Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer
Open accessAbstract
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.
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The clinical trial of Hedgehog pathway inhibition in PDAC failed to show benefit and reported decreased patient survival in combination with gemcitabine chemotherapy.
“The clinical trial designed to recapitulate the advantageous effect of Hedgehog pathway inhibition in mouse models of pancreatic ductal adenocarcinoma (PDAC)166 failed to show such benefit and paradoxically reported decreased patient survival in combination with gemcitabine chemotherapy (NCT01130142)169.”
From A framework for advancing our understanding of cancer-associated fibroblasts (2020) · cites this paper as [166]
Initial preclinical data in mouse models suggested that hyaluronidase combined with chemotherapy showed promise.
“Initial preclinical data in mouse models suggested that use of hyaluronidase combined with chemotherapy showed great promise140,157”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [157]
Inhibiting proliferation of CAFs by co-administering IPI-926, which inhibits hedgehog signaling, with gemcitabine increases tumor drug sensitivity in mouse models of pancreatic ductal adenocarcinoma.
“Furthermore, inhibiting the proliferation of CAFs by co‐administering IPI‐926, which inhibits the hedgehog signaling, with the chemotherapeutic drug gemcitabine increasing tumor drug sensitivity in the mouse models of pancreatic ductal adenocarcinoma [104].”
From Tumor microenvironment signaling and therapeutics in cancer progression (2023) · cites this paper as [104]
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- Authors
- Olive, K. P., Jacobetz, M. A., Davidson, C. J., Gopinathan, A., McIntyre, D., Honess, D., Madhu, B., Goldgraben, M. A., Caldwell, M. E., Allard, D., Frese, K. K., DeNicola, G., Feig, C., Combs, C., Winter, S. P., Ireland-Zecchini, H., Reichelt, S., Howat, W. J., Chang, A., Dhara, M., Wang, L., Rückert, F., Grützmann, R., Pilarsky, C., Izeradjene, K., Hingorani, S. R., Huang, P., Davies, S. E., Plunkett, W., Egorin, M., Hruban, R. H., Whitebread, N., McGovern, K., Adams, J., Iacobuzio-Donahue, C., Griffiths, J., & Tuveson, D. A.
- Affiliations
- Cancer Research UK (GB)
- Abramson Cancer Center (US)
- Cancer Research UK, Cambridge Research Institute, The Li Ka Shing Centre, Robinson Way, Cambridge CB2 ORE, UK.
- Johns Hopkins University (US)
- Shanghai Jiao Tong University (CN)
- University Hospital Carl Gustav Carus (DE)
- University of Washington (US)
- Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
- National Health Service (GB)
- The University of Texas MD Anderson Cancer Center (US)
- University of Pittsburgh Medical Center (US)
- Infinity Pharmaceuticals (United States) (US)
- Departments of Oncology and Pathology, The Sol Goldman Pancreatic Cancer Research Center, Sidney Cancer Center and Johns Hopkins University, Baltimore, MD 21287, USA.
- Corresponding author
- Jacobetz, Michael A.
- Davidson, Christian J.
- Gopinathan, Aarthi
- Tuveson, David A.
- ORCID
- Olive, Kenneth P.
- Davidson, Christian J.
- Gopinathan, Aarthi
- McIntyre, Dominick
- Madhu, Basetti
- Goldgraben, Mae A.
- Frese, Kristopher K.
- DeNicola, Gina
- Feig, Christine
- Reichelt, Stefanie
- Howat, William J.
- Wang, Lifu
- Rückert, Felix
- Grützmann, Robert
- Pilarsky, Christian
- Izeradjene, Kamel
- Hingorani, Sunil R.
- Huang, Pearl
- Davies, Susan E.
- Plunkett, William
- Hruban, Ralph H.
- McGovern, Karen
- Adams, Julian
- Griffiths, John
- Tuveson, David A.
- Venue
- Science
- Published
- 2009-06-12
- Volume
- 324
- Issue
- 5933
- Pages
- 1457-1461
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC2998180
- OpenAlex
- W2107441200
- Cited by
- 3,170
- References
- 28
- Citations by year
- 2026: 105 · 2025: 117 · 2024: 118 · 2023: 151 · 2022: 178 · 2021: 223 · 2020: 208 · 2019: 192 · 2018: 212 · 2017: 217 · 2016: 227 · 2015: 225 · 2014: 212 · 2013: 208 · 2012: 235
- FWCI
- 95.14
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (CA101973, F32CA123939, CA105490, K08CA106610, CA 15704+, U01CA084291, CA114028, CA111292, U01CA105490, F32CA123887, R01CA101973, CA084291, K08CA114028, P30CA015704)
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Hedgehog Signaling Pathway Studies
- Health Sciences › Medicine › Surgery › Pancreatitis Pathology and Treatment
- Keywords
- pancreatic ductal adenocarcinoma, Hedgehog signaling inhibition, gemcitabine, chemotherapy delivery, drug resistance, tumor vascularization, tumor perfusion, combination therapy, mouse tumor model
- MeSH terms
- Zinc Finger Protein GLI1, Smoothened Receptor, Gemcitabine, Animals, Antineoplastic Agents, Antineoplastic Combined Chemotherapy Protocols, Deoxycytidine, Disease Models, Animal, Humans, Neoplasm Transplantation, Neovascularization, Pathologic, Pancreatic Neoplasms, Veratrum Alkaloids, Signal Transduction, Stromal Cells, Apoptosis, Drug Resistance, Neoplasm, Carcinoma, Pancreatic Ductal, Receptors, G-Protein-Coupled, Cell Line, Tumor, Cell Proliferation, Mice, Kruppel-Like Transcription Factors, Hedgehog Proteins
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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