Abstract 6699: Development of a fully modified miR-34a (FM-miR-34a) cancer therapeutic: a translational research study

Abstract MicroRNAs (miRNAs) regulate gene expression by binding to sites within the 3′ untranslated region (UTR) of target mRNAs and exert negative control through mRNA cleavage or translational repression. In cancer, downregulation of tumor-suppressive miRNAs is common, prompting exploration of miRNA restoration strategies for inhibiting tumor growth and suppressing key oncogenic pathways. MicroRNA-34a (miR-34a), known for its tumor-suppressive properties, has advanced to clinical trials as an anti-cancer agent. However, clinical implementation faces challenges such as precise tumor-targeted delivery, susceptibility to degradation in circulation, rapid renal clearance and hindered cytosolic entry due to endosomal entrapment. We tackled a few obstacles by generating a first-in-class fully modified miR-34a (FM-miR-34a) supported by a ligand-mediated vehicle-free delivery platform which exhibited enhanced stability and sustained target gene repression in vitro and in vivo. Prior to the generation of FM-miR-34a, the molecule would have degraded in circulation quickly. However, with FM-miR-34a showing increased stability in serum, we can now aim to increase the circulation half-life of the molecule, which would allow more miR-34a to be biologically available. To achieve this, we incorporated an albumin-binding moiety within the delivery ligand, allowing the molecule to bind to human serum albumin, the most abundant protein in blood. This in turn increases the overall molecular weight of the cancer therapeutic, pushing it over the renal clearance limit and thus increasing its circulation half-life. We also observe a potent combinatorial anti-tumor response when FM-miR-34a is combined with paclitaxel, a standard chemotherapy for breast cancer. Paclitaxel induces mitotic arrest at G2/M and apoptosis at G0 and G1/S phases, making it an ideal partner for synergistic effects with miR-34a. This approach will potentially allow for reduced dosing of paclitaxel and contribute to better therapeutic efficacy, thus improving quality of life of triple negative breast cancer patients. The research, thus, aims to contribute to the development of a robust therapeutic agent utilizing the miR-34a restoration strategy, addressing delivery challenges, and exploring synergies with existing treatments for enhanced efficacy against cancer. Citation Format: Shreyas Ganesan Iyer, Digambar Waiker, Ana C. Betustak, Sharjeel Anjum, Andrea L. Kasinski. Development of a fully modified miR-34a (FM-miR-34a) cancer therapeutic: a translational research study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6699.