美国加州大学Davide Ruggero小组报道了靶向前列腺癌的小分子RNA疗法。相关论文于2025年3月20日发表于国际顶尖学术期刊《癌细胞》杂志上。

为了了解这种易变性是否可以治疗最致命的前列腺癌——去势抵抗性前列腺癌（CRPC），研究团队研究了一种临床小分子佐他替芬，它靶向RNA解旋酶和翻译因子真核起始因子4A （eIF4A）。佐他替芬在患者源性和异种移植模型中抑制肿瘤发生，并在激素治疗的同时延长体内生存期。全基因组转录组、翻译组和蛋白质组学分析揭示了两个重要的翻译靶点：雄激素受体（AR）， CRPC中的关键致癌基因，以及缺氧诱导因子1A (HIF1A)，缺氧中必不可少的癌症调节剂。研究团队解决了这些致癌mRNA的5′ UTRs的结构，并通过这个小分子惊人地观察到这些选择mRNA的复杂结构重塑。值得注意的是，用佐他替芬治疗的肿瘤对抗雄激素治疗和放疗更加敏感。因此，“翻译体疗法”为治疗最致命的癌症提供了额外的策略。

研究人员表示，通过靶向RNA结构主题化小分子来调节蛋白质表达是一种尚未开发的癌症治疗途径。

附：英文原文

Title: Small-molecule RNA therapeutics to target prostate cancer

Author: Duygu Kuzuoglu-Ozturk, Hao G. Nguyen, Lingru Xue, Emma Figueredo, Vishvak Subramanyam, Isabelle Liu, Kenya Bonitto, Ashish Noronha, Adrianna Dabrowska, Janet E. Cowan, Juan A. Oses-Prieto, Alma L. Burlingame, Stephen T. Worland, Peter R. Carroll, Davide Ruggero

Issue&Volume: 2025-03-20

Abstract: Tuning protein expression by targeting RNA structure using small molecules is an unexplored avenue for cancer treatment. To understand whether this vulnerability could be therapeutically targeted in the most lethal form of prostate cancer, castration-resistant prostate cancer (CRPC), we use a clinical small molecule, zotatifin, that targets the RNA helicase and translation factor eukaryotic initiation factor 4A (eIF4A). Zotatifin represses tumorigenesis in patient-derived and xenograft models and prolonged survival in vivo alongside hormone therapy. Genome-wide transcriptome, translatome, and proteomic analysis reveals two important translational targets: androgen receptor (AR), a key oncogene in CRPC, and hypoxia-inducible factor 1A (HIF1A), an essential cancer modulator in hypoxia. We solve the structure of the 5′ UTRs of these oncogenic mRNAs and strikingly observe complex structural remodeling of these select mRNAs by this small molecule. Remarkably, tumors treated with zotatifin become more sensitive to anti-androgen therapy and radiotherapy. Therefore, “translatome therapy” provides additional strategies to treat the deadliest cancers.

DOI: 10.1016/j.ccell.2025.02.027

Source: https://www.cell.com/cancer-cell/abstract/S1535-6108(25)00079-0