Cancer

In vitro, cell culture and mouse studies identified a dimeric quinacrine-based PPT1 inhibitor that could help treat colorectal cancer, drug-resistant pancreatic cancer or drug-resistant melanoma. Chemical synthesis and in vitro testing of dimeric quinacrine analogs yielded a compound that inhibited growth of a human pancreatic cancer cell line with an IC₅₀ value below 100 nM, and in vitro and cell based-binding assays identified PPT1 as the compound's target. In a mouse pancreatic cancer cell line resistant to Gemzar gemcitabine, the compound decreased tumorsphere formation compared with vehicle. In a mouse model of Gemzar-resistant pancreatic cancer, the compound inhibited tumor growth compared with vehicle and the compound plus Gemzar inhibited tumor growth compared with either agent alone. In a xenograft mouse model of hydroxychloroquine-resistant melanoma, the compound decreased tumor growth compared with vehicle. In a xenograft mouse model of colorectal cancer, the compound decreased tumor growth and increased survival. Next steps could include testing the compound in additional models of colorectal, pancreatic and melanoma cancers.

Eli Lilly and Co. markets the nucleoside analog Gemzar to treat non-small cell lung cancer (NSCLC) and breast, ovarian and pancreatic cancers, and has the compound in Phase III testing to treat biliary cancer and cervical cancer and in Phase II testing to treat bladder cancer...