title: Nintedanib Is a Highly Effective Therapeutic for Neuroendocrine Carcinoma of the Pancreas (PNET) in the Rip1Tag2 Transgenic Mouse Model.
abstract: OBJECTIVE
  Pancreatic neuroendocrine tumors (PNET) represent a rare but challenging heterogeneous group of cancers with an increasing incidence over the last number of decades. Herein, we report an in-depth evaluation of the new antiangiogenic small-molecule tyrosine kinase inhibitor (TKI) nintedanib in the preclinical Rip1Tag2 transgenic mouse model of neuroendocrine carcinoma of the pancreas (insulinoma).
  
  
  METHODS
  We have assessed the antiangiogenic and antitumor activity of nintedanib, in comparison with other antiangiogenic TKI, by treating Rip1Tag2 transgenic mice with different treatment schedules complemented with histopathologic, cell biologic, and biochemical analyses.
  
  
  RESULTS
  Prolonged nintedanib treatment of Rip1Tag2 mice has led to a strong suppression of angiogenesis, accompanied by a reduced tumor burden, which translated into a significant prolongation of survival. Despite nintedanib's inhibitory action on perivascular cells, the blood vessels remaining after therapy displayed a considerably mature phenotype with tight perivascular cell coverage and preserved perfusion. Nintedanib treatment did not increase local tumor invasiveness or metastasis to the liver and pancreatic lymph nodes--a phenomenon that has been observed with antiangiogenic treatments of Rip1Tag2 transgenic mice in other laboratories. In contrast with the strong reduction in blood microvessel densities, nintedanib did not have any impact on tumor lymphangiogenesis.
  
  
  CONCLUSIONS
  Based on our findings, we propose the clinical evaluation of the antiangiogenic drug nintedanib as a new treatment modality for PNET patients, notably in a direct comparison with already established therapeutic regimens, such as sunitinib.
authors.affiliation: Department of Biomedicine, University of Basel, Basel, Switzerland.
authors.forename: Ruben
authors.initials: R
authors.lastname: Bill
authors.affiliation: Department of Biomedicine, University of Basel, Basel, Switzerland.
authors.forename: Ernesta
authors.initials: E
authors.lastname: Fagiani
authors.affiliation: Department of Biomedicine, University of Basel, Basel, Switzerland.
authors.forename: Adrian
authors.initials: A
authors.lastname: Zumsteg
authors.affiliation: Department of Biomedicine, University of Basel, Basel, Switzerland.
authors.forename: Helena
authors.initials: H
authors.lastname: Antoniadis
authors.affiliation: Department of Biomedicine, University of Basel, Basel, Switzerland.
authors.forename: David
authors.initials: D
authors.lastname: Johansson
authors.affiliation: Department of Biomedicine, University of Basel, Basel, Switzerland.
authors.forename: Simon
authors.initials: S
authors.lastname: Haefliger
authors.affiliation: Department of Biomedicine, University of Basel, Basel, Switzerland.
authors.forename: Imke
authors.initials: I
authors.lastname: Albrecht
authors.affiliation: Boehringer Ingelheim Austria RCV GmbH & Co KG, Vienna, Austria.
authors.forename: Frank
authors.initials: F
authors.lastname: Hilberg
authors.affiliation: Department of Biomedicine, University of Basel, Basel, Switzerland. gerhard.christofori@unibas.ch.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Christofori
mesh_terms: D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000235:genetics*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D018278:Carcinoma, Neuroendocrine / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D005260:Female; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D007328:Insulin / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D010641:Phenotype; D011401:Promoter Regions, Genetic; D015398:Signal Transduction / Q000187:drug effects; D047368:Tumor Burden; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000378:metabolism
chemical_list: D000952:Antigens, Polyomavirus Transforming; D000970:Antineoplastic Agents; D007211:Indoles; D007328:Insulin; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2; D040321:Vascular Endothelial Growth Factor Receptor-3; C530716:nintedanib