ARTICLE | Distillery Therapeutics


January 11, 2017 12:53 AM UTC

Cell culture and mouse studies suggest dual inhibition of the HGF/SF/c-MET/Src and SHH/IGF-1/IGF1R pathways could help treat pancreatic ductal adenocarcinoma (PDAC). In human PDAC cell lines, the Src inhibitor Sprycel dasatinib or an IGF1R inhibitor tool compound decreased cell surface levels of annexin A2 (ANXA2), which is required for PDAC invasiveness. In co-culture of a human PDAC cell line and human cancer-associated fibroblasts, fibroblast knockdown of HGF/SF or IGF-1 decreased cancer cell invasiveness compared with normal expression of the two genes. Also in the co-culture, the c-MET inhibitor capmatinib plus an SHH/IGF-1 inhibitor tool compound decreased ANXA2 levels in cancer cells compared with either agent alone. In spontaneous and orthotopic xenograft mouse models of PDAC, the inhibitor combination decreased cancer cell levels of ANXA2 compared with either agent alone, and in the orthotopic xenograft model, the combination decreased primary tumor growth and the number of metastases compared with vehicle. Next steps could include combining and testing other inhibitors of the two pathways in PDAC models.

Incyte Corp. and Novartis AG have capmatinib (INC280) in Phase II testing for liver cancer, non-small cell lung cancer (NSCLC) and solid tumors...