Delta-like protein 3 expression and therapeutic targeting in neuroendocrine prostate cancer
Delta-like protein 3 expression and therapeutic targeting in neuroendocrine prostate cancer
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DOI：
10.1126/scitranslmed.aav0891
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发表时间：
2019-03-20
影响因子：
17.1
通讯作者：
Beltran, Himisha
中科院分区：
文献类型：
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作者：
Puca, Loredana;Gavyert, Katie;Beltran, Himisha
在一部分晚期前列腺癌患者中，组织学转化为小细胞神经内分泌前列腺癌，这是治疗耐药的一种机制。Rovalpituzumab tesirine（SC16LD6.5）是一种靶向δ样蛋白3（DLL 3）的抗体-药物偶联物，最初开发用于小细胞肺癌。我们发现DLL 3在大多数去势抵抗性神经内分泌前列腺癌（CRPC-NE）（47例中的36例，76.6%）和去势抵抗性前列腺癌（56例中的7例，12.5%）中表达。它在局限性前列腺癌（194例中的1例）和良性前列腺（103例中的0例）中显示极低表达或无表达。DLL 3表达与神经内分泌标志物表达、RB 1缺失和侵袭性临床特征相关。循环肿瘤细胞中的DLL 3与匹配的转移性活检一致（87%）。用单剂量的SC16LD6.5治疗表达DLL 3的前列腺癌异种移植物导致完全和持久的反应，而DLL 3阴性模型不敏感。我们强调了一名神经内分泌前列腺癌患者，该患者在1期试验中接受SC16LD6.5治疗时具有有意义的临床和放射学反应。总体而言，我们的研究结果表明，DLL 3优先在CRPC-NE中表达，并提供了在DLL 3阳性转移性前列腺癌患者中靶向DLL 3的基本原理。
Histologic transformation to small cell neuroendocrine prostate cancer occurs in a subset of patients with advanced prostate cancer as a mechanism of treatment resistance. Rovalpituzumab tesirine (SC16LD6.5) is an antibody-drug conjugate that targets delta-like protein 3 (DLL3) and was initially developed for small cell lung cancer. We found that DLL3 is expressed in most of the castration-resistant neuroendocrine prostate cancer (CRPC-NE) (36 of 47, 76.6%) and in a subset of castration-resistant prostate adenocarcinomas (7 of 56, 12.5%). It shows minimal to no expression in localized prostate cancer (1 of 194) and benign prostate (0 of 103). DLL3 expression correlates with neuroendocrine marker expression, RB1 loss, and aggressive clinical features. DLL3 in circulating tumor cells was concordant with matched metastatic biopsy (87%). Treatment of DLL3-expressing prostate cancer xenografts with a single dose of SC16LD6.5 resulted in complete and durable responses, whereas DLL3-negative models were insensitive. We highlight a patient with neuroendocrine prostate cancer with a meaningful clinical and radiologic response to SC16LD6.5 when treated on a phase 1 trial. Overall, our findings indicate that DLL3 is preferentially expressed in CRPC-NE and provide rationale for targeting DLL3 in patients with DLL3-positive metastatic prostate cancer.