E-Mail karger@karger.com Original Paper Neuroendocrinology 2013;97:331–340 DOI: 10.1159/000347063 Antitumor Effect of Everolimus in Preclinical Models of High-Grade Gastroenteropancreatic Neuroendocrine Carcinomas Julien Bollard a Christophe Couderc a Martine Blanc a Gilles Poncet a, b Florian Lepinasse a, c Valérie Hervieu a, c Géraldine Gouysse c Carole Ferraro-Peyret a, c Noura Benslama a, b Thomas Walter a, b Jean-Yves Scoazec a, c Colette Roche a a Endocrine Differentiation and Tumorigenesis Laboratory, Centre de Recherche en Cancérologie de Lyon, INSERM U1052-CNRS UMR5286, Université de Lyon, Faculté Laënnec, b Hospices Civils de Lyon, Hôpital Edouard Herriot, Fédération des Spécialités Digestives and c Hospices Civils de Lyon, Hôpital Edouard Herriot, Service d’Anatomie Pathologique, Lyon, France ptosis and in situ expression of mTOR pathway components were assessed. Results: The expression of mTOR pathway components was comparable in STC-1 and GluTag cells and in human PDNECs and could be inhibited in vitro by everoli- mus. In vivo, the tumor volume of STC-1 and GluTag xeno- grafts was significantly reduced in treated animals (6.05 ± 1.84% as compared to 21.76 ± 3.88% in controls). Everolimus treatment also induced a significant decrease in Ki67 index and in the phosphorylation levels of the two major effectors of mTOR, p70S6K and 4E-BP1. Conclusion: Our experimental data suggest that mTOR inhibition could be considered a therapeutic option for high-grade gastroenteropancreatic neuroendocrine tumors. Copyright © 2013 S. Karger AG, Basel Introduction Gastroenteropancreatic neuroendocrine tumors (GEP NETs) are a distinctive subset of malignant tumors re- taining most of the structural, phenotypic and functional characteristics of normal endocrine cells of the digestive tract, which belong to the diffuse neuroendocrine cell sys- Key Words Poorly differentiated neuroendocrine tumors · Preclinical models · Animal model · mTOR · Everolimus Abstract Background/Aims: While the range of therapeutic options for well-differentiated gastroenteropancreatic neuroendo- crine tumors has recently increased with the emergence of targeted therapies, such as mTOR inhibitors, there is no re- cent progress in the treatment of poorly differentiated neu- roendocrine carcinomas (PDNECs). Since PDNECs have been shown to strongly express mTOR pathway components, the aim of the present study was to assess the antitumor effect of the mTOR inhibitor everolimus in preclinical models of PDNECs. Methods: The expression of mTOR pathway com- ponents and their response to everolimus were assessed in two neuroendocrine cell lines: STC-1 and GluTag. A xeno- graft model of intrahepatic dissemination in the nude mouse, based on the intrasplenic injection of either STC-1 and GluTag tumor cells, was used. Animals were started on everolimus treatment 3 days after injection. The effects of treatment on tumor growth, proliferative capacities, apo- Received: October 8, 2012 Accepted after revision: January 13, 2013 Published online: May 22, 2013 Colette Roche INSERM U1052, Faculté de Médecine Laënnec 7, rue Guillaume Paradin FR–69372 Lyon Cedex 8 (France) E-Mail colette.roche  @  inserm.fr © 2013 S. Karger AG, Basel 0028–3835/13/0974–0331$38.00/0 www.karger.com/nen Downloaded by: 198.143.37.1 - 12/30/2015 3:00:21 PM