Inhibition of Hedgehog Signaling Enhances Delivery of Chemotherapy in a Mouse Model of Pancreatic Cancer

• DOI: 10.1126/science.1171362
• Publication Date: 2009-05-22T01:44:31Z
• Authors: Kenneth P. Olive; Michael A. Jacobetz; Christian J. Davi...; Aarthi Gopinathan; Dominick McIntyre; Davina Honess; Basetti Madhu; Mae A. Goldgraben; Meredith E. Caldwell; David Allard; Kristopher K. Frese; Gina DeNicola; Christine Feig; Chelsea Combs; Stephen P. Winter; Heather Ireland-Z...; Stefanie Reichelt; William J. Howat; Alex Chang; Mousumi Dhara; Lifu Wang; Felix Rückert; Robert Grützmann; Christian Pilarsky; Kamel Izeradjene; Sunil R. Hingorani; Pearl Huang; Susan E. Davies; William Plunkett; Merrill Egorin; Ralph H. Hruban; Nigel Whitebread; Karen McGovern; Julian Adams; Christine Iacobuz...; John Griffiths; David A. Tuveson
• Keywords: 0301 basic medicine; Neovascularization, Pathologic; Kruppel-Like Transcription Factors; Antineoplastic Agents; Apoptosis; Deoxycytidine; Smoothened Receptor; Receptors, G-Protein-Coupled; 3. Good health; Pancreatic Neoplasms; Disease Models, Animal; Mice; 03 medical and health sciences; Drug Resistance, Neoplasm; Cell Line, Tumor; Antineoplastic Combined Chemotherapy Protocols; Animals; Humans; Hedgehog Proteins; Neoplasm Transplantation; Carcinoma, Pancreatic Ductal; Cell Proliferation; Signal Transduction

Pancreatic ductal adenocarcinoma (PDA) is among the most lethal human cancers in part because it insensitive to many chemotherapeutic drugs. Studying a mouse model of PDA that refractory clinically used drug gemcitabine, we found tumors this were poorly perfused and vascularized, properties are shared with PDA. We tested whether delivery efficacy gemcitabine mice could be improved by coadministration IPI-926, depletes tumor-associated stromal tissue inhibition Hedgehog cellular signaling pathway. The combination therapy produced transient increase intratumoral vascular density concentration leading stabilization disease. Thus, inefficient may an important contributor chemoresistance pancreatic cancer.