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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...

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Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2012
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.
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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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