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

Abstract

ObjectivePancreatic 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.MethodsUsing 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.ResultsPEGPH20 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.ConclusionsThe 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.

CTGF antagonism with mAb FG-3019 enhances chemotherapy response without increasing drug delivery in murine ductal pancreas cancer

“…We have recently shown that pharmacological inhibition of SHH by IPI-926 and the enzymatic degradation of HA by PEGPH20 improved chemotherapy delivery either through increased mean vessel density and stromal depletion or by reexpansion and endothelial fenestration formation of blood vessels, respectively (12,16). Here we investigated whether increased accumulation of active gemcitabine triphosphate (2′,2′-difluorodeoxycytidine-5′-triphosphate; dFdCTP) without additional modifications of the tumor vasculature or stromal composition would be sufficient to improve therapeutic response in tumor-bearing KPC mice.…”

“…In addition, megadalton glycosaminoglycan hyaluronan (HA) is profusely found in the ECM of murine and human PDA and maintains a high interstitial fluid pressure, thus compressing blood vessels (13)(14)(15). We and others have recently provided evidence that enzymatic degradation of HA by PEGPH20 significantly increased vessel patency and perfusion without increasing the density of tumor vessels, resulting in increased active gemcitabine levels in the tumor (15,16). Both the antismoothened and hyaluronidase therapeutic approaches resulted in transient antitumor responses and prolonged survival in the KPC mouse model.…”

Emerging therapies for pancreatic ductal carcinoma

“…The authors found that when combined with gemcitabine, PEGPH20 inhibited tumor growth and prolonged survival vs. gemcitabine alone in mice models. [33] A summary of antifibrotic therapies and their respective mechanisms of action are listed in Table 2.…”

“…[33] A study by Provenzano et al assessed the possibilities for using enzymes to target the stroma with hopes to increase efficacy of chemotherapy. [34] The authors used PEGPH20 to deplete hyaluronan in mice PDAC cells.…”

“…Olmesartan Reduce collagen deposition and reduce activation of alpha-smooth muscle actin [29] Non-anticoagulant low molecular weight heparin (S-NACH) Mechanism unknown, but has shown improved chemo uptake into the tumor [30] Pirfenidone Reduces fibroblast production, alpha-smooth muscle actin, pro-collagen mRNA, and proteins; not yet studied in pancreatic cancer [32] PEGPH20 Depletes hyaluronan, an extracellular matrix tumor component; results in normalized interstitial fluid pressure and improved drug delivery [33,34] Another novel idea for reducing PDAC fibrosis could involve experimental treatment with a new antifibrotic agent called pirfenidone. While the agent has only been FDAapproved to treat idiopathic pulmonary fibrosis, the mechanism of action should translate successfully in the treatment of PDAC.…”