Abstract

Pancreatic cancer is the fourth leading cause of cancer-related deaths in this country, and there is currently no effective targeted treatment for this deadly disease. A dire need exists to rapidly translate our molecular understanding of this devastating disease into effective, novel therapeutic options. Mesothelin is a candidate target protein shown by a number of laboratories to be specifically overexpressed in pancreatic cancers and not in the adjacent normal tissue. Translational investigations have shown promising results using this molecule as a therapeutic target (e.g., vaccine strategies). In addition, the mesothelin promoter has been cloned and dissected and can therefore be used as a vehicle for regulating expression of DNA sequences. Using a novel, proven, biodegradable nanoparticulate system, we sought to target mesothelin-expressing pancreatic cancer cells with a potent suicide gene, diphtheria toxin-A (DT-A). We first confirmed reports that a majority of pancreatic cancer cell lines and resected pancreatic ductal adenocarcinoma specimens overexpressed mesothelin at the mRNA and protein levels. High mesothelin-expressing pancreatic cancer cell lines produced more luciferase than cell lines with undetectable mesothelin expression when transfected with a luciferase sequence under the regulation of the mesothelin promoter. We achieved dramatic inhibition of protein translation (>95%) in mesothelin-expressing pancreatic cancer cell lines when DT-A DNA, driven by the mesothelin promoter, was delivered to pancreatic cancer cells. We show that this inhibition effectively targets the death of pancreatic cancer cells that overexpress mesothelin. The work presented here provides evidence that this strategy will work in pre-clinical mouse pancreatic cancer models, and suggests that such a strategy will work in the clinical setting against the majority of pancreatic tumors, most of which overexpress mesothelin.