Georgia Cancer Center, Augusta University, Augusta, Georgia 30912, United States.
Department of Pediatrics Hematology, The First Hospital of Jilin University, Changchun 130021, China.
Mol Pharm. 2024 Nov 4;21(11):5749-5760. doi: 10.1021/acs.molpharmaceut.4c00743. Epub 2024 Oct 10.
Androgen deprivation therapy has been the primary treatment strategy for advanced prostate cancer (PCa). But most patients develop castration resistance over time. For FDA-approved second-generation androgen receptor (AR) antagonists, including enzalutamide (ENZ) and abiraterone (AA), patients who initially respond to them eventually develop resistance. The key mechanism for resistance to ENZ/AA involves AR splice variants (AR-Vs) and specifically AR-V7. Current AR antagonists cannot target AR-V7 due to its lack of the C-terminal ligand-binding domain (LBD) but keeping the AR N-terminal domain (NTD) which still can activate androgen-responsive genes. Therefore, targeting the AR NTD and AR-V7 is critically important to overcome ENZ resistance. Unfortunately, AR NTD has been considered an "undruggable" target due to the difficulty in defining its three-dimensional (3D) structure. In this context, siRNA is highly suitable to address this undruggable target. However, siRNA cannot freely diffuse into cells, and a carrier is needed. In this regard, nucleic acid-based aptamers are highly suitable for cell type-specific delivery of siRNA In this study, we have developed a serum-stable bivalent prostate-specific membrane antigen (PSMA) aptamer-AR-V7 siRNA chimera (PAP). The results show that PAP can knock down both AR-full length and AR-V7 in PSMA-expressing castration-resistant cells. It can resensitize ENZ in cell lines and PCa xenografts. ENZ combined with PAP can significantly inhibit 22Rv1 xenograft growth in mice without experiencing castration. Owing to the low toxicity, PAP has potential to offer a new antiandrogen treatment for current ENZ-resistant PCa.
去势治疗一直是晚期前列腺癌（PCa）的主要治疗策略。但大多数患者随着时间的推移会产生去势抵抗。对于 FDA 批准的第二代雄激素受体（AR）拮抗剂，包括恩扎卢胺（ENZ）和阿比特龙（AA），最初对它们有反应的患者最终会产生耐药性。对 ENZ/AA 产生耐药性的关键机制涉及 AR 剪接变异体（AR-Vs），特别是 AR-V7。由于缺乏 C 端配体结合域（LBD），但保留 AR N 端结构域（NTD），当前的 AR 拮抗剂无法靶向 AR-V7，而 NTD 仍然可以激活雄激素反应基因。因此，靶向 AR NTD 和 AR-V7 对于克服 ENZ 耐药性至关重要。不幸的是，由于难以定义其三维（3D）结构，AR NTD 一直被认为是一个“不可成药”的靶点。在这种情况下，siRNA 非常适合解决这个不可成药的靶点。然而，siRNA 不能自由扩散到细胞内，需要载体。在这方面，核酸适配体非常适合特异性递送 siRNA。在这项研究中，我们开发了一种血清稳定的双价前列腺特异性膜抗原（PSMA）适配体-AR-V7 siRNA 嵌合体（PAP）。结果表明，PAP 可以敲低 PSMA 表达的去势抵抗细胞中的全长 AR 和 AR-V7。它可以使 ENZ 在细胞系和 PCa 异种移植模型中重新敏感。ENZ 与 PAP 联合使用可以显著抑制 22Rv1 异种移植在小鼠中的生长，而无需去势。由于 PAP 毒性低，它有可能为当前 ENZ 耐药的 PCa 提供一种新的抗雄激素治疗方法。
