Department of Urology and Paediatric Urology, University Hospital Bonn, Bonn, Germany.
Department of Urology Uro-Oncology, Robot-Assisted and Specialized Urologic Surgery, University Hospital Cologne, Köln, Germany.
Cancer Med. 2024 Jun;13(12):e7320. doi: 10.1002/cam4.7320.
Improved survival rates have been observed in castration-resistant prostate cancer (CRPC) due to advancements in treatment options. However, individuals with brain metastases still have limited therapeutic options and an unfavorable prognosis. Therefore, there is an urgent need to explore new therapeutic avenues, such as antibody-drug conjugates (ADCs), which have demonstrated significant clinical activity against active brain metastases in solid tumors. Our objective was to determine the expression levels of the ADC targets Trop-2 and NECTIN-4 in cerebral metastasized CRPC (mCRPC).
Immunohistochemical staining of Trop-2 and NECTIN-4 with evaluation of H-score was performed in CRPC brain metastases (n = 31). Additionally, we examined Trop-2 protein expression in prostate cancer cell lines and studied their responsiveness to the anti-Trop-2 ADC Sacituzumab govitecan (SG) in vitro.
Our analysis revealed that most patients exhibited moderate to strong Trop-2 expression [n = 27/31 with H-score ≥100, median H-score 220 (IQR 180-280)], while NECTIN-4 was absent in all cerebral metastases. Mechanistically, we demonstrated that the efficacy of SG depends on Trop-2 expression levels in vitro. Overexpression of Trop-2 in Trop-2-negative PC-3 cells led to sensitization to SG, whereas CRISPR-Cas9-mediated knockdown of Trop-2 in Trop-2-expressing DU-145 cells conferred resistance to SG.
The substantial expression of Trop-2 in cerebral metastases, along with our preclinical in vitro results, supports the efficacy of SG in treating cerebral mCRPC. Thus, our results extend the understanding of the potential of ADCs in prostate cancer treatment and provide an additional treatment strategy for the challenging subset of patients with cerebral metastases.
由于治疗选择的进步，在去势抵抗性前列腺癌（CRPC）中观察到生存率提高。然而，有脑转移的患者的治疗选择仍然有限，预后不佳。因此，迫切需要探索新的治疗途径，例如抗体药物偶联物（ADC），其在实体瘤的活跃脑转移中显示出显著的临床活性。我们的目的是确定 Trop-2 和 NECTIN-4 的 ADC 靶点在脑转移的 CRPC（mCRPC）中的表达水平。
对 31 例 CRPC 脑转移患者进行 Trop-2 和 NECTIN-4 的免疫组织化学染色，并评估 H 评分。此外，我们还研究了 Trop-2 蛋白在前列腺癌细胞系中的表达，并研究了它们对抗 Trop-2 ADC Sacituzumab govitecan（SG）的体外反应性。
我们的分析表明，大多数患者表现出中等至强的 Trop-2 表达[H 评分≥100 的 n=27/31，中位数 H 评分 220（IQR 180-280）]，而所有脑转移均无 NECTIN-4。从机制上讲，我们证明了 SG 的疗效取决于 Trop-2 的表达水平。在 Trop-2 阴性的 PC-3 细胞中过表达 Trop-2 导致对 SG 的敏感性增加，而在 Trop-2 表达的 DU-145 细胞中用 CRISPR-Cas9 介导的 Trop-2 敲低则导致对 SG 的耐药性。
脑转移中 Trop-2 的大量表达，以及我们的体外临床前结果，支持 SG 治疗脑 mCRPC 的疗效。因此，我们的结果扩展了 ADC 在前列腺癌治疗中的潜力的理解，并为具有脑转移的挑战性患者提供了额外的治疗策略。
