Targeting Notch in Pancreatic Cancer


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Natalie Cook1,Kris Frese1,Mike Jacobetz1,Meredith Caldwell-Jacobetz1,Tashinga Bapiro1,Aimee Michael2,Christopher Winter2,Duncan Jodrell1,David Tuveson1
1Cancer Research UK Cambridge Research Institute, Cambridge, United Kingdom,2Merck Research Laboratories, Boston, United States

Background

Pancreatic cancer is an almost uniformly lethal disease with no effective therapeutic options, emphasizing the urgent need for new approaches.  Components of the Notch signalling cascade have been shown to be upregulated in human pancreatic ductal adenocarcinoma (PDA), suggesting this pathway may be an attractive therapeutic target.

Method

By expressing endogenous KRASG12D and conditionally mutant p53 alleles our laboratory has created a spontaneous murine model of PDA, the KPC model. This model accurately recapitulates the pathophysiological aspects of human pancreatic cancer and also demonstrates poor response to gemcitabine, the standard treatment for patients. We have used these mice to evaluate the efficacy of gamma secretase inhibitors (GSI), drugs that impair Notch receptor cleavage. The same mice have also been bred to mice harbouring a conditional dominant negative mastermind allele (DN-MM) to genetically impair the Notch pathway in pancreatic cancer tumour cells.

Results

KPC mice treated with GSI and gemcitabine lived significantly longer than either treatment alone (median survival; vehicle: 9 days vs. combination treatment: 26 days; (p=0.002)). Furthermore, combination therapy significantly inhibited tumour growth and increased apoptosis and necrosis in the pancreatic tumours. The GSI effectively inhibited certain Notch pathway components and target genes. Preliminary data indicates the combination treatment caused increased levels of hypoxia in the tumours due to a decrease in vasculature within the tumour.  Interestingly, the genetic antagonism of the Notch pathway with DN-MM had negligible effects on early pancreatic cancer intitiation in mice expressing KRASG12D, supporting our hypothesis that GSI affects both the microenvironment and tumour cells to mediate anti-tumour effects.

Conclusion

In a pre-clinical model of pancreatic cancer we have shown that GSI and gemcitabine prolong survival. Our results have been extended to a phase I/II clinical trial for patients with metastatic pancreatic cancer that we opened in May 2010.