Copyright ©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastrointest Oncol. Apr 15, 2016; 8(4): 380-388
Published online Apr 15, 2016. doi: 10.4251/wjgo.v8.i4.380
Targeting inflammation in pancreatic cancer: Clinical translation
Colin William Steele, Nina Angharad Kaur Gill, Nigel Balfour Jamieson, Christopher Ross Carter
Colin William Steele, Nigel Balfour Jamieson, Christopher Ross Carter, Department of Pancreaticobiliary Surgery, Glasgow Royal Infirmary, Glasgow G4 0SF, United Kingdom
Nina Angharad Kaur Gill, Department of General Surgery, South Glasgow University Hospital, Glasgow G51 4TF, United Kingdom
Author contributions: Steele CW drafted this review; Kaur Gill NA contributed the literature review and table; Jamieson NB and Carter CR edited the final manuscript.
Conflict-of-interest statement: We have no conflicts of interest to disclose.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Correspondence to: Colin William Steele, MD, Department of Pancreaticobiliary Surgery, Glasgow Royal Infirmary, Queen Elizabeth Building, Glasgow G4 0SF, United Kingdom.
Telephone: +44-0141-2114000
Received: November 29, 2015
Peer-review started: November 30, 2015
First decision: December 28, 2015
Revised: January 5, 2016
Accepted: February 14, 2016
Article in press: February 16, 2016
Published online: April 15, 2016

Preclinical modelling studies are beginning to aid development of therapies targeted against key regulators of pancreatic cancer progression. Pancreatic cancer is an aggressive, stromally-rich tumor, from which few people survive. Within the tumor microenvironment cellular and extracellular components exist, shielding tumor cells from immune cell clearance, and chemotherapy, enhancing progression of the disease. The cellular component of this microenvironment consists mainly of stellate cells and inflammatory cells. New findings suggest that manipulation of the cellular component of the tumor microenvironment is possible to promote immune cell killing of tumor cells. Here we explore possible immunogenic therapeutic strategies. Additionally extracellular stromal elements play a key role in protecting tumor cells from chemotherapies targeted at the pancreas. We describe the experimental findings and the pitfalls associated with translation of stromally targeted therapies to clinical trial. Finally, we discuss the key inflammatory signal transducers activated subsequent to driver mutations in oncogenic Kras in pancreatic cancer. We present the preclinical findings that have led to successful early trials of STAT3 inhibitors in pancreatic adenocarcinoma.

Keywords: Pancreatic cancer, Inflammation, Stroma, Microenvironment

Core tip: Many advances have been made in preclinical assessment of therapies in pancreatic cancer. Here we review the successes and failures of translation to clinical trial of therapies targeting the pancreatic cancer microenvironment. Using data from preclinical trials we expose opportunities for further clinical trial within pancreatic cancer. We focus on therapies that modulate the immune response to pancreatic cancer, stromally active therapies and therapies targeting inflammatory signal transduction that are key in pancreatic cancer progression. We provide experimental results that have led to clinical trial and those findings that may be exploited in future. We attempt to rationalize the failure of certain therapies to translate to clinical practice and provide a realistic overview of why at present tumor microenvironment targeted therapies are not licensed in pancreatic cancer.