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Review Pancreatic Cancer Breaking the Barrier—PEGylated Recombinant Human Hyaluronidase (PEGPH20)—A New Therapeutic Approach to the Treatment of Pancreatic Ductal Adenocarcinoma Andrew Hendifar 1 and Andrea Bullock 2 1. Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, US; 2. Division of Hematology-Oncology, Beth Israel Deaconess Medical Center, Boston, US N ew therapeutic approaches are urgently needed to improve survival for patients with metastatic pancreatic ductal adenocarcinoma (PDA). This carcinoma is characterized by a hyaluronan (HA)-rich desmoplastic stroma that raises tumor interstitial fluid pressure (IFP), which in turn compresses the vasculature and impedes access of anti-cancer therapies and immune cells to tumor sites. It is this biophysical barrier that is the target for PEGylated recombinant human hyaluronidase (PEGPH20; pegvorhyaluronidase alfa), which degrades HA polymers to tetra- and hexa-saccharides to remodel the tumor stroma. In preclinical models, PEGPH20 reduced IFP, and expanded tumor vasculature to improve perfusion, which increased access for innate immune cells, antibodies and therapeutic agents. The results of a phase Ib study have suggested benefits in overall survival and progression-free survival (PFS) for patients with tumors that accumulate HA (termed HA-High) treated with a combination of gemcitabine and PEGPH20. A phase II study (HALO 109-202) demonstrated that HA could be a potential biomarker for identifying patients who may be most suitable for PEGPH20 treatment. HALO 109-202 showed positive outcomes for PFS especially in HA-High patients treated with PEGPH20 plus nab-paclitaxel and gemcitabine. A randomized, double-blind, phase III study (HALO 109-301) exploring the benefits of PEGPH20 in HA-High patients with PDA is ongoing. Other PEGPH20-based combinations are being investigated in multiple stroma-rich cancers, including lung, gastric, and breast. PEGPH20 is the most advanced therapy targeting the tumor stroma and has the potential to form the therapeutic backbone for the treatment of stroma-rich tumors. Keywords Pancreatic ductal adenocarcinoma (PDA), tumor microenvironment (TME), hyaluronan (HA), PEGylated recombinant human hyaluronidase (PEGPH20) Disclosure: Andrew Hendifar has participated in a consulting or advisory role with Novartis, Ipsen, Perthera, and Xbiotech and received travel/accommodation/expenses from Halozyme. Andrea Bullock has stock and other ownership interests in Amgen, Johnson & Johnson, and Medtronic, participated in a consulting or advisory role with Celgene, Halozyme, and Bayer, and received travel/accommodation/expenses from Halozyme. Acknowledgments: Medical writing assistance was provided by James Gilbart at Touch Medical Media, and funded by Halozyme. Compliance with Ethics Guidelines: This study involves a review of the literature and did not involve any studies with human or animal subjects performed by any of the authors. Authorship: All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship of this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval to the version to be published. Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any noncommercial use, distribution, adaptation, and reproduction provided the original author(s) and source are given appropriate credit. Received: September 29, 2017 Accepted: November 7, 2017 Citation: Oncology & Hematology Review, 2017;13(2):107–11 Corresponding Author: Andrew Hendifar, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, US. E: Support: The publication of this article was supported by Halozyme. The views and opinions expressed are those of the author and do not necessarily reflect those of Halozyme. TOU CH MED ICA L MEDIA Despite progress in managing many cancer types in recent decades, metastatic pancreatic ductal adenocarcinoma (PDA), accounting for over 90% of all malignancies of the pancreas, continues to have an extremely poor prognosis. Indeed, in the US PDA has an estimated 5-year survival rate of 8% for all patients and 3% for metastatic disease. 1,2 PDA is now the third leading cause of cancer death in the US and this is predicted to increase to be the second biggest cause of cancer death in the US by 2020–2030. 3,4 Outcomes in PDA have not improved substantially over the last 30 years. 1 This mainly arises from the patient having reached a metastatic stage at the time of diagnosis with poor response to therapy. The lack of progress in developing effective therapies for PDA is due to the nature of the disease: tumor cells co-opt multiple cellular and extracellular mechanisms to form a complex cancer organ with a marked propensity towards metastasis and resistance to therapy. 5 Against this bleak picture, improved understanding of the pathophysiology behind PDA, the identification of molecular mechanisms underlying its aggressive nature, and improved access to the tumor site have enabled some exciting developments. This increased knowledge raises hope for more successful approaches to managing this disease. The tumor microenvironment The development, progression and aggressiveness of PDA are significantly affected by components of the tumor microenvironment (TME), which 107