目的:由于治疗方案的改进,去势抵抗性前列腺癌(CRPC)的生存率提高。然而,脑转移患者的治疗选择仍然有限,预后不良.因此,迫切需要探索新的治疗途径,如抗体-药物缀合物(ADC),已证明对实体瘤中活动性脑转移具有显着的临床活性。我们的目的是确定脑转移CRPC(mCRPC)中ADC靶标Trop-2和NECTIN-4的表达水平。
方法:在CRPC脑转移中进行Trop-2和NECTIN-4的免疫组织化学染色并评估H评分(n=31)。此外,我们检测了前列腺癌细胞系中Trop-2蛋白的表达,并在体外研究了它们对抗Trop-2ADCSacituzumabgovitecan(SG)的反应性.
结果:我们的分析显示,大多数患者表现出中度至强Trop-2表达[n=27/31,H评分≥100,中位数H评分220(IQR180-280)],而NECTIN-4在所有脑转移中均不存在。机械上,我们证明了SG的功效取决于Trop-2的体外表达水平。Trop-2在Trop-2阴性PC-3细胞中的过表达导致对SG致敏,而CRISPR-Cas9介导的Trop-2在表达Trop-2的DU-145细胞中的敲低赋予对SG的抗性。
结论:Trop-2在脑转移瘤中的大量表达,以及我们的体外临床前结果,支持SG治疗脑mCRPC的疗效。因此,我们的结果扩展了对ADC在前列腺癌治疗中的潜力的理解,并为具有挑战性的脑转移患者亚组提供了额外的治疗策略.
OBJECTIVE: 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).
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.