Notch signaling plays a crucial role during pancreatic development by maintaining pancreatic progenitor cells in an undifferentiated state. Notch signaling is activated in premalignant PanIN lesions (pancreatic intraepithelial neoplasia), and pancreatic cancer cell lines exhibit heightened sensitivity to Notch pathway inhibition. To determine whether the evolution from PanIN to adenocarcinoma requires Notch signaling, we performed a preventive trial in mice by inhibiting gamma secretase, an essential mediator of Notch signaling. Gamma secretase inhibition prevented the development of adenocarcinoma when animals bearing premalignant PanIN lesions were treated for several weeks. The drug was well tolerated. These results suggest that progression from premalignant PanIN lesions to pancreatic adenocarcinoma requires active Notch signaling. The Notch pathway may provide an attractive target for prevention or therapy in this treatment‐refractory malignancy.

Citation Information: Cancer Prev Res 2010;3(1 Suppl):CN10-02.