Abstract 4514: Transcription down-regulation of c-Myc through nucleic acid clamp-mediated stabilization of the promoter G-quadruplex

Abstract

Abstract MYC overexpression occurs in up to 80% of all cancers. Down-regulating MYC's expression is an effective therapeutic strategy for the treatment of many of these cancers, and particularly for non-Hodgkin's lymphoma (NHL). NHL is the fifth most common cancer type, accounting for 5% of all cancers and 4% of all cancer deaths. Developing MYC-targeting therapeutics will be very impactful to NHL patients. In the current study, we have developed a nucleic acid clamp to transcriptionally down-regulate MYC expression by stabilizing the G-quadruplex (G4) formed in the nuclease hypersensitivity element III1 promoter region. The clamps complement nucleotides on the 5’- and 3’- regions flanking the G4-forming sequence, linked together with an 18 angstrom abasic moiety. To date, the binding affinity and specificity, G4 structure stabilizing ability, MYC down-regulation capability, and the selective cytotoxicity on cancerous vs non-cancerous cell lines of these clamps have been confirmed by EMSA and electronic circular dichroism, DMS footprinting, luciferase reporter assay, and MTS viability assay respectively. Recently, various replacements have been explored to replace the abasic moiety with non-complementary nucleic acids and to optimize the phosphate backbone with peptide nucleic acids. In addition, complexation with block co-polymers is under investigation to develop a functionalizable nanotherapeutic for NHL. The highly selective G4 stabilizing ability of the clamps used in the current approach offers an advantage over traditional G4 stabilizing small molecules. This novel approach is a promising therapeutic for the treatment of MYC related malignancies, and provides a framework for future G4-therapeutic development for other high-value genes, such as kRAS, VEGF, c-KIT and many more. Citation Format: Taisen Hao, Tracy Brooks. Transcription down-regulation of c-Myc through nucleic acid clamp-mediated stabilization of the promoter G-quadruplex. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4514.