4.7 Article

Gamma secretase inhibition promotes hypoxic necrosis in mouse pancreatic ductal adenocarcinoma

期刊

JOURNAL OF EXPERIMENTAL MEDICINE
卷 209, 期 3, 页码 437-444

出版社

ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20111923

关键词

-

资金

  1. Cancer Research UK Funding Source: Medline
  2. NCI NIH HHS [F32CA123887-01, F32 CA123887] Funding Source: Medline
  3. Cancer Research UK [15678] Funding Source: researchfish

向作者/读者索取更多资源

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.

作者

我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。

评论

主要评分

4.7
评分不足

次要评分

新颖性
-
重要性
-
科学严谨性
-
评价这篇论文

推荐

暂无数据
暂无数据