Cancer Research UK Cambridge Research Institute, Robinson Way, Cambridge CB2 0RE, England, UK.
J Exp Med. 2012 Mar 12;209(3):437-44. doi: 10.1084/jem.20111923. Epub 2012 Feb 20.
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.
胰腺导管腺癌 (PDA) 是一种高度致命的疾病，对医学干预具有抗性。研究表明，Notch 通路拮抗作用可预防小鼠模型中胰腺前病变的进展，但在已建立的 PDA 肿瘤中尚未确定其潜在益处。我们证明，γ分泌酶抑制剂 MRK003 可有效抑制 KPC 小鼠晚期 PDA 模型中的肿瘤内 Notch 信号。尽管 MRK003 单药治疗未能延长 KPC 小鼠的寿命，但 MRK003 与化疗药物吉西他滨联合使用可延长生存期。联合治疗可杀死肿瘤内皮细胞，并协同促进广泛的缺氧性坏死。这些结果表明，PDA 的少血管特性可被利用为治疗弱点，并且通过 γ 分泌酶抑制对肿瘤内皮细胞和肿瘤细胞的双重靶向构成了临床转化的合理依据。
