Jacobetz, M. A., Chan, D. S., Neesse, A., Bapiro, T. E., Cook, N., Frese, K. K., Feig, C., Nakagawa, T., Caldwell, M. E., Zecchini, H. I., Lolkema, M. P., Jiang, P., Kultti, A., Thompson, C. B., Maneval, D. C., Jodrell, D. I., Frost, G. I., Shepard, H. M., Skepper, J. N., Tuveson, D. A. (January 2013) Hyaluronan impairs vascular function and drug delivery in a mouse model of pancreatic cancer. Gut, 62 (1). pp. 112-20. ISSN 1468-3288 (Electronic)0017-5749 (Linking)
Abstract
OBJECTIVE: Pancreatic ductal adenocarcinoma (PDA) is characterised by stromal desmoplasia and vascular dysfunction, which critically impair drug delivery. This study examines the role of an abundant extracellular matrix component, the megadalton glycosaminoglycan hyaluronan (HA), as a novel therapeutic target in PDA. METHODS: Using a genetically engineered mouse model of PDA, the authors enzymatically depleted HA by a clinically formulated PEGylated human recombinant PH20 hyaluronidase (PEGPH20) and examined tumour perfusion, vascular permeability and drug delivery. The preclinical utility of PEGPH20 in combination with gemcitabine was assessed by short-term and survival studies. RESULTS: PEGPH20 rapidly and sustainably depleted HA, inducing the re-expansion of PDA blood vessels and increasing the intratumoral delivery of two chemotherapeutic agents, doxorubicin and gemcitabine. Moreover, PEGPH20 triggered fenestrations and interendothelial junctional gaps in PDA tumour endothelia and promoted a tumour-specific increase in macromolecular permeability. Finally, combination therapy with PEGPH20 and gemcitabine led to inhibition of PDA tumour growth and prolonged survival over gemcitabine monotherapy, suggesting immediate clinical utility. CONCLUSIONS: The authors demonstrate that HA impedes the intratumoral vasculature in PDA and propose that its enzymatic depletion be explored as a means to improve drug delivery and response in patients with pancreatic cancer.
| Item Type: | Paper |
|---|---|
| Uncontrolled Keywords: | Animals Antineoplastic Agents/administration & dosage Antineoplastic Combined Chemotherapy Protocols/pharmacology/ therapeutic use Carcinoma, Pancreatic Ductal/blood supply/ drug therapy/mortality/physiopathology Cell Adhesion Molecules/administration & dosage/pharmacology Deoxycytidine/administration & dosage/analogs & derivatives Doxorubicin/administration & dosage Drug Delivery Systems Drug Resistance, Neoplasm/drug effects/ physiology Hyaluronic Acid/ physiology Hyaluronoglucosaminidase/administration & dosage/pharmacology Immunohistochemistry Kaplan-Meier Estimate Mice Mice, Transgenic Pancreatic Neoplasms/blood supply/ drug therapy/mortality/physiopathology Recombinant Proteins/administration & dosage/pharmacology Tissue Array Analysis Treatment Outcome Tumor Markers, Biological/ physiology |
| Subjects: | diseases & disorders > cancer > drugs and therapies organism description > animal > mammal > rodent > mouse diseases & disorders > cancer > cancer types > pancreatic cancer |
| CSHL Authors: | |
| Communities: | CSHL labs > Tuveson lab |
| Depositing User: | Matt Covey |
| Date: | January 2013 |
| Date Deposited: | 22 Jul 2015 20:44 |
| Last Modified: | 22 Jul 2015 20:44 |
| PMCID: | PMC3551211 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/31640 |
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