Inhibition of Hedgehog Signaling Enhances Delivery of Chemotherapy in a Mouse Model of Pancreatic Cancer
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.
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.
Get full access to this article
View all available purchase options and get full access to this article.
Supplementary Material
File (olive-som.pdf)
- Download
- 3.34 MB
References and Notes
1
Li D., Xie K., Wolff R., Abbruzzese J. L., Lancet 363, 1049 (2004).
2
Burris H. A., et al., J. Clin. Oncol. 15, 2403 (1997).
3
Tempero M., et al., J. Clin. Oncol. 21, 3402 (2003).
4
Bruns C. J., et al., Int. J. Cancer 102, 101 (2002).
5
Shimamura T., et al., Cancer Res. 67, 9903 (2007).
6
Verma A., et al., Clin. Cancer Res. 14, 2476 (2008).
7
Duan J. X., et al., J. Med. Chem. 51, 2412 (2008).
8
Melisi D., et al., Mol. Cancer Ther. 7, 829 (2008).
9
Schultz R. M., et al., Oncol. Res. 5, 223 (1993).
10
Hingorani S. R., et al., Cancer Cell 7, 469 (2005).
11
Hruban R. H., et al., Cancer Res. 66, 95 (2006).
12
Cook N., Olive K. P., Frese K., Tuveson D. A., Methods Enzymol. 439, 73 (2008).
13
Materials and methods are available as supporting material on Science Online.
14
Abbruzzese J. L., et al., J. Clin. Oncol. 9, 491 (1991).
15
Tredan O., Galmarini C. M., Patel K., Tannock I. F., J. Natl. Cancer Inst. 99, 1441 (2007).
16
Minchinton A. I., Tannock I. F., Nat. Rev. Cancer 6, 583 (2006).
17
Egorin M. J., Hildebrand R. C., Cimino E. F., Bachur N. R., Cancer Res. 34, 2243 (1974).
18
Yauch R. L., et al., Nature 455, 406 (2008).
19
Bailey J. M., et al., Clin. Cancer Res. 14, 5995 (2008).
20
Thayer S. P., et al., Nature 425, 851 (2003).
21
Tian H., et al., Proc. Natl. Acad. Sci. U.S.A. 106, 4254 (2009).
22
Nolan-Stevaux O., et al., Genes Dev. 23, 24 (2009).
23
Johnson J. I., et al., Br. J. Cancer 84, 1424 (2001).
24
Sofuni A., et al., J. Gastroenterol. 40, 518 (2005).
25
Sakamoto H., et al., Ultrasound Med. Biol. 34, 525 (2008).
26
Van Cutsem E., et al., J. Clin. Oncol. 27, 2231 (2009).
27
Pola R., et al., Nat. Med. 7, 706 (2001).
28
Langer S. J., Ghafoori A. P., Byrd M., Leinwand L., Nucleic Acids Res. 30, 3067 (2002).
(0)eLetters
eLetters is a forum for ongoing peer review. eLetters are not edited, proofread, or indexed, but they are screened. eLetters should provide substantive and scholarly commentary on the article. Embedded figures cannot be submitted, and we discourage the use of figures within eLetters in general. If a figure is essential, please include a link to the figure within the text of the eLetter. Please read our Terms of Service before submitting an eLetter.
Log In to Submit a ResponseNo eLetters have been published for this article yet.
Information & Authors
Information
Published In
Science
Volume 324 | Issue 5933
12 June 2009
12 June 2009
Copyright
Copyright © 2009, American Association for the Advancement of Science.
Article versions
You are viewing the most recent version of this article.
