Abstract
Abstract Despite extensive efforts to develop effective delivery technologies for nucleic acid based therapeutic agents, it remains a challenge to deliver therapeutic miRNAs to cancer cells. We have recently developed a novel approach to modify miRNAs by replacing uracil with 5-Fluorouracil (5-FU) in the guide strand of the miRNA molecule (e.g. miR-129, miR-15a). This modification combines the power of 5-FU with tumor suppressor miRNAs to create a potent, and multi-targeted therapeutic molecule without altering the function of the native miRNA. miRNA with this modification have a number of unique features such as retaining target specificity, vehicle free delivery, enhanced potency, and stability. To demonstrate the general applicability of this approach to other tumor suppressor miRNAs, in this study, we have screened a number of miRNA mimics incorporating this modification (e.g. miR-215, miR-140, miR-200c, miR-194, let-7g, miR-502, miR-506) in several major cancer types including colon cancer, pancreatic cancer, and breast cancer. Our results show that the 5-FU modified miRNAs are more potent (low nM range) at inhibiting cancer cell proliferation than the native miRNAs. More importantly, the miRNA mimics are able to eliminate chemoresistant cancer stem like cells. These modified mimics can be delivered into cancer cells without the aid of a delivery vehicle. The modification also did not alter target specificity of the miRNAs, a critical feature of these miRNA mimics. This work demonstrates the potential of this modification to be applied to a broad spectrum of miRNAs in different cancers, and represents a significant advancement in the development of therapeutic miRNAs for cancer treatment. Citation Format: Andrew Fesler, Shixiang Guo, Zachary Ye, Matthew Godwin, Hyaizha Wang, Jingfang Ju. Development of 5-FU modified tumor suppressor miRNAs as a platform for miRNA based cancer therapeutics [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 4403.
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