mrk-003 and Carcinoma--Pancreatic-Ductal

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.

Topics: Amyloid Precursor Protein Secretases; Animals; Carcinoma, Pancreatic Ductal; Cell Line, Tumor; Cell Proliferation; Cyclic S-Oxides; Deoxycytidine; Drug Synergism; Drug Therapy, Combination; Endothelial Cells; Gemcitabine; Humans; Hypoxia; Mice; Mice, Mutant Strains; Necrosis; Pancreatic Neoplasms; Protease Inhibitors; Receptors, Notch; Signal Transduction; Thiadiazoles; Translational Research, Biomedical

The Notch signaling pathway is required for the expansion of undifferentiated pancreatic progenitor cells during embryonic development and has been implicated in the progression of pancreatic ductal adenocarcinoma (PDAC). The interaction of Notch ligands with their receptors promotes a gamma-secretase-dependent cleavage of the Notch receptor and release of the Notch intracellular domain, which translocates to the nucleus and activates transcription. We investigated the role of this pathway in PDAC progression.. We tested the effects of a gamma-secretase inhibitor (GSI) that blocks Notch signaling in PDAC cell lines and a genetically engineered mouse model of PDAC (Kras p53 L/+ mice).. Notch signaling was activated in PDAC precursors and advanced tumors. The GSI inhibited the growth of premalignant pancreatic duct-derived cells in a Notch-dependent manner. Additionally, in a panel of over 400 human solid tumor-derived cell lines, PDAC cells, as a group, were more sensitive to the GSI than any other tumor type. Finally, the GSI completely inhibited tumor development in the genetically engineered model of invasive PDAC (P < .005, chi2 test; compared with mice exposed to vehicle).. These results suggest that Notch signaling is required for PDAC progression. Pharmacologic targeting of this pathway offers therapeutic potential in this treatment-refractory malignancy.

Topics: Amyloid Precursor Protein Secretases; Animals; Carcinoma, Pancreatic Ductal; Cell Line; Cell Line, Tumor; Cyclic S-Oxides; Disease Progression; Humans; Mice; Mice, Transgenic; Pancreatic Neoplasms; Receptors, Notch; Signal Transduction; Thiadiazoles