Department of Biochemistry and Molecular Biology, Augusta University, 1410 Laney Walker Boulevard, Augusta, GA, 30912, USA.
Department of Urology, Augusta University, Augusta, GA, USA.
Sci Rep. 2024 Feb 2;14(1):2816. doi: 10.1038/s41598-024-53269-9.
Neuroendocrine prostate cancer (NEPC) is a highly lethal variant of castration-resistant prostate cancer (CRPC) with poor survival rates. Current treatment options for NEPC are limited to highly toxic platinum drugs highlighting the urgent need for new therapies. This study aimed to develop a novel therapeutic approach using engineered exosomes against NEPC. Exosomes were modified to target CEACAM5, an NEPC surface antigen, by attaching CEACAM5 antibodies to HEK293T exosomes. These exosomes were loaded with drugs inhibiting EZH2 and the androgen receptor (AR) as recent research shows a persistent role of AR in NEPC wherein it plays a concerted role with EZH2 in driving neuronal gene programs. In vitro experiments with NEPC cell lines demonstrated that CEACAM5-targeted exosomes were specifically taken up by NEPC cells, leading to reduced cellular viability and decreased expression of neuronal markers. Further in vivo tests using a NEPC patient-derived xenograft model (LuCaP145.1) showed significant tumor regression in mice treated with engineered exosomes compared to control mice receiving IgG-labeled exosomes. These results suggest that CEACAM5-engineered exosomes hold promise as a targeted therapy for NEPC. Importantly, our exosome engineering strategy is versatile and can be adapted to target various surface antigens in prostate cancer and other diseases.
神经内分泌前列腺癌（NEPC）是一种具有高致死率的去势抵抗性前列腺癌（CRPC）变异体，患者生存率低。目前针对 NEPC 的治疗选择有限，仅限于高度毒性的铂类药物，这凸显了对新疗法的迫切需求。本研究旨在开发一种使用工程化外泌体针对 NEPC 的新型治疗方法。通过将 CEACAM5 抗体附着到 HEK293T 外泌体上来修饰外泌体，使其靶向 CEACAM5，CEACAM5 是 NEPC 表面抗原。这些外泌体装载有抑制 EZH2 和雄激素受体（AR）的药物，因为最近的研究表明 AR 在 NEPC 中持续发挥作用，它与 EZH2 协同作用，驱动神经元基因程序。针对 NEPC 细胞系的体外实验表明，CEACAM5 靶向的外泌体被 NEPC 细胞特异性摄取，导致细胞活力降低和神经元标志物表达减少。进一步使用 NEPC 患者来源的异种移植模型（LuCaP145.1）进行的体内测试表明，与接受 IgG 标记的外泌体的对照小鼠相比，用工程化外泌体治疗的小鼠肿瘤明显消退。这些结果表明，CEACAM5 工程化外泌体有望成为 NEPC 的一种靶向治疗方法。重要的是，我们的外泌体工程化策略具有通用性，可以适应针对前列腺癌和其他疾病的各种表面抗原。
