Wang Licheng, Lu Change, Wang Xin'an, Wu Denglong
Department of Urology, Tongji Hospital, School of Medicine, Tongji University, 389 Xincun Road, Putuo District, Shanghai, 200065, China.
Department of Urology, Tongji Hospital, School of Medicine, Tongji University, 389 Xincun Road, Putuo District, Shanghai, 200065, China.
Eur J Med Chem. 2025 Oct 15;296:117829. doi: 10.1016/j.ejmech.2025.117829. Epub 2025 May 30.
Prostate cancer (PCa) is one of the most prevalent malignancies among men worldwide and remains the second leading cause of cancer-related mortality in this population. While androgen deprivation therapy (ADT) is initially effective, most patients eventually progress to castration-resistant prostate cancer (CRPC), a stage characterized by aggressive disease behavior and limited treatment options. Prostate-specific membrane antigen (PSMA) has emerged as a pivotal biomarker in PCa pathogenesis, with its overexpression in malignant cells providing a compelling target for both diagnostic imaging and therapeutic intervention.This review explores the multifaceted role of PSMA in tumor progression, highlighting its involvement in neoangiogenesis, metabolic reprogramming, and therapeutic vulnerabilities. We critically examine the latest advancements in PSMA-targeted treatment strategies, including radioligand therapy (e.g., Lu-PSMA-617), antibody-drug conjugates, bispecific T-cell engagers, and small-molecule PSMA inhibitors. Clinical studies have demonstrated that PSMA-directed therapies can significantly reduce prostate-specific antigen (PSA) levels, improve radiographic progression-free survival (rPFS), and enhance patient-reported quality of life. However, challenges such as heterogeneous PSMA expression and acquired resistance necessitate further investigation. Ongoing clinical trials are actively exploring combinatory approaches, integrating PSMA-targeted therapy with radiotherapy, chemotherapy, and immunotherapy to optimize therapeutic efficacy. This review underscores the promise of PSMA-targeted strategies in advancing precision medicine for mCRPC, paving the way for improved survival outcomes and a better quality of life for affected patients.
前列腺癌（PCa）是全球男性中最常见的恶性肿瘤之一，并且仍然是该人群中癌症相关死亡率的第二大主要原因。虽然雄激素剥夺疗法（ADT）最初是有效的，但大多数患者最终会进展为去势抵抗性前列腺癌（CRPC），这一阶段的特征是疾病行为侵袭性强且治疗选择有限。前列腺特异性膜抗原（PSMA）已成为PCa发病机制中的关键生物标志物，其在恶性细胞中的过表达为诊断成像和治疗干预提供了极具吸引力的靶点。本综述探讨了PSMA在肿瘤进展中的多方面作用，强调了其在新生血管生成、代谢重编程和治疗易损性中的作用。我们批判性地审视了PSMA靶向治疗策略的最新进展，包括放射性配体疗法（如Lu-PSMA-617）、抗体药物偶联物、双特异性T细胞衔接器和小分子PSMA抑制剂。临床研究表明，PSMA导向疗法可显著降低前列腺特异性抗原（PSA）水平，改善影像学无进展生存期（rPFS），并提高患者报告的生活质量。然而，诸如PSMA表达异质性和获得性耐药等挑战需要进一步研究。正在进行的临床试验正在积极探索联合方法，将PSMA靶向治疗与放疗、化疗和免疫疗法相结合，以优化治疗效果。本综述强调了PSMA靶向策略在推进mCRPC精准医学方面的前景，为改善受影响患者的生存结果和提高生活质量铺平了道路。
