Elsevier

Pharmacology & Therapeutics

Volume 173, May 2017, Pages 146-158
Pharmacology & Therapeutics

Associate editor: B. Teicher
Pancreatic cancer models for translational research

https://doi.org/10.1016/j.pharmthera.2017.02.013Get rights and content

Abstract

Pancreatic cancer is a cruel, progressive disease that is highly metastatic and barely treatable, a situation that is devastating for patients, family members, oncologists, clinicians and scientists. Open questions that need to be resolved by research into pancreatic cancer relate to its aggressiveness, the underlying molecular causes, the factors that promote tumor progression, the ways cancer cells interact with their environments, and whether more effective therapeutic options can be developed.

Studies over the last 15 years have provided some partial answers, but in the absence of a real cure the main agenda remains: to identify new therapeutic targets, predictive markers and novel treatment strategies that would help the disease under control. These goals can be advanced by translational research based on clinically relevant and standardized protocols and more reliable disease models. This review gives an overview of the preclinical in vitro and in vivo models for pancreatic cancer that are currently available. The restrictions on applicability, strengths and limitations of various experimental platforms including 3D organoids, syngeneic xenografts and genetically engineered mice are considered with respect to the complexity of pancreating cancer. Patient-derived xenografts (PDX) presently offer the most promise for translational research, so a particular emphasis is placed on key features as preclinical models for pancreatic cancer and their advancement toward precise simulations of clinical problems.

Introduction

Pancreatic cancer (PC) continues to have one of the worst prognoses for patients due to the late onset of symptoms and the advanced stage that the disease usually reaches before diagnosis. These factors as well as specific anatomical features mean that 80% of patients who cannot be treated by surgery. They often suffer from metastases in the liver and lung, yielding an overall survival rate of less than 20% one year after diagnosis. Pancreatic cancer is the fifth most common cause of cancer deaths in Europe overall, with more than 104,000 victims in 2012 (6% of all cancer related deaths) (Ferlay et al., 2013). In the United States the situation is even worse: pancreatic cancer is the 4th leading cause of cancer-related deaths, with 53,070 new cases and 41,780 fatalities estimated for 2016 (Siegel, Miller, & Jemal, 2016). The development of pancreatic tumors is promoted by a combination of genetic familiar history, environmental and lifestyle factors, and additional causes remain to be identified (Barone, Corrado, Gemignani, & Landi, 2016). 95% of all cases of PC are diagnosed as ductal adenocarcinomas (PDAC) of exocrine origin which exhibit different stages of differentiation. Nearly all tumors harbor a mutation in the Kras oncogene, frequently accompanied by subsequent genetic alterations in the p53, SMAD4 and CDKN2A genes. Pancreatic tumors are characterized by genetic instability, intratumoral heterogeneity and distinct desmoplastic stroma (Hidalgo et al., 2015).

Despite the knowledge that has been gained regarding the biology and mechanisms that underlie PDAC tumorigenicity over the last 15 years, there remains a need for better diagnostic and prognostic markers and particularly improved therapeutic strategies (Falasca, Kim, & Casari, 2016). Only moderate progress has been made in the latter are, in contrast to other solid malignancies, despite numerous preclinical investigations and clinical trials. In 1997, gemcitabine emerged as an alternative to 5-Fluorouracil as a first-line therapy that was applied in some cases but ultimately improved overall survival by only a few weeks. The next clinical milestone was the introduction of the FOLFIRINOX treatment scheme (5-fluoruracil, leucovorin, oxaliplatin and irinotecan) for patients with an advanced stage of the disease, which contributed to a small improvement in survival on the one hand but strong side effects on the other. Nab-paclitaxel (Abraxane) was approved for standard of care in 2013 and, in combination with gemcitabine, remains the most effective and tolerated drug. The poor clinical situation and remaining challenges can be summarized by noting that only three improvements have been introduced over the last 20 years, leaving the 5-year overall survival rate below 8%.

Recently the American Society of Clinical Oncology (ASCO) published guidelines for the handling of potentially curable (respectable), locally advanced (non-respectable) and metastatic PDAC (2016; www.asco.org/guidelineswiki). After considering relevant literature from the years 2004 to 2015, their recommendations for therapeutic interventions included FOLFORINOX, radiation and/or gemcitabine in combination with nab-paclitaxel. In addition to these measures and the approval of second line liposomal irinotecan, there is still a desperate need for novel drugs, improved radiation protocols and more avenues for second- and third-line therapies (Strobel & Büchler, 2016), with a push to enroll more patients in clinical trials. A search of the “Pubmed” database for pancreatic cancer yields more than 82,000 entries, which documents the engagement of scientists all over the world in efforts to understand the disease and find new approaches. Currently, this mission is making use of preclinical tools that are multifaceted, specific and tailored to particular, research-orientated applications. This article considers a range of in vitro and in vivo models of pancreatic cancer that are being implemented in current preclinical research and have been designed for translational purposes. Here we provide an overview of platforms for basic and advanced experimental research, with a focus on those devoted to the biology of pancreatic cancer and improving therapeutic options for patients.

Section snippets

Translational research (TR) – meaning and claims

TR aims to derive discoveries from basic and advanced laboratory research and apply them to studies of human beings. The NIH divides these efforts into two stages, from basic to clinical research (T1) and from clinical research to applicable practice settings for patients (T2), with the goals of improving public health and reducing cancer incidence, morbidity and mortality (Rubio et al., 2010).

Translational research in oncology combines the perspectives of scientists working in basic research,

Two-D (2D) cell cultures

Cell lines of various cancer entities have been widely used in basic research into cancer biology and in proof-of-concept studies for many years. Monolayer cultures are cost-effective and useful for high-throughput drug screening, but they do not reflect the holistic complexity of cancer. The in vitro propagation of pancreatic cancer cells was first described in the early sixties (Dobrynin, 1963). The intervening years have seen the establishment of more than 20 human PDAC cell lines for use in

Syngeneic tumor grafts

Syngeneic mouse models, also known as allograft mouse tumor systems, were developed about 50 years ago but were relegated to the backseat of preclinical oncology as the concept of directly targeting human cancer genes or proteins gained prominence. Syngeneic tumor models have been developed and are commonly used in the study of malignancies such as colon cancer (CT-26), breast cancer (4T1), lung cancer (LewisLung), melanoma (B16F10) and leukemia (P388). The number of such robust models

Future perspectives for PDX models

Patient-derived xenografts currently come closest to addressing the urgent needs that arise in late preclinical research: due to their use of the right species, renewable resources and their preservation of the initial clonal heterogeneity of pancreatic tumors. There is abundant evidence that they recapitulate neoplastic cell architecture and conserve genetic and phenotypical biology at the histological and molecular levels. This makes PDX models pivotal platforms for therapeutic screening, the

Conclusions

Pancreatic cancer is a malignancy with a rather low incidence, leading to the regrettable fact that early diagnostic screenings (as established for breast and colorectal cancer) have not yet become routine or feasible in normal public health care settings. Thus diagnosis is usually only made at a point when the disease has reached a high degree of malignancy that will likely be fatal. The consequences – which put a strain on both patients and clinicians – are treatment resistance, metastasis,

Conflict of interest

The authors declare that there are no conflicts of interest.

Acknowledgment

The authors would like to thank Russ Hodge for proofread and amendment of the manuscript.

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