Hyaluronan impairs vascular function and drug delivery in a mouse model of pancreatic cancer

Gut. 2013 Jan;62(1):112-20. doi: 10.1136/gutjnl-2012-302529. Epub 2012 Mar 30.

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.

Publication types

  • Evaluation Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Biomarkers, Tumor / physiology*
  • Carcinoma, Pancreatic Ductal / blood supply
  • Carcinoma, Pancreatic Ductal / drug therapy*
  • Carcinoma, Pancreatic Ductal / mortality
  • Carcinoma, Pancreatic Ductal / physiopathology
  • Cell Adhesion Molecules / administration & dosage
  • Cell Adhesion Molecules / pharmacology
  • Deoxycytidine / administration & dosage
  • Deoxycytidine / analogs & derivatives
  • Doxorubicin / administration & dosage
  • Drug Delivery Systems*
  • Drug Resistance, Neoplasm / drug effects
  • Drug Resistance, Neoplasm / physiology*
  • Hyaluronic Acid / physiology*
  • Hyaluronoglucosaminidase / administration & dosage
  • Hyaluronoglucosaminidase / pharmacology
  • Immunohistochemistry
  • Kaplan-Meier Estimate
  • Mice
  • Mice, Transgenic
  • Pancreatic Neoplasms / blood supply
  • Pancreatic Neoplasms / drug therapy*
  • Pancreatic Neoplasms / mortality
  • Pancreatic Neoplasms / physiopathology
  • Recombinant Proteins / administration & dosage
  • Recombinant Proteins / pharmacology
  • Tissue Array Analysis
  • Treatment Outcome

Substances

  • Antineoplastic Agents
  • Biomarkers, Tumor
  • Cell Adhesion Molecules
  • Recombinant Proteins
  • Deoxycytidine
  • Doxorubicin
  • Hyaluronic Acid
  • gemcitabine
  • Hyaluronoglucosaminidase
  • hyaluronidase PH-20