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Improving drug delivery to pancreatic cancer: breaching the stromal fortress by targeting hyaluronic acid
  1. Patrick Michl,
  2. Thomas M Gress
  1. Department of Gastroenterology, Endocrinology, Metabolism and Infectiology, University Hospital, Philipps-University, Marburg, Germany
  1. Correspondence to Professor Thomas M Gress, Department of Gastroenterology, Endocrinology, Metabolism and Infectiology, University of Marburg, Baldinger Strasse, D-35043 Marburg, Germany; thomas.gress{at}med.uni-marburg.de

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The dismal prognosis of pancreatic cancer has not significantly changed over the last few decades. The incidence and mortality of this tumour entity are still almost identical, associated with a 5-year survival of <5%. Given the appalling outcome of the disease and the numerous regimens tested in clinical trials over recent years that have proved futile, there is an urgent need for novel therapeutic approaches to improve the situation.

Pancreatic cancer is characterised by an extensive desmoplastic reaction consisting of a variety of stromal cells such as pancreatic stellate cells, activated fibroblasts and inflammatory cells embedded in a dense extracellular matrix comprising numerous components such as collagens and glycosaminoglycans. During the last few decades, the role of this stromal reaction has been largely neglected by the majority of research efforts, which have instead focused directly on the tumour cells as the main determinant of drug resistance. The role of the stroma as a ‘fortress’ fencing off the tumour cells from drugs applied in the circulation has only very recently1 been recognised and addressed systematically after the advent of appropriate mouse models that faithfully recapitulate human disease, in particular its intense stromal reaction.2

In 2009, Olive et al examined in a landmark paper the impact of targeting sonic hedgehog signalling as one major pathway known to stimulate stromal reaction.3 After systemic administration of the hedgehog inhibitor, IPI926, the authors observed a significant depletion of tumour-associated stroma associated with an increase in intratumoral vascular density and concentration of the coadministered cytotoxic agent, gemcitabine. On the basis of these data, the authors proposed that inefficient drug delivery due to the intense stromal reaction may be an important contributor to chemoresistance in pancreatic cancer.3

In this issue of the journal, the …

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