PO.ET06.04 · 实验与分子治疗

靶向致癌性miR-181a加工的癌症治疗性抑制

Therapeutic inhibition of oncogenic miR-181a processing for cancer therapy

编号 3001 展板 23 时间 4/20 02:00–05:00 区域 Section 13 主讲 Grace McIntyre, BS

分会场 Molecular Targets 1

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作者与单位 Authors & Affiliations

Grace McIntyre¹, Jessica Mathew², Zoe Jackson³, Meghana Choragudi⁴, Madison Uyemura¹, Aaron Robida⁵, Renju Jacob⁵, Jose Colina¹, Jiaming Yao⁶, Hang Yang Wong⁷, Rachel Offenheim⁸, Mark Kunkel⁹, Sriram Chandrasekaran³, Peter Toogood⁷, Analisa DiFeo¹

¹Department of Pathology, University of Michigan, Ann Arbor, MI,²Chemistry, College of Literature, Science, and the Arts, University of Michigan, Ann Arbor, MI,³Biomedical Engineering, University of Michigan, Ann Arbor, MI,⁴School of Public Health, University of Michigan, Ann Arbor, MI,⁵Center for Chemical Genomics, University of Michigan, Ann Arbor, MI,⁶College of Literature, Science, and the Arts, University of Michigan, Ann Arbor, MI,⁷College of Pharmacy, University of Michigan, Ann Arbor, MI,⁸Medical School, Queens University, Kingston, ON, Canada,⁹Frederick National Laboratory of Cancer Research, National Cancer Institute, Frederick, MD

摘要 Abstract

中文摘要

背景：致癌性microRNA-181a（miR-181a）是肿瘤发病机制的主调控因子，通过抑制STING、WNT和TGFbeta信号等关键通路，在多种癌症谱系中驱动癌症的起始、进展、转移和免疫逃逸。虽然miR-181a的基因消融具有强效的抗肿瘤作用且耐受性良好，但目前尚无靶向miR-181a的疗法，存在关键的治疗空白。靶向miR-181a提供了一种有前景的策略，因为它同时调控多条致癌通路，这与作用于单一靶点的现有疗法不同。基于核苷酸的miRNA靶向疗法已取得重大进展，已开展超过1,300项靶向miRNA的临床试验；然而在生物利用度、稳定性和有效递送方面仍存在挑战。因此，靶向miR-181a加工的小分子药理学策略代表了一种有吸引力的替代方案，具有更优的药代动力学特性、更好的稳定性和更强的递送潜力。在此，我们报告了SMIR-181s（miR-181a小分子抑制剂）的发现与表征，这是一类新型化合物，可改变miR-181a的生物合成并抑制癌症特性。结果：使用基于生物传感器的高通量筛选平台在miR-181a依赖性癌细胞系中，我们鉴定出一种新型miR-181a生物合成小分子抑制剂。筛选鉴定出一类七种SMIR-181s，它们损害miR-181a的成熟，导致前体miR-181a的积累和成熟体的耗竭。机制研究揭示，SMIR-181s通过诱导TARBP2（反式激活反应结合蛋白2）的降解介导这种耗竭，TARBP2是一种RNA结合蛋白，充当miR-181a等应激诱导miRNA的调节器。重要的是，SMIR-181s在NCI-60癌细胞系panel中展现出广泛的细胞毒性，对miR-181a高表达肿瘤细胞疗效增强，同时不影响正常细胞。此外，这些化合物触发凋亡，并展现出与NCI-60数据库中所有已知药物不同的新型作用机制。结论：总的来说，这项工作强调了miR-181a作为预测性生物标志物的潜力，为靶向miRNA加工的小分子建立了概念验证，并提出SMIR-181类作为治疗广泛的miR-181a驱动恶性肿瘤的首创（first-in-class）候选药物。

查看英文原文 English abstract

Background: Oncogenic microRNA-181a (miR-181a) is a master regulator of tumor pathogenesis, driving cancer initiation, progression, metastasis, and immune evasion across diverse cancer lineages by suppressing critical pathways such as STING, WNT, and TGFbeta signaling. While genetic ablation of miR-181a is potently anti-tumorigenic and well tolerated, no therapies currently exist targeting miR-181a, presenting a critical therapeutic gap. Targeting miR-181a offers a promising strategy as it regulates multiple oncogenic pathways simultaneously, unlike existing therapies that act on a single target. Nucleotide-based miRNA-targeting therapies have made significant advances with more than 1,300 clinical trials having been conducted to target miRNAs; yet challenges remain in bioavailability, stability, and effective delivery. Therefore, a small molecule pharmacological strategy targeting miR-181a processing represents an attractive alternative with superior pharmacokinetic properties, improved stability, and enhanced delivery potential. Here, we report the discovery and characterization of SMIR-181s (Small Molecule Inhibitors of miR-181a), a novel class of compounds that alter miR-181a biogenesis and suppress cancer properties. Results: Using a high-throughput biosensor-based screening platform in miR-181a dependent cancer lines, we identified a novel small molecule inhibitor of miR-181a biogenesis. Screening identified a class of seven SMIR-181s, that impair miR-181a maturation, resulting in the accumulation of precursor miR-181a accumulation and depletion of mature. Mechanistic studies reveal that SMIR-181s mediate this depletion by inducing degradation of TARBP2 (Trans-Activating Responsive Binding Protein 2), an RNA-binding protein that acts as a rheostat for stress-induced miRNAs such as miR-181a. Importantly, SMIR-181s display broad cytotoxicity across the NCI-60 cancer cell line panel, with enhanced efficacy in miR-181a high tumor cells while sparing normal cells. Furthermore, these compounds trigger apoptosis and exhibit a novel mechanism of action distinct from all known agents in the NCI-60 database. Conclusions: Collectively, this work emphasizes miR-181a's potential as a predictive biomarker, establishes proof-of-concept for small molecules that target miRNA processing, and nominates the SMIR-181 class as first-in-class candidates for the treatment of a broad spectrum of miR-181a-driven malignancies.

利益披露 Disclosure

G. McIntyre, None.. J. Mathew, None.. Z. Jackson, None.. M. Choragudi, None.. M. Uyemura, None.. A. Robida, None. R. Jacob, RxPlora g., Board of Directors, non-salaried role). J. Colina, None.. J. Yao, None.. H. Yang Wong, None.. R. Offenheim, None. M. Kunkel, Frederick National Laboratory of Cancer Research Employment. S. Chandrasekaran, None. P. Toogood, Lycera Patent. Zoetis LLC Patent. A. DiFeo, CircNova ). Sparc ). Moderna ). Rogel Cancer Center ). Barbra Ann Robson Foundation ). The Silver Family Foundation ). The Debra A. and Dean A. Frick Ovarian Cancer Research Fund ).

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