Molecular Target-Based Therapy of Pancreatic Cancer

Pancreatic cancer is genetically complex, and without effective therapy. Mutations in the Kirsten- ras (K- ras ) oncogene occur early and frequently (∼90%) during pancreatic cancer development and progression. In this context, K- ras represents a potential molecular target for the therapy of this highly aggressive cancer. We now show that a bipartite adenovirus expressing a novel cancer-specific apoptosis-inducing cytokine gene, mda-7 /interleukin-24 (IL-24), and a K- ras AS gene, but not either gene alone, promotes growth suppression, induction of apoptosis, and suppression of tumor development mediated by K- ras mutant pancreatic cancer cells. Equally, the combination of an adenovirus expressing mda-7 /IL-24 and pharmacologic and genetic agents simultaneously blocking K- ras or downstream extracellular regulated kinase 1/2 signaling also promotes similar inhibitory effects on the growth and survival of K- ras mutant pancreatic carcinoma cells. This activity correlates with the reversal of a translational block in mda-7 /IL-24 mRNA in pancreatic cancer cells that limits message association with polysomes, thereby impeding translation into protein. Our study provides support for a “dual molecular targeted therapy” involving oncogene inhibition and selective cancer apoptosis-inducing gene expression with potential for effectively treating an invariably fatal cancer. (Cancer Res 2006; 66(4): 2403-13)