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

It's All in the Delivery

Pancreatic cancer is almost universally associated with a poor prognosis, in part because the tumors are resistant to chemotherapeutic drugs. Working with a mouse tumor model that displays many features of the human disease,

Olive et al.

(p. 1457 , published online 21 May; see the Perspective by

Olson and Hanahan

) found that the tumors were poorly vascularized, a factor likely to impede drug delivery. Treatment of the mice with the chemotherapeutic drug gemcitabine in combination with a drug that depletes tumor-associated stromal tissue led to an increase in tumor vasculature, enhanced delivery of gemcitabine, and a delay in disease progression. Thus, drugs targeting the tumor stroma may merit investigation as a way to enhance the efficacy of conventional chemotherapy for pancreatic cancer.