Molecular Subtyping and Precision Medicine for Pancreatic Cancer

Abstract

Substantial progress in recent years has dramatically increased our knowledge of the molecular basis of cancer, revealing new potential therapeutic targets and paving the way for effective personalised medicine for the treatment of many tumour types. However, pancreatic cancer has been lagging behind in this success and continues to be one of the most lethal solid malignancies. Its molecular heterogeneity and the unselected design of the majority of clinical trials to date can in part explain the reason for our failure to make a significant change in the survival outcomes for patients with pancreatic cancer. A changing paradigm in drug development is required to validate the new molecular taxonomy and to rapidly translate preclinical discovery into clinical trials. Here, we review the molecular subtyping of pancreatic cancer, the challenges in identifying effective treatment regimens according to defined low-prevalence molecular subgroups and we illustrate a new model of translational therapeutic development that was established in the U.K. (Precision-Panc) as a potentially effective solution to improve outcomes for patients with pancreatic cancer.

Keywords: Precision-Panc; molecular subtypes; pancreatic cancer; pancreatic ductal adenocarcinoma; precision medicine.

Figure 1

Molecular targets in pancreatic cancer. Potential molecular targets in pancreatic cancer, including therapeutic targeting of single-gene alterations, or possibly larger subgroups that are identified by whole genome sequencing (locally rearranged or unstable genomes), mutational signatures or transcriptomic subtypes. The pie diagram shows specific compounds currently under clinical investigation based on single-gene alterations or targeting the stroma or altered metabolism. However, this list continues to expand and “Other” includes potential other targets based on encouraging preclinical evidence with various drugs with similar mechanisms of action being evaluated.

Figure 2

Precision-Panc Master Protocol and different Pancreatic canceR Individualised Multi-arm Umbrella Study (PRIMUS) studies. CTU (Clinical Trials Unit), FOLFOX-A (FOLFOX and nab-paclitaxel), GA (gemcitabine and nab-paclitaxel), ATRA (all-trans retinoic acid).