GEMMs as preclinical models for testing pancreatic cancer therapies.

Aarthi Gopinathan,Duncan I Jodrell,Owen J Sansom,Jennifer P Morton

doi:10.1242/dmm.021055

Abstract

ABSTRACTPancreatic ductal adenocarcinoma is the most common form of pancreatic tumour, with a very limited survival rate and currently no available disease-modifying treatments. Despite recent advances in the production of genetically engineered mouse models (GEMMs), the development of new therapies for pancreatic cancer is still hampered by a lack of reliable and predictive preclinical animal models for this disease. Preclinical models are vitally important for assessing therapies in the first stages of the drug development pipeline, prior to their transition to the clinical arena. GEMMs carry mutations in genes that are associated with specific human diseases and they can thus accurately mimic the genetic, phenotypic and physiological aspects of human pathologies. Here, we discuss different GEMMs of human pancreatic cancer, with a focus on the Lox-Stop-Lox (LSL)-KrasG12D; LSL-Trp53R172H; Pdx1-cre (KPC) model, one of the most widely used preclinical models for this disease. We describe its application in preclinical research, highlighting its advantages and disadvantages, its potential for predicting clinical outcomes in humans and the factors that can affect such outcomes, and, finally, future developments that could advance the discovery of new therapies for pancreatic cancer.

Highlights

Pancreatic cancers are a group of diseases that affect both the endocrine and exocrine compartments of the pancreas
Disease progression occurs through a series of pre-invasive pancreatic intraepithelial neoplasia (PanIN), which are graded according to their severity of dysplasia and nuclear atypia
We focus in particular on one of the most widely used genetically engineered mouse models (GEMMs) of pancreatic cancer, the LSL-KrasG12D; LSL-Trp53R172H; Pdx1-cre (KPC) model, and its use in the preclinical testing of anti-cancer agents

Summary

Introduction

Pancreatic cancers are a group of diseases that affect both the endocrine and exocrine compartments of the pancreas. PDACs are primarily glandular, sarcomatoid, colloid and adenosquamous (see Box 2) tumours occur (Hruban and Adsay, 2009) These tumours are characterized by a dense desmoplastic stroma, consisting of extracellular matrix proteins – such as collagens, laminin and fibronectin – together with fibroblasts and immune cells (Adler, 2004). In vivo anti-cancer drug evaluation has been carried out in xenograft models (see Box 2), which can be and rapidly generated in immunodeficient mice by the implantation of tumour cells or of tissues into ectopic or orthotopic sites (Richmond and Su, 2008). Nanoparticle albumin-bound paclitaxel (nab-paclitaxel): a paclitaxel formulation that uses albumin, the main protein of human blood plasma, to bind paclitaxel and to facilitate its transport out of the bloodstream and into the tumour Studies show that this formulation increases the therapeutic efficacy of paclitaxel compared to its conventional formulation. In particular, tumours are demonstrably stromal in nature, and the complex interactions between tumour and stromal cells might alter

G Liver met

Findings

Conclusions