Development of gene therapy to target pancreatic cancer.

Pancreatic cancer remains one of the most difficult cancers to treat. Its high propensity to infiltrate and metastasize early from a small primary focus necessitates development of a new therapy which can track down the disseminated cancer cells in vivo. Gene therapy may offer new opportunities for a variety of targeting strategies, and we review here some of our work related to the development of targeted gene therapy: 1) Targeting by specific molecular abnormality: Many pancreatic cancer cells show "addiction" to K-ras mutation, while normal cells appear resistant to suppression of K-ras-mediated signaling by antisense K-ras RNA expression adenoviral vector. 2) Targeting by in vivo tumor characteristics: In a peritoneal dissemination model, intraperitoneal lipofection/polyfection can deliver and express transgenes highly preferentially in tumor nodules. 3) Targeting by vector: An efficient protocol for construction of an adenovirus expression vector library has been developed, which will enable a direct functional selection of fiber knob-modified targeting vector species for given cells. 4) Targeting by tumor immunity: Several cytokines not only induce direct cytotoxicity, but are also expected to activate specific immunity to achieve targeted suppression of cancer cells in vivo. Unlike parenteral administration of short-lived recombinant interferon protein, local interferon gene transfer can provide a target tissue-restricted distribution and sustained expression, which may improve the efficacy/safety balance of cytokine therapy. Cancer gene therapy development is, in general, at the stage of proof of principles and safety. However, it is an art of integrated science. The recent rapid progress of related sciences and technologies will expand the potential and consolidate the clinical reality of gene therapy.