Submission history
Received: 26 January 2009
Accepted: 23 April 2009
Published in print: 12 June 2009
Acknowledgments
We thank the animal care staffs of the Cambridge Research Institute (CRI), University of Pennsylvania Translational Research Labs, FHCRC, and University Hospital Dresden as well as the histology and genomics cores at CRI, and P. Calses for technical assistance. We also thank B. Bean of Transnetyx Inc. for developing high-throughput genotyping assays for the KPC mice. This research was supported by the Lustgarten Foundation, the University of Cambridge and Cancer Research UK, The Li Ka Shing Foundation and Hutchison Whampoa Limited, the National Institute for Health Research Cambridge Biomedical Research Centre, and NIH (grants CA101973, CA111292, CA084291, and CA105490 to D.A.T.; K08 CA106610 to C.I.-D.; and CA15704 and CA114028 to S.R.H.). S.R.H. was supported by a grant from the Mead Foundation. Preliminary studies were supported by a grant from the University of Pennsylvania/GlaxoSmithKline Alternative Drug Discovery Initiative. K.P.O. and K.K.F. were supported by NIH under Ruth L. Kirschstein National Research Service Awards F32CA123939-02 (K.P.O.) and F32CA123887-01 (K.K.F.). In addition to being an officer of Infinity Pharmaceuticals, J.A. is a member of the Senior Advisory Boards of Constellation Pharma and Auspex Pharma. Cancer Research Technology, which is associated with Cancer Research UK, has filed a U.S. provisional patent application related to this work.
Authors
Metrics & Citations
Metrics
Article Usage
Altmetrics
Citations
Cite as
- Kenneth P. Olive et al.
Export citation
Select the format you want to export the citation of this publication.
Cited by
- TSPAN8+ myofibroblastic cancer–associated fibroblasts promote chemoresistance in patients with breast cancer, Science Translational Medicine, 16, 741, (2024)./doi/10.1126/scitranslmed.adj5705
- Perspective Chapter: Critical Role of Hedgehog in Tumor Microenvironment, Tumor Microenvironment - New Insights [Working Title], (2023).https://doi.org/10.5772/intechopen.108831
- The Microbiome-TIME Axis: A Host of Possibilities, Microorganisms, 11, 2, (288), (2023).https://doi.org/10.3390/microorganisms11020288
- Emerging Role of Cancer-Associated Fibroblasts in Progression and Treatment of Hepatocellular Carcinoma, International Journal of Molecular Sciences, 24, 4, (3941), (2023).https://doi.org/10.3390/ijms24043941
- Understanding the Roles of the Hedgehog Signaling Pathway during T-Cell Lymphopoiesis and in T-Cell Acute Lymphoblastic Leukemia (T-ALL), International Journal of Molecular Sciences, 24, 3, (2962), (2023).https://doi.org/10.3390/ijms24032962
- Mutant K-Ras in Pancreatic Cancer: An Insight on the Role of Wild-Type N-Ras and K-Ras-Dependent Cell Cycle Regulation, Current Issues in Molecular Biology, 45, 3, (2505-2520), (2023).https://doi.org/10.3390/cimb45030164
- Molecular Research in Pancreatic Cancer: Small Molecule Inhibitors, Their Mechanistic Pathways and Beyond, Current Issues in Molecular Biology, 45, 3, (1914-1949), (2023).https://doi.org/10.3390/cimb45030124
- IL18 Receptor Signaling Inhibits Intratumoral CD8+ T-Cell Migration in a Murine Pancreatic Cancer Model, Cells, 12, 3, (456), (2023).https://doi.org/10.3390/cells12030456
- Therapeutic Strategies to Overcome Fibrotic Barriers to Nanomedicine in the Pancreatic Tumor Microenvironment, Cancers, 15, 3, (724), (2023).https://doi.org/10.3390/cancers15030724
- Targeting Periostin Expression Makes Pancreatic Cancer Spheroids More Vulnerable to Natural Killer Cells, Biomedicines, 11, 2, (270), (2023).https://doi.org/10.3390/biomedicines11020270
- See more
Loading...
View Options
Check Access
Log in to view the full text
AAAS login provides access to Science for AAAS Members, and access to other journals in the Science family to users who have purchased individual subscriptions.
- Become a AAAS Member
- Activate your AAAS ID
- Purchase Access to Other Journals in the Science Family
- Account Help
Log in via OpenAthens.
Log in via Shibboleth.
More options
Register for free to read this article
As a service to the community, this article is available for free. Login or register for free to read this article.
Buy a single issue of Science for just $15 USD.