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Originally published in Science Express on 21 May 2009
Science 12 June 2009:
Vol. 324. no. 5933, pp. 1457 - 1461
DOI: 10.1126/science.1171362
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Reports

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

Kenneth P. Olive,1 Michael A. Jacobetz,1,* Christian J. Davidson,2,* Aarthi Gopinathan,1,2,* Dominick McIntyre,1 Davina Honess,1 Basetti Madhu,1 Mae A. Goldgraben,1 Meredith E. Caldwell,1 David Allard,1 Kristopher K. Frese,1 Gina DeNicola,1,2 Christine Feig,1 Chelsea Combs,2 Stephen P. Winter,1 Heather Ireland-Zecchini,1 Stefanie Reichelt,1 William J. Howat,1 Alex Chang,3 Mousumi Dhara,3 Lifu Wang,2,4 Felix Rückert,5 Robert Grützmann,5 Christian Pilarsky,5 Kamel Izeradjene,6 Sunil R. Hingorani,6 Pearl Huang,7 Susan E. Davies,8 William Plunkett,9 Merrill Egorin,10 Ralph H. Hruban,3 Nigel Whitebread,11 Karen McGovern,11 Julian Adams,11 Christine Iacobuzio-Donahue,3 John Griffiths,1 David A. Tuveson1,{dagger}

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

1 Cancer Research UK, Cambridge Research Institute, The Li Ka Shing Centre, Robinson Way, Cambridge CB2 ORE, UK.
2 Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.
3 Departments of Oncology and Pathology, The Sol Goldman Pancreatic Cancer Research Center, Sidney Cancer Center and Johns Hopkins University, Baltimore, MD 21287, USA.
4 Department of Gastroenterology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China.
5 Department of Surgery, University Hospital Dresden, Fetscherstrasse 74, 01307 Dresden, Germany.
6 Clinical Research and Public Health Sciences Division, Fred Hutchinson Cancer Research Center (FHCRC), and University of Washington, Seattle, WA 98109, USA.
7 Oncology Franchise, Merck and Company, North Wales, PA 19454, USA.
8 Department of Histopathology, Addenbrooke’s Hospital, Cambridge University Hospitals National Health Service (NHS) Foundation Trust, Cambridge CB2 2QQ, UK.
9 M. D. Anderson Cancer Center, University of Texas, Houston, TX 77030, USA.
10 Division of Hematology and Oncology, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA.
11 Infinity Pharmaceuticals, Cambridge, MA 01239, USA.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: david.tuveson{at}cancer.org.uk

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THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
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