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Submitted on January 26, 2009
Accepted on April 23, 2009
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 3,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 3,Christine Feig 1,Chelsea Combs 2,Stephen P. Winter 1,Heather Ireland 1,Stefanie Reichelt 1,William J. Howat 1,Alex Chang 4,Mousumi Dhara 4,Lifu Wang 5,Felix Rückert 6,Robert Grützmann 6,Christian Pilarsky 6,Kamel Izeradjene 7,Sunil R. Hingorani 7,Pearl Huang 8,Susan E. Davies 9,William Plunkett 10,Merrill Egorin 11,Ralph H. Hruban 4,Nigel Whitebread 12,Karen McGovern 12,Julian Adams 12,Christine Iacobuzio-Donahue 4,John Griffiths 1,David A. Tuveson 1*
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 Cancer Research UK, Cambridge Research Institute, The Li Ka Shing Centre, Robinson Way, Cambridge, CB2 ORE, UK.; Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA 19104, USA. 4 Departments of Oncology and Pathology, The Sol Goldman Pancreatic Cancer Research Center, Sidney Cancer Center and Johns Hopkins University, Baltimore, MD 21287, USA. 5 Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.; Department of Gastroenterology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China. 6 Department of Surgery, University Hospital Dresden, Fetscherstr. 74, 01307 Dresden, Germany. 7 Clinical Research and Public Health Sciences Division, Fred Hutchinson Cancer Research Center, and University of Washington, Seattle, WA 98109, USA. 8 Oncology Franchise, Merck and Co, North Wales, PA 19454, USA. 9 Department of Histopathology, Addenbrooke’s Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, CB2 2QQ, UK. 10 Univ. of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. 11 Division of Hematology and Oncology, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA. 12 Infinity Pharmaceuticals Inc, Cambridge, MA 01239, USA.
* To whom correspondence should be addressed.
David A. Tuveson , E-mail: david.tuveson{at}cancer.org.uk
These authors contributed equally to this work.
Pancreatic ductal adenocarcinoma (PDA) is among the most lethalhuman cancers, in part because it is insensitive to many chemotherapeuticdrugs. Studying a mouse model of PDA that is refractory to theclinically used drug gemcitabine, we found that the tumors inthis model were poorly perfused and poorly vascularized, propertiesthat are shared with human PDA. We tested whether the deliveryand efficacy of gemcitabine in the mice could be improved bycoadministration of IPI-926, a drug that depletes tumor-associatedstromal tissue by inhibiting the Hedgehog cellular signalingpathway. The combination therapy produced a transient increasein intratumoral vascular density and intratumoral concentrationof gemcitabine, leading to transient stabilization of disease.Thus, inefficient drug delivery may be an important contributorto chemoresistance in pancreatic cancer.
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