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Pancreas
Hyaluronan impairs vascular function and drug delivery in a mouse model of pancreatic cancer
  1. Michael A Jacobetz1,
  2. Derek S Chan1,2,
  3. Albrecht Neesse1,
  4. Tashinga E Bapiro1,2,
  5. Natalie Cook1,2,
  6. Kristopher K Frese1,
  7. Christine Feig1,
  8. Tomoaki Nakagawa1,
  9. Meredith E Caldwell1,
  10. Heather I Zecchini1,
  11. Martijn P Lolkema1,
  12. Ping Jiang3,
  13. Anne Kultti3,
  14. Curtis B Thompson3,
  15. Daniel C Maneval3,
  16. Duncan I Jodrell1,
  17. Gregory I Frost3,
  18. H M Shepard3,
  19. Jeremy N Skepper4,
  20. David A Tuveson1,2
  1. 1Cancer Research UK Cambridge Research Institute, Cambridge, UK
  2. 2Department of Oncology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
  3. 3Halozyme Therapeutics, Inc., San Diego, California, USA
  4. 4Multi-Imaging Centre, Physiology Development and Neuroscience, University of Cambridge, Cambridge, UK
  1. Correspondence to Dr David Tuveson, Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre, Cambridge CB2 0RE, UK; david.tuveson{at}cancer.org.uk

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.

  • Pancreatic cancer
  • tumour microenvironment
  • hyaluronan
  • drug delivery
  • carcinogenesis
  • cancer vaccines
  • cancer immunobiology
  • cancer genetics
  • pancreatic fibrosis
  • pancreatic disease
  • pancreatic tumours
  • cancer
  • extracellular matrix
  • epithelial cell growth
  • stem cells
  • epithelial cell adhesion
  • cancer
  • matrix
  • fibrosis
  • pharmacology
  • pharmacokinetics
  • cell death
  • oxidative stress

This is an open-access article distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits use, distribution, and reproduction in any medium, provided the original work is properly cited, the use is non commercial and is otherwise in compliance with the license. See: http://creativecommons.org/licenses/by-nc/3.0/ and http://creativecommons.org/licenses/by-nc/3.0/legalcode

https://doi.org/10.1136/gutjnl-2012-302529

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    Footnotes

    • DSC and AN contributed equally to this work.

    • Funding This research was supported by 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 the European Commission Seventh Framework Programme (FP7 Health 2010 2.4.1-6, contract number 256974). AN was supported by the Mildred Scheel Postdoctoral Fellowship by the Deutsche Krebshilfe. NC was supported by a Cancer Research UK Clinician Fellowship. CF was supported by the EMBO long-term fellowship and by a Marie Curie Intra European Fellowship within the Seventh European Community Framework Programme. MPL has received a Dutch Cancer Foundation Fellowship grant (UU2008-4380) to support this work. DT and DIJ are group leaders in the Cancer Research UK Cambridge Research Institute.

    • Competing interests DCM, CBT, PJ, AK, HMS and GIF are employees of Halozyme.

    • Provenance and peer review Not commissioned; internally peer reviewed.