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Gamma secretase inhibition promotes hypoxic necrosis in mouse pancreatic ductal adenocarcinoma
Pancreatic ductal adenocarcinoma (PDA) is a highly lethal disease that is refractory to medical intervention. Notch pathway antagonism has been shown to prevent pancreatic preneoplasia progression in mouse models, but potential benefits in the setting of an established PDA tumor have not been establ...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The Rockefeller University Press
2012
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3302221/ https://www.ncbi.nlm.nih.gov/pubmed/22351932 http://dx.doi.org/10.1084/jem.20111923 |
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author | Cook, Natalie Frese, Kristopher K. Bapiro, Tashinga E. Jacobetz, Michael A. Gopinathan, Aarthi Miller, Jodi L. Rao, Sudhir S. Demuth, Tim Howat, William J. Jodrell, Duncan I. Tuveson, David A. |
author_facet | Cook, Natalie Frese, Kristopher K. Bapiro, Tashinga E. Jacobetz, Michael A. Gopinathan, Aarthi Miller, Jodi L. Rao, Sudhir S. Demuth, Tim Howat, William J. Jodrell, Duncan I. Tuveson, David A. |
author_sort | Cook, Natalie |
collection | PubMed |
description | Pancreatic ductal adenocarcinoma (PDA) is a highly lethal disease that is refractory to medical intervention. Notch pathway antagonism has been shown to prevent pancreatic preneoplasia progression in mouse models, but potential benefits in the setting of an established PDA tumor have not been established. We demonstrate that the gamma secretase inhibitor MRK003 effectively inhibits intratumoral Notch signaling in the KPC mouse model of advanced PDA. Although MRK003 monotherapy fails to extend the lifespan of KPC mice, the combination of MRK003 with the chemotherapeutic gemcitabine prolongs survival. Combination treatment kills tumor endothelial cells and synergistically promotes widespread hypoxic necrosis. These results indicate that the paucivascular nature of PDA can be exploited as a therapeutic vulnerability, and the dual targeting of the tumor endothelium and neoplastic cells by gamma secretase inhibition constitutes a rationale for clinical translation. |
format | Online Article Text |
id | pubmed-3302221 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | The Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-33022212012-09-12 Gamma secretase inhibition promotes hypoxic necrosis in mouse pancreatic ductal adenocarcinoma Cook, Natalie Frese, Kristopher K. Bapiro, Tashinga E. Jacobetz, Michael A. Gopinathan, Aarthi Miller, Jodi L. Rao, Sudhir S. Demuth, Tim Howat, William J. Jodrell, Duncan I. Tuveson, David A. J Exp Med Brief Definitive Report Pancreatic ductal adenocarcinoma (PDA) is a highly lethal disease that is refractory to medical intervention. Notch pathway antagonism has been shown to prevent pancreatic preneoplasia progression in mouse models, but potential benefits in the setting of an established PDA tumor have not been established. We demonstrate that the gamma secretase inhibitor MRK003 effectively inhibits intratumoral Notch signaling in the KPC mouse model of advanced PDA. Although MRK003 monotherapy fails to extend the lifespan of KPC mice, the combination of MRK003 with the chemotherapeutic gemcitabine prolongs survival. Combination treatment kills tumor endothelial cells and synergistically promotes widespread hypoxic necrosis. These results indicate that the paucivascular nature of PDA can be exploited as a therapeutic vulnerability, and the dual targeting of the tumor endothelium and neoplastic cells by gamma secretase inhibition constitutes a rationale for clinical translation. The Rockefeller University Press 2012-03-12 /pmc/articles/PMC3302221/ /pubmed/22351932 http://dx.doi.org/10.1084/jem.20111923 Text en © 2012 Cook et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/). |
spellingShingle | Brief Definitive Report Cook, Natalie Frese, Kristopher K. Bapiro, Tashinga E. Jacobetz, Michael A. Gopinathan, Aarthi Miller, Jodi L. Rao, Sudhir S. Demuth, Tim Howat, William J. Jodrell, Duncan I. Tuveson, David A. Gamma secretase inhibition promotes hypoxic necrosis in mouse pancreatic ductal adenocarcinoma |
title | Gamma secretase inhibition promotes hypoxic necrosis in mouse pancreatic ductal adenocarcinoma |
title_full | Gamma secretase inhibition promotes hypoxic necrosis in mouse pancreatic ductal adenocarcinoma |
title_fullStr | Gamma secretase inhibition promotes hypoxic necrosis in mouse pancreatic ductal adenocarcinoma |
title_full_unstemmed | Gamma secretase inhibition promotes hypoxic necrosis in mouse pancreatic ductal adenocarcinoma |
title_short | Gamma secretase inhibition promotes hypoxic necrosis in mouse pancreatic ductal adenocarcinoma |
title_sort | gamma secretase inhibition promotes hypoxic necrosis in mouse pancreatic ductal adenocarcinoma |
topic | Brief Definitive Report |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3302221/ https://www.ncbi.nlm.nih.gov/pubmed/22351932 http://dx.doi.org/10.1084/jem.20111923 |
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