Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma

Cancer Cell. 2012 Mar 20;21(3):418-29. doi: 10.1016/j.ccr.2012.01.007.

Abstract

Pancreatic ductal adenocarcinomas (PDAs) are characterized by a robust fibroinflammatory response. We show here that this desmoplastic reaction generates inordinately high interstitial fluid pressures (IFPs), exceeding those previously measured or theorized for solid tumors, and induces vascular collapse, while presenting substantial barriers to perfusion, diffusion, and convection of small molecule therapeutics. We identify hyaluronan, or hyaluronic acid (HA), as the primary matrix determinant of these barriers and show that systemic administration of an enzymatic agent can ablate stromal HA from autochthonous murine PDA, normalize IFP, and re-expand the microvasculature. In combination with the standard chemotherapeutic, gemcitabine, the treatment permanently remodels the tumor microenvironment and consistently achieves objective tumor responses, resulting in a near doubling of overall survival.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / blood supply
  • Adenocarcinoma / drug therapy
  • Adenocarcinoma / pathology
  • Animals
  • Animals, Genetically Modified
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Carcinoma, Pancreatic Ductal / blood supply
  • Carcinoma, Pancreatic Ductal / drug therapy*
  • Carcinoma, Pancreatic Ductal / pathology
  • Cell Adhesion Molecules / administration & dosage
  • Cell Adhesion Molecules / therapeutic use
  • Deoxycytidine / administration & dosage
  • Deoxycytidine / analogs & derivatives*
  • Deoxycytidine / pharmacology
  • Deoxycytidine / therapeutic use
  • Drug Evaluation, Preclinical
  • Extracellular Fluid / drug effects
  • Hyaluronic Acid / metabolism
  • Hyaluronic Acid / physiology*
  • Hyaluronoglucosaminidase / administration & dosage
  • Hyaluronoglucosaminidase / pharmacology
  • Hyaluronoglucosaminidase / therapeutic use
  • Mice
  • Microvessels / drug effects
  • Pancreatic Neoplasms / blood supply
  • Pancreatic Neoplasms / drug therapy*
  • Pancreatic Neoplasms / pathology
  • Polyethylene Glycols / administration & dosage
  • Polyethylene Glycols / therapeutic use*
  • Stromal Cells / drug effects
  • Stromal Cells / pathology
  • Tumor Microenvironment / drug effects

Substances

  • Cell Adhesion Molecules
  • Deoxycytidine
  • Polyethylene Glycols
  • Hyaluronic Acid
  • gemcitabine
  • Hyaluronoglucosaminidase
  • hyaluronidase PH-20