Abstract A57: Antisense oligonucleotide therapeutics with receptor-targeted delivery in triple-negative breast cancer cells via microRNA blockade without passenger strand side effects

Abstract

Abstract Triple-negative breast cancer (TNBC) attacks >40,000 young women annually in the US, and has no molecular targeted therapies. MicroRNAs drive many forms of cancer, and they modulate multiple gene pathways simultaneously. Highly expressed microRNA miR-17-5p is distinctive in TNBC and contributes to cancer cell survival. We hypothesized that reduction of miR-17-5p activity by delivering oligonucleotide-based antagomiRs specifically to breast cancer cells via receptor-mediated endocytosis would inhibit metastatic behavior of TNBC cells. Using a luciferase reporter system harboring a miR-17-5p binding site in the 3′ untranslated region of the luciferase gene, we assessed the efficacy of various antagomiRs. Contrary to conventional wisdom, that only one of the two strands in a pre-miRNA duplex is active, such as miR-17-5p, we previously observed that a full-length miR-17-5p DNA-LNA blocker created additional off-target effects by mimicking miR-17-3p, implying that therapeutic microRNA blockers should be designed to avoid resemblance to the opposing strands. We designed guide strand specific blockers of miR-17-5p composed of gapmers with anionic backbone derivatives 2′-fluoro-arabino nucleic acid (FANA), and 2′-aminomethyl-bridged nucleic acid (NC-BNA). Since most breast cancer cells overexpress insulin-like growth factor receptor (IGF1R), a peptide derivative of the IGF1 was conjugated to anti-miR-17-5p antagomiRs to achieve breast cancer cell-specific delivery. Our results showed that in multiple TNBC cell lines, the NC-BNA 15mers displayed high efficacy with sub-nM activity for miR-17-5p blockade and significant inhibition of cell growth. Anti-miR-17-5p-IGF1 peptide conjugate successfully inhibited miR-17-5p activity in the luciferase reporter system. We are further examining the effects of NC-BNA-peptides in multiple TNBC cell lines. Our study provides a good basis for the development of a new TNBC targeted therapy. Supported by Bound Therapeutics LLC. Conflict of interest: pending TJU PCT/US2015/015681 patent application licensed to Bound Therapeutics LLC. Citation Format: Yuan-Yuan Jin, Eric Wickstrom. Antisense oligonucleotide therapeutics with receptor-targeted delivery in triple-negative breast cancer cells via microRNA blockade without passenger strand side effects [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr A57.