PDX-1 is a therapeutic target for pancreatic cancer, insulinoma and islet neoplasia using a novel RNA interference platform

• Published in: PloS one Vol. 7; no. 8; p. e40452
• Main Authors: Liu, Shi-He, Rao, Donald D, Nemunaitis, John, Senzer, Neil, Zhou, Guisheng, Dawson, David, Gingras, Marie-Claude, Wang, Zhaohui, Gibbs, Richard, Norman, Michael, Templeton, Nancy S, Demayo, Francesco J, O'Malley, Bert, Sanchez, Robbi, Fisher, William E, Brunicardi, F Charles
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 08.08.2012; Public Library of Science (PLoS)
• Subjects: Animal models; Animals; Apoptosis; Biology; Cancer; Cancer genetics; Cell Line, Tumor; Cell Proliferation; Cells (Biology); Cellular biology; Disease Models, Animal; Gene expression; Gene therapy; Genomes; Glucose Tolerance Test; Health aspects; Homeobox; Homeodomain Proteins - metabolism; Humans; Hyperinsulinemia; Hypoglycemia; Immunohistochemistry; Immunohistochemistry - methods; In Situ Nick-End Labeling; Insulin; Insulin - metabolism; Insulinoma; Insulinoma - therapy; Interference; Islets of Langerhans - metabolism; Laboratory animals; Lung cancer; Male; Medical research; Medicine; Mice; Mice, SCID; Neoplasm Transplantation; Neuroendocrine tumors; Pancreas; Pancreas - metabolism; Pancreatic cancer; Pancreatic diseases; Pancreatic Neoplasms - therapy; Pathology; Physicians; Polypeptides; Ribonucleic acid; RNA; RNA Interference; RNA-mediated interference; Rodents; Surgery; Therapeutic applications; Trans-Activators - metabolism; Tumors; Xenografts; Xenotransplantation; Los Angeles California; California; United States > US; Texas
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0040452

Pancreatic and duodenal homeobox-1 (PDX-1) is a transcription factor that regulates insulin expression and islet maintenance in the adult pancreas. Our recent studies demonstrate that PDX-1 is an oncogene for pancreatic cancer and is overexpressed in pancreatic cancer. The purpose of this study was to demonstrate that PDX-1 is a therapeutic target for both hormonal symptoms and tumor volume in mouse models of pancreatic cancer, insulinoma and islet neoplasia. Immunohistochemistry of human pancreatic and islet neoplasia specimens revealed marked PDX-1 overexpression, suggesting PDX-1 as a "drugable" target within these diseases. To do so, a novel RNA interference effector platform, bifunctional shRNA(PDX-1), was developed and studied in mouse and human cell lines as well as in mouse models of pancreatic cancer, insulinoma and islet neoplasia. Systemic delivery of bi-shRNA(humanPDX-1) lipoplexes resulted in marked reduction of tumor volume and improved survival in a human pancreatic cancer xenograft mouse model. bi-shRNA(mousePDX-1) lipoplexes prevented death from hyperinsulinemia and hypoglycemia in an insulinoma mouse model. shRNA(mousePDX-1) lipoplexes reversed hyperinsulinemia and hypoglycemia in an immune-competent mouse model of islet neoplasia. PDX-1 was overexpressed in pancreatic neuroendocrine tumors and nesidioblastosis. These data demonstrate that PDX-1 RNAi therapy controls hormonal symptoms and tumor volume in mouse models of pancreatic cancer, insulinoma and islet neoplasia, therefore, PDX-1 is a potential therapeutic target for these pancreatic diseases.