PT  - JOURNAL ARTICLE
AU  - Michael A Jacobetz
AU  - Derek S Chan
AU  - Albrecht Neesse
AU  - Tashinga E Bapiro
AU  - Natalie Cook
AU  - Kristopher K Frese
AU  - Christine Feig
AU  - Tomoaki Nakagawa
AU  - Meredith E Caldwell
AU  - Heather I Zecchini
AU  - Martijn P Lolkema
AU  - Ping Jiang
AU  - Anne Kultti
AU  - Curtis B Thompson
AU  - Daniel C Maneval
AU  - Duncan I Jodrell
AU  - Gregory I Frost
AU  - H M Shepard
AU  - Jeremy N Skepper
AU  - David A Tuveson
TI  - Hyaluronan impairs vascular function and drug delivery in a mouse model of pancreatic cancer
AID  - 10.1136/gutjnl-2012-302529
DP  - 2013 Jan 01
TA  - Gut
PG  - 112--120
VI  - 62
IP  - 1
4099  - http://gut.bmj.com/content/62/1/112.short
4100  - http://gut.bmj.com/content/62/1/112.full
SO  - Gut2013 Jan 01; 62
AB  - 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.