Promoting Tumor Suppressor Activity in Pancreatic Cancer
Abstracts
Initial Award Abstract |
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Pancreatic ductal adenocarcinoma (PDA) is the fourth leading cause of cancer deaths, with an average life expectancy of 6 months after diagnosis. Tobacco use is estimated to cause 20-30% of PDA cases, and smoking also lowers the age of onset due to carcinogens in smoke, eg. NNK. Together the data underscore the need for new therapeutic and preventive avenues for this deadly disease, especially for smokers and others at high risk. We identified a gene, E2A that is inhibited in tumors form PDA patients. Remarkably, when we restored E2A activity in cells from patient tumors, the cells permanently stopped growing. In order to find a way to increase E2A activity in patients we screened for drugs that promote E2A activity. From a screen of 4375 known pharmaceuticals we identified Pitavastatin and Amlexanox. Preliminary studies in the lab show that each drug has an inhibitory effect on PDA cell growth. Importantly however, the combination is more effective than either drug alone. Here we propose to test the drugs individually and in combination in mouse models of PDA that include smoking related carcinogens. We will investigate both therapeutic and preventive efficacy of the drugs. A prophylactic approach to PDA would be especially important for smokers and other high-risk patients. Additionally, we will study the mechanisms by which the drugs induce E2A activity. Because the drugs are already known to be safe in humans, success in the proposed studies could provide a quick path to the clinic. |
