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Science 324 (5933): 1457-1461

Copyright © 2009 by the American Association for the Advancement of Science

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}

Abstract: 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}

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A. Gopinathan, G. M. DeNicola, K. K. Frese, N. Cook, F. A. Karreth, J. Mayerle, M. M. Lerch, T. Reinheckel, and D. A. Tuveson (2012)
Gut 61, 877-884
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Genetically Engineered Mouse Models: Closing the Gap between Preclinical Data and Trial Outcomes.
M. Singh, C. L. Murriel, and L. Johnson (2012)
Cancer Res. 72, 2695-2700
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Cancer drug pan-resistance: pumps, cancer stem cells, quiescence, epithelial to mesenchymal transition, blocked cell death pathways, persisters or what?.
P. Borst (2012)
Open Bio 2, 120066
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Hedgehog pathway inhibitor saridegib (IPI-926) increases lifespan in a mouse medulloblastoma model.
M. J. Lee, B. A. Hatton, E. H. Villavicencio, P. C. Khanna, S. D. Friedman, S. Ditzler, B. Pullar, K. Robison, K. F. White, C. Tunkey, et al. (2012)
PNAS 109, 7859-7864
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Abstract IA5: Developing therapeutics in mice with ductal pancreatic cancer.
D. A. Tuveson (2012)
Clin. Cancer Res. 18, IA5
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Generation of primary tumors with Flp recombinase in FRT-flanked p53 mice.
C.-L. Lee, E. J. Moding, X. Huang, Y. Li, L. Z. Woodlief, R. C. Rodrigues, Y. Ma, and D. G. Kirsch (2012)
Dis. Model. Mech. 5, 397-402
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Cotargeting MAPK and PI3K Signaling with Concurrent Radiotherapy as a Strategy for the Treatment of Pancreatic Cancer.
T. M. Williams, A. R. Flecha, P. Keller, A. Ram, D. Karnak, S. Galban, C. J. Galban, B. D. Ross, T. S. Lawrence, A. Rehemtulla, et al. (2012)
Mol. Cancer Ther. 11, 1193-1202
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The activity of Gli transcription factors is essential for Kras-induced pancreatic tumorigenesis.
M. Rajurkar, W. E. De Jesus-Monge, D. R. Driscoll, V. A. Appleman, H. Huang, J. L. Cotton, D. S. Klimstra, L. J. Zhu, K. Simin, L. Xu, et al. (2012)
PNAS 109, E1038-E1047
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Gamma secretase inhibition promotes hypoxic necrosis in mouse pancreatic ductal adenocarcinoma.
N. Cook, K. K. Frese, T. E. Bapiro, M. A. Jacobetz, A. Gopinathan, J. L. Miller, S. S. Rao, T. Demuth, W. J. Howat, D. I. Jodrell, et al. (2012)
J. Exp. Med. 209, 437-444
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New strategies and designs in pancreatic cancer research: consensus guidelines report from a European expert panel.
J.- L. Van Laethem, C. Verslype, J. L. Iovanna, P. Michl, T. Conroy, C. Louvet, P. Hammel, E. Mitry, M. Ducreux, T. Maraculla, et al. (2012)
Ann. Onc. 23, 570-576
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nab-Paclitaxel Potentiates Gemcitabine Activity by Reducing Cytidine Deaminase Levels in a Mouse Model of Pancreatic Cancer.
K. K. Frese, A. Neesse, N. Cook, T. E. Bapiro, M. P. Lolkema, D. I. Jodrell, and D. A. Tuveson (2012)
Cancer Discovery 2, 260-269
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The extracellular matrix: A dynamic niche in cancer progression.
P. Lu, V. M. Weaver, and Z. Werb (2012)
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Hedgehog Signaling Inhibition Blocks Growth of Resistant Tumors through Effects on Tumor Microenvironment.
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Cancer Res. 72, 897-907
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Origins of tumor-associated macrophages and neutrophils.
V. Cortez-Retamozo, M. Etzrodt, A. Newton, P. J. Rauch, A. Chudnovskiy, C. Berger, R. J. H. Ryan, Y. Iwamoto, B. Marinelli, R. Gorbatov, et al. (2012)
PNAS 109, 2491-2496
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Stratification of Nucleoside Analog Chemotherapy Using 1-(2'-Deoxy-2'-18F-Fluoro-{beta}-D-Arabinofuranosyl)Cytosine and 1-(2'-Deoxy-2'-18F-Fluoro-{beta}-L-Arabinofuranosyl)-5-Methylcytosine PET.
J. T. Lee, D. O. Campbell, N. Satyamurthy, J. Czernin, and C. G. Radu (2012)
J. Nucl. Med. 53, 275-280
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