Published online Apr 15, 2016. doi: 10.4251/wjgo.v8.i4.380
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.
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.