Targeting of human cancers by miRNAs delivered by mesenchymal stem cell derived microparticles.

Abstract

e14062 Background: Recent data has shown that several oncogenic and tumor suppressor kinases that are deregulated in human cancers can be targeted via specific miRNA sequences. miRNAs can inhibit oncogenic kinase activity as well as upregulate tumor suppressor kinases in cancer cells, leading to inhibition of tumor processes such as invasion, migration and resistance to apoptosis. Examples include the inhibition of PLK1 activity that is overexpressed in breast, ovarian, pancreatic and colorectal cancers by the ectopic expression of miR-10b, miR-100 or miR-593, and the targeting of the increased FAK expression in breast cancer cells by miR-7. Methods: In this study, we have employed preclinical models of cancer disease and have utilized advanced genomics technologies in combination with innovative in vivo imaging techniques to conduct pharmacokinetics and pharmacodynamics studies as well as safety and efficacy studies in order to establish a mechanism of action and demonstrate that miRNA-loaded microparticles can interfere with tumor promoting kinase activity in vivo Results: Our results demonstrate that delivering specific miRNAs targeted against aberrant protein kinase activity may potentially be a novel approach to selectively inhibit cancer cell processes. Conclusions: We report the development of a new microRNA-based approach to target cancer cells by potentially interfering in multiple signaling pathways that are mediated by kinase-dependent mechanisms. We propose that therapeutic miRNA sequences can be delivered to cancer cells via microparticles (MPs) derived from umbilical cord mesenchymal stem cells (MSCs). The engineered MPs home selectively to tumor sites via specific chemokine receptors, fuse with the cell membrane and incorporate miRNA directly into the target cancer cells.