title: Hyaluronan impairs vascular function and drug delivery in a mouse model of pancreatic cancer.
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.
authors.affiliation: Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre, Cambridge CB2 0RE, UK.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Jacobetz
authors.forename: Derek S
authors.initials: DS
authors.lastname: Chan
authors.forename: Albrecht
authors.initials: A
authors.lastname: Neesse
authors.forename: Tashinga E
authors.initials: TE
authors.lastname: Bapiro
authors.forename: Natalie
authors.initials: N
authors.lastname: Cook
authors.forename: Kristopher K
authors.initials: KK
authors.lastname: Frese
authors.forename: Christine
authors.initials: C
authors.lastname: Feig
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Nakagawa
authors.forename: Meredith E
authors.initials: ME
authors.lastname: Caldwell
authors.forename: Heather I
authors.initials: HI
authors.lastname: Zecchini
authors.forename: Martijn P
authors.initials: MP
authors.lastname: Lolkema
authors.forename: Ping
authors.initials: P
authors.lastname: Jiang
authors.forename: Anne
authors.initials: A
authors.lastname: Kultti
authors.forename: Curtis B
authors.initials: CB
authors.lastname: Thompson
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Maneval
authors.forename: Duncan I
authors.initials: DI
authors.lastname: Jodrell
authors.forename: Gregory I
authors.initials: GI
authors.lastname: Frost
authors.forename: H M
authors.initials: HM
authors.lastname: Shepard
authors.forename: Jeremy N
authors.initials: JN
authors.lastname: Skepper
authors.forename: David A
authors.initials: DA
authors.lastname: Tuveson
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000502:physiology*; D021441:Carcinoma, Pancreatic Ductal / Q000098:blood supply / Q000188:drug therapy* / Q000401:mortality / Q000503:physiopathology; D015815:Cell Adhesion Molecules / Q000008:administration & dosage / Q000494:pharmacology; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D004317:Doxorubicin / Q000008:administration & dosage; D016503:Drug Delivery Systems; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000502:physiology*; D006820:Hyaluronic Acid / Q000502:physiology*; D006821:Hyaluronoglucosaminidase / Q000008:administration & dosage / Q000494:pharmacology; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D051379:Mice; D008822:Mice, Transgenic; D010190:Pancreatic Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000401:mortality / Q000503:physiopathology; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology; D046888:Tissue Array Analysis; D016896:Treatment Outcome; D000093542:Gemcitabine
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D015815:Cell Adhesion Molecules; D011994:Recombinant Proteins; D003841:Deoxycytidine; D004317:Doxorubicin; D006820:Hyaluronic Acid; D006821:Hyaluronoglucosaminidase; C066852:hyaluronidase PH-20; D000093542:Gemcitabine