Distinct Response of Circulating microRNAs to the Treatment of Pancreatic Cancer

Abstract

An early detection and monitoring of pancreatic adenocarcinoma has been very challenging, which makes it one of the deadliest cancers today. This has stimulated research to explore new therapeutic strategies and new ways of following treatment response. We believe that miRNAs play an important role in cancer, and circulating miRNAs from peripheral blood could not only be used as early diagnostic biomarkers, but their expression profile could give us a valuable clue about response to therapy.

We focus on targeting tumor-stroma interaction in a pancreatic cancer xenograft mouse model, with two small molecule inhibitors: (1) a fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor, PD173074; and (2) an anaplastic lymphoma kinase receptor (ALK) kinase inhibitor, TAE684. Both drugs reduced COLO357PL pancreatic cancer cell proliferation and disruption of endothelial cell monolayer by cancer cells in vitro. In vivo, initial treatment with both drugs reduced mitosis and angiogenesis similarly. First, we identified serum miRNA expression changes as a response to the tumor presence. Furthermore, we describe a distinctive set of circulating miRNAs that corresponds to each initial treatment before necrotic changes took place and influenced miRNA expression pattern. More importantly, in our study we distinguish between drug effect on the tumor versus host, based on the miRNA expression changes in tumor tissue and the circulation. Finally, we show a connection between successful treatment of pancreatic cancer xenografts and the circulating miRNA expression pattern.

The approach of determining circulating miRNA expression levels and patterns upon the initial treatment could be of immense importance for pancreatic cancer patients in finding the effective drug (combination) treatment and might be a model to expand to other cancers and treatment evaluations.