Context

Prostate-specific membrane antigen (PSMA) is a transmembrane glycoprotein overexpressed in most prostate cancers and exploited as a target for PSMA-targeted therapies. Different approaches to target PSMA-expressing cancer cells have been developed, showing promising results in clinical trials.

Objective

To discuss the regulation of PSMA expression and the main PSMA-targeted therapeutic concepts illustrating their clinical development and rationalizing combination approaches with examples.

Evidence acquisition

We performed a detailed literature search using PubMed and reviewed the American Society of Clinical Oncology and European Society of Medical Oncology annual meeting abstracts up to September 2023.

Evidence synthesis

We present an overarching description of the different strategies to target PSMA. The outcomes of PSMA-targeted therapies strongly rely on surface-bound PSMA expression. However, PSMA heterogeneity at different levels (interpatient and inter/intratumoral) limits the efficacy of PSMA-targeted therapies. We highlight the molecular mechanisms governing PSMA regulation, the understanding of which is crucial to designing therapeutic strategies aimed at upregulating PSMA expression. Thus far, homeobox B13 (HOXB13) and androgen receptor (AR) have emerged as critical transcription factors positively and negatively regulating PSMA expression, respectively. Furthermore, epigenetic regulation of PSMA has been also reported recently. In addition, many established therapeutic approaches harbor the potential to upregulate PSMA levels as well as potentiate DNA damage mediated by current radioligands.

Conclusions

PSMA-targeted therapies are rapidly advancing, but their efficacy is strongly limited by the heterogeneous expression of the target. A thorough comprehension of how PSMA is regulated will help improve the outcomes through increasing PSMA expression and will provide the basis for synergistic combination therapies.

Patient summary

Prostate-specific membrane antigen (PSMA) is overexpressed in most prostate cancers. PSMA-targeted therapies have shown promising results, but the heterogeneous expression of PSMA limits their efficacy. We propose to better elucidate the regulation of PSMA expression to increase the levels of the target and improve the therapeutic outcomes.

中文翻译：

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前列腺特异性膜抗原靶向治疗前列腺癌：改善治疗结果

 语境

前列腺特异性膜抗原 (PSMA) 是一种跨膜糖蛋白，在大多数前列腺癌中过度表达，并被用作 PSMA 靶向治疗的靶点。已经开发出针对表达 PSMA 的癌细胞的不同方法，并在临床试验中显示出有希望的结果。

 客观的

讨论 PSMA 表达的调节和主要的 PSMA 靶向治疗概念，通过实例说明其临床发展并合理化组合方法。

 证据获取

我们使用 PubMed 进行了详细的文献检索，并回顾了截至 2023 年 9 月的美国临床肿瘤学会和欧洲肿瘤内科学会年会摘要。

 证据综合

我们对针对 PSMA 的不同策略进行了总体描述。 PSMA 靶向治疗的结果强烈依赖于表面结合的 PSMA 表达。然而，不同水平（患者间和瘤间/瘤内）的 PSMA 异质性限制了 PSMA 靶向治疗的疗效。我们重点介绍控制 PSMA 调节的分子机制，了解其对于设计旨在上调 PSMA 表达的治疗策略至关重要。迄今为止，同源盒 B13 (HOXB13) 和雄激素受体 (AR) 已分别作为正向和负向调节 PSMA 表达的关键转录因子。此外，最近还报道了 PSMA 的表观遗传调控。此外，许多已建立的治疗方法具有上调 PSMA 水平以及增强当前放射性配体介导的 DNA 损伤的潜力。

 结论

PSMA 靶向疗法正在迅速发展，但其疗效受到靶标异质表达的强烈限制。彻底理解 PSMA 的调控方式将有助于通过增加 PSMA 表达来改善结果，并为协同联合疗法奠定基础。

 患者总结

前列腺特异性膜抗原（PSMA）在大多数前列腺癌中过度表达。 PSMA 靶向疗法已显示出有希望的结果，但 PSMA 的异质表达限制了其疗效。我们建议更好地阐明 PSMA 表达的调节，以提高靶标水平并改善治疗结果。