and gastrointestinal neuroendocrine tumors: results of the Phase II Talent trial (GETNE1509). 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(https:\/\/doi.org\/10.1158\/1535-7163.MCT-09-0274)"},{"key":"bib21","series-title":"New England Journal of Medicine","first-page":"501","article-title":"Sunitinib malate for the treatment of pancreatic neuroendo- crine tumors","volume":"364","author":"Raymond","year":"2011","unstructured":"Raymond EDahan LRaoul JLBang YJBorbath ILombard-Bohas CValle JMetrakos PSmith DVinik A, 2011Sunitinib malate for the treatment of pancreatic neuroendo- crine tumors. New England Journal of Medicine364501\u2013513. (https:\/\/doi.org\/10.1056\/NEJMoa1003825)"},{"key":"bib22","series-title":"Neuroendocrinology","first-page":"383","article-title":"Cabozantinib and tivantinib, but not INC280, induce antiproliferative and antimigratory effects in human neuroendocrine tumor cells in vitro: evidence for 'off-target' effects not mediated by c-met inhibition","volume":"103","author":"Reuther","year":"2016","unstructured":"Reuther CHeinzle VSpampatti MVlotides Gde Toni ESp\u00f6ttl GMaurer JN\u00f6lting SG\u00f6ke B & Auernhammer CJ2016Cabozantinib and tivantinib, but not INC280, induce antiproliferative and antimigratory effects in human neuroendocrine tumor cells in vitro: evidence for 'off-target' effects not mediated by c-met inhibition. Neuroendocrinology103383\u2013401. (https:\/\/doi.org\/10.1159\/000439431)"},{"key":"bib23","series-title":"Cancer Discovery","first-page":"270","article-title":"Suppression of tumor invasion and metastasis by concurrent inhibition of c-Met and VEGF signaling in pancreatic neuroendocrine tumors","volume":"2","author":"Sennino","year":"2012","unstructured":"Sennino BIshiguro-Oonuma TWei YNaylor RMWilliamson CWBhagwandin VTabruyn SPYou WKChapman HAChristensen JG, 2012Suppression of tumor invasion and metastasis by concurrent inhibition of c-Met and VEGF signaling in pancreatic neuroendocrine tumors. Cancer Discovery2270\u2013287. (https:\/\/doi.org\/10.1158\/2159-8290.CD-11-0240)"},{"key":"bib24","series-title":"Endocrine-Related Cancer","first-page":"411","article-title":"A phase II study of axitinib in advanced neuroendocrine tumors","volume":"23","author":"Strosberg","year":"2016","unstructured":"Strosberg JRCives MHwang JWeber TNickerson MAtreya CEVenook AKelley RKValone TMorse B, 2016A phase II study of axitinib in advanced neuroendocrine tumors. Endocrine-Related Cancer23411\u2013418. (https:\/\/doi.org\/10.1530\/ERC-16-0008)"},{"key":"bib25","series-title":"Neuroendocrinology","first-page":"268","article-title":"VEGF secretion by neuroendocrine tumor cells is inhibited by octreotide and by inhibitors of the PI3K\/Akt\/mTOR pathway","volume":"91","author":"Villaume","year":"2010","unstructured":"Villaume KBlanc MGouysse GWalter TCouderc CNejjari MVercherat CCordier-Bussat MRoche C & Scoazec JY2010VEGF secretion by neuroendocrine tumor cells is inhibited by octreotide and by inhibitors of the PI3K\/Akt\/mTOR pathway. Neuroendocrinology91268\u2013278. (https:\/\/doi.org\/10.1159\/000289569)"},{"key":"bib26","series-title":"Endocrine-Related Cancer","first-page":"R67","article-title":"Zebrafish as an innovative model for neuroendocrine tumors","volume":"21","author":"Vitale","year":"2014","unstructured":"Vitale GGaudenzi GDicitore ACotelli FFerone D & Persani L2014Zebrafish as an innovative model for neuroendocrine tumors. Endocrine-Related Cancer21R67\u2013R83. (https:\/\/doi.org\/10.1530\/ERC-13-0388)"},{"key":"bib27","series-title":"Lancet. Oncology","first-page":"1489","article-title":"Surufatinib in advanced pancreatic neuroendocrine tumours (SANET-p): a randomised, double-blind, placebo-controlled, phase 3 study","volume":"21","author":"Xu","year":"2020a","unstructured":"Xu JShen LBai CWang WLi JYu XLi ZLi EYuan XChi Y, 2020aSurufatinib in advanced pancreatic neuroendocrine tumours (SANET-p): a randomised, double-blind, placebo-controlled, phase 3 study. Lancet. Oncology211489\u20131499. (https:\/\/doi.org\/10.1016\/S1470-2045(2030493-9)"},{"key":"bib28","series-title":"Lancet. 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(https:\/\/doi.org\/10.1016\/S1470-2045(2030496-4)"},{"key":"bib29","series-title":"Molecular Cancer Therapeutics","first-page":"2298","article-title":"Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth","volume":"10","author":"Yakes","year":"2011","unstructured":"Yakes FMChen JTan JYamaguchi KShi YYu PQian FChu FBentzien FCancilla B, 2011Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. Molecular Cancer Therapeutics102298\u20132308. (https:\/\/doi.org\/10.1158\/1535-7163.MCT-11-0264)"},{"key":"bib30","series-title":"New England Journal of Medicine","first-page":"514","article-title":"Everolimus for advanced pancreatic neuroendocrine tumors","volume":"364","author":"Yao","year":"2011","unstructured":"Yao JCShah MHIto TBohas CLWolin EMVan Cutsem EHobday TJOkusaka TCapdevila Jde Vries EG, 2011Everolimus for advanced pancreatic neuroendocrine tumors. New England Journal of Medicine364514\u2013523. 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