PDX-1 is a therapeutic target for pancreatic cancer, insulinoma and islet neoplasia using a novel RNA interference platform.
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.
Department of Surgery, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California, United States of America.
Shi-He
SH
Liu
Donald D
DD
Rao
John
J
Nemunaitis
Neil
N
Senzer
Guisheng
G
Zhou
David
D
Dawson
Marie-Claude
MC
Gingras
Zhaohui
Z
Wang
Richard
R
Gibbs
Michael
M
Norman
Nancy S
NS
Templeton
Francesco J
FJ
Demayo
Bert
B
O'Malley
Robbi
R
Sanchez
William E
WE
Fisher
F Charles
FC
Brunicardi
D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004195:Disease Models, Animal; D005951:Glucose Tolerance Test; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D020287:In Situ Nick-End Labeling; D007328:Insulin / Q000378:metabolism; D007340:Insulinoma / Q000628:therapy*; D007515:Islets of Langerhans / Q000378:metabolism*; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D010179:Pancreas / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000628:therapy*; D034622:RNA Interference; D015534:Trans-Activators / Q000378:metabolism*
D018398:Homeodomain Proteins; D007328:Insulin; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein