Activity of the T-type calcium channel antagonist Mibefradil in pancreatic cancer xenografts

B49 Background: Pancreatic cancer is the forth leading cancer death in US. More than 80% of pancreatic adenocarcinomas are unresectable on diagnosis. The standard treatment in this setting is gemcitabine. Response rates are lower than 10%. Novel therapies are urgently needed. Mibefradil is a T-type calcium channel inhibitor that exerts a cytostatic effect on cancer cells. Here we explored the activity of Mibefradil in a direct pancreatic cancer xenografts model using a molecular mimicry approach to select tumors more likely to be sensitive to the drug. Methods: We first normalized the activity of Mibefradil across the NCI-60 cell lines and defined cell lines as sensitive and resistant if the normalized GI50 -1, respectively. We used a molecular mimicry approach to predict Mibefradil sensitivity of seven xenografts based on their pathway expression similarity to NCI-60 cell lines. We treated these selected xenografts with Mibefradil 65mg/Kg PO bid for 28 days. Results: Xenograft Panc 219 was predicted as the most sensitive to Mibefradil based on its molecular mimicry with ME2, the top cell line sensitive to Mibefradil. The TGI for Panc 219 was 12%. Xenograft Panc 215 was predicted to be resistant based on its connection to NSCLC4, the top cell line resistant to Mibefradil. The TGI for 215 was 145%. The rest of the xenografts were connected to resistant cell lines and were found to be resistant when treated with the drug. Conclusions: Mibefradil was very effective in treating a patient derived pancreas xenograft model and this activity was correctly predicted based on the activity of the drug against a reference set of cancer cell lines. This approach may help to identify patients for clinical trials with Mibefradil.