Pharmacologic profile of INT-1B3: A novel synthetic microRNA 193a-3p mimic for therapeutic intervention in oncology

MicroRNAs (miRNAs) are a family of small, non-coding RNAs and serve as small snippets of genetic material that regulate gene expression. As a result, miRNAs modulate a wide range of biological processes including; cell cycle control and apoptosis, cell signaling and differentiation, cell adhesion and motility. Thus, it is not surprising that their misregulation is linked to cancer initiation, treatment response, and metastasis. Due to the inherent ability of miRNAs to concurrently target multiple pathways, their therapeutic potential to be used as anti-cancer drugs is attractive. In this study, we are investigating the mode of action and development of a novel synthetic miRNA mimic (INT-1B3) as a therapeutic candidate for substitution and functional restoration of a depleted miRNA in variety of cancers. To identify miRNAs that control the survival of cancer cells, we performed a functional miRNA screening in which a wide range of relevant miRNAs were selected and miR-193a-3p was chosen as the potential candidate for further preclinical characterization. Compelling evidence demonstrate a tumor suppressor function for miR-193a-3p in many cancer types and link its reduced expression with cancer, metastasis and therapy resistance. Consistent with the described role for miR-193a-3p in literature, our cell-based assays conducted in various experimental tumor cell systems demonstrated efficient target engagement leading to reduced cell proliferation/survival, cell cycle arrest and induction of apoptosis, inhibition of cell motility as well as a potential immune-modulatory role (via adenosine-mediated tumor immune evasion). Furthermore, development of a novel lipid nanoparticle-based formulation as an efficient delivery system demonstrated a marked anti-tumor activity of INT-1B3 as single agent following systemic administration in tumor-bearing mice. Robust tumor growth inhibition in these experimental tumor models is correlated and consistent with efficient target engagement in tumor cells and relevant organs. We are currently investigating the in vitro and in vivo effect of INT-1B3 in variety of cancer types including hepatocellular carcinoma, melanoma and triple negative breast cancer. Our data thus far supports an anti-tumor role for INT-1B3 and encourages further preclinical and clinical investigation. Citation Format: Sanaz Yahyanejad, Thijs de Gunst, Iman Schultz, Harm den Boer, Monica Raimo, Bryony Telford, Rogier Vos, Laurens van Pinxteren, Roel Schaapveld, Michel Janicot. Pharmacologic profile of INT-1B3: A novel synthetic microRNA 193a-3p mimic for therapeutic intervention in oncology [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4405.