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

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      1 , 1 , 2 , 1 , 1 , 2 , 1 , 2 , 1 , 1 , 1 , 1 , 1 , 1 , 3 , 3 , 3 , 3 , 1 , 3 , 3 , 4 , 1 , 2 ,
      Gut
      BMJ Group
      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

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          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.

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          Most cited references34

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          Activated Kras and Ink4a/Arf deficiency cooperate to produce metastatic pancreatic ductal adenocarcinoma.

          Pancreatic ductal adenocarcinoma ranks among the most lethal of human malignancies. Here, we assess the cooperative interactions of two signature mutations in mice engineered to sustain pancreas-specific Cre-mediated activation of a mutant Kras allele (KrasG12D) and deletion of a conditional Ink4a/Arf tumor suppressor allele. The phenotypic impact of KrasG12D alone was limited primarily to the development of focal premalignant ductal lesions, termed pancreatic intraepithelial neoplasias (PanINs), whereas the sole inactivation of Ink4a/Arf failed to produce any neoplastic lesions in the pancreas. In combination, KrasG12D expression and Ink4a/Arf deficiency resulted in an earlier appearance of PanIN lesions and these neoplasms progressed rapidly to highly invasive and metastatic cancers, resulting in death in all cases by 11 weeks. The evolution of these tumors bears striking resemblance to the human disease, possessing a proliferative stromal component and ductal lesions with a propensity to advance to a poorly differentiated state. These findings in the mouse provide experimental support for the widely accepted model of human pancreatic adenocarcinoma in which activated KRAS serves to initiate PanIN lesions, and the INK4A/ARF tumor suppressors function to constrain the malignant conversion of these PanIN lesions into lethal ductal adenocarcinoma. This faithful mouse model may permit the systematic analysis of genetic lesions implicated in the human disease and serve as a platform for the identification of early disease markers and for the efficient testing of novel therapies.
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            Gemcitabine plus bevacizumab compared with gemcitabine plus placebo in patients with advanced pancreatic cancer: phase III trial of the Cancer and Leukemia Group B (CALGB 80303).

            The combination of gemcitabine plus bevacizumab produced a 21% response rate and a median survival of 8.8 months in a multicenter phase II trial in patients with metastatic pancreatic cancer. These encouraging data led Cancer and Leukemia Group B (CALGB) to conduct a double-blind, placebo-controlled, randomized phase III trial of gemcitabine/bevacizumab versus gemcitabine/placebo in advanced pancreatic cancer patients. Eligible patients had no prior therapy for advanced disease, Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2, no tumor invasion of adjacent organs, and no increased bleeding risk. The primary end point was overall survival. Patients were stratified by performance status, extent of disease, and prior radiotherapy. Patients received gemcitabine at 1,000 mg/m(2) over 30 minutes on days 1, 8, and 15 every 28 days and bevacizumab at 10 mg/kg or placebo on days 1 and 15 every 28 days. Between June 2004 and April 2006, 602 patients were enrolled onto the study and 535 were treated. Median overall survival was 5.8 months for gemcitabine/bevacizumab and 5.9 months for gemcitabine/placebo (P = .95). Median progression-free survival was 3.8 and 2.9 months, respectively (P = .07). Overall response rates were 13% and 10%, respectively. Patients with a performance status of 0, 1, and 2 survived a median of 7.9, 4.8, and 2.4 months, respectively. The only statistically significant differences in grades 3 and 4 toxicity occurred for hypertension (10% v 3%; P or = 3 was equivalent in both arms (14% and 15%, respectively). The addition of bevacizumab to gemcitabine does not improve survival in advanced pancreatic cancer patients.
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              Regulation of transport pathways in tumor vessels: role of tumor type and microenvironment.

              Novel anti-neoplastic agents such as gene targeting vectors and encapsulated carriers are quite large (approximately 100-300 nm in diameter). An understanding of the functional size and physiological regulation of transvascular pathways is necessary to optimize delivery of these agents. Here we analyze the functional limits of transvascular transport and its modulation by the microenvironment. One human and five murine tumors including mammary and colorectal carcinomas, hepatoma, glioma, and sarcoma were implanted in the dorsal skin-fold chamber or cranial window, and the pore cutoff size, a functional measure of transvascular gap size, was determined. The microenvironment was modulated: (i) spatially, by growing tumors in subcutaneous or cranial locations and (ii) temporally, by inducing vascular regression in hormone-dependent tumors. Tumors grown subcutaneously exhibited a characteristic pore cutoff size ranging from 200 nm to 1.2 microm. This pore cutoff size was reduced in tumors grown in the cranium or in regressing tumors after hormone withdrawal. Vessels induced in basic fibroblast growth factor-containing gels had a pore cutoff size of 200 nm. Albumin permeability was independent of pore cutoff size. These results have three major implications for the delivery of therapeutic agents: (i) delivery may be less efficient in cranial tumors than in subcutaneous tumors, (ii) delivery may be reduced during tumor regression induced by hormonal ablation, and (iii) permeability to a molecule is independent of pore cutoff size as long as the diameter of the molecule is much less than the pore diameter.
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                Author and article information

                Journal
                Gut
                Gut
                gut
                gutjnl
                Gut
                BMJ Group (BMA House, Tavistock Square, London, WC1H 9JR )
                0017-5749
                1468-3288
                January 2013
                30 March 2012
                : 62
                : 1
                : 112-120
                Affiliations
                [1 ]Cancer Research UK Cambridge Research Institute, Cambridge, UK
                [2 ]Department of Oncology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
                [3 ]Halozyme Therapeutics, Inc., San Diego, California, USA
                [4 ]Multi-Imaging Centre, Physiology Development and Neuroscience, University of Cambridge, Cambridge, UK
                Author notes
                [Correspondence to ] Dr David Tuveson, Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre, Cambridge CB2 0RE, UK; david.tuveson@ 123456cancer.org.uk

                DSC and AN contributed equally to this work.

                Article
                gutjnl-2012-302529
                10.1136/gutjnl-2012-302529
                3551211
                22466618
                a086fa39-a835-4128-897f-f2467104e066
                Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions

                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

                History
                : 19 March 2012
                Categories
                Original Articles
                Pancreas
                1506
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                Gastroenterology & Hepatology
                cancer,cancer genetics,cancer immunobiology,cancer vaccines,carcinogenesis,cell death,drug delivery,epithelial cell adhesion,epithelial cell growth,extracellular matrix,fibrosis,hyaluronan,matrix,oxidative stress,pancreatic cancer,pancreatic disease,pancreatic fibrosis,pancreatic tumours,pharmacokinetics,pharmacology,stem cells,tumour microenvironment

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