CEACAM5 的调控与抗 CEACAM5-SN38 抗体药物偶联物在神经内分泌前列腺癌中的治疗效果。
Regulation of CEACAM5 and Therapeutic Efficacy of an Anti-CEACAM5-SN38 Antibody-drug Conjugate in Neuroendocrine Prostate Cancer.
机构信息
Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
Immunomedics, Inc., Morris Plains, New Jersey.
出版信息
Clin Cancer Res. 2021 Feb 1;27(3):759-774. doi: 10.1158/1078-0432.CCR-20-3396. Epub 2020 Nov 16.
PURPOSE
Neuroendocrine prostate cancer (NEPC) is an aggressive form of castration-resistant prostate cancer (CRPC) for which effective therapies are lacking. We previously identified carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) as a promising NEPC cell surface antigen. Here we investigated the scope of CEACAM5 expression in end-stage prostate cancer, the basis for CEACAM5 enrichment in NEPC, and the therapeutic potential of the CEACAM5 antibody-drug conjugate labetuzumab govitecan in prostate cancer.
EXPERIMENTAL DESIGN
The expression of CEACAM5 and other clinically relevant antigens was characterized by multiplex immunofluorescence of a tissue microarray comprising metastatic tumors from 34 lethal metastatic CRPC (mCRPC) cases. A genetically defined neuroendocrine transdifferentiation assay of prostate cancer was developed to evaluate mechanisms of CEACAM5 regulation in NEPC. The specificity and efficacy of labetuzumab govitecan was determined in CEACAM5 prostate cancer cell lines and patient-derived xenografts models.
RESULTS
CEACAM5 expression was enriched in NEPC compared with other mCRPC subtypes and minimally overlapped with prostate-specific membrane antigen, prostate stem cell antigen, and trophoblast cell surface antigen 2 expression. We focused on a correlation between the expression of the pioneer transcription factor and to determine that ASCL1 can drive neuroendocrine reprogramming of prostate cancer which is associated with increased chromatin accessibility of the core promoter and CEACAM5 expression. Labetuzumab govitecan induced DNA damage in CEACAM5 prostate cancer cell lines and marked antitumor responses in CEACAM5 CRPC xenograft models including chemotherapy-resistant NEPC.
CONCLUSIONS
Our findings provide insights into the scope and regulation of CEACAM5 expression in prostate cancer and strong support for clinical studies of labetuzumab govitecan for NEPC.
目的
神经内分泌前列腺癌（NEPC）是一种侵袭性的去势抵抗性前列腺癌（CRPC），目前缺乏有效的治疗方法。我们之前发现癌胚抗原相关细胞黏附分子 5（CEACAM5）是一种很有前途的 NEPC 细胞表面抗原。在这里，我们研究了 CEACAM5 在晚期前列腺癌中的表达范围，这是 NEPC 中 CEACAM5 富集的基础，以及 CEACAM5 抗体药物偶联物 labetuzumab govitecan 在前列腺癌中的治疗潜力。
实验设计
通过对包含 34 例致命转移性 CRPC（mCRPC）转移瘤的组织微阵列进行多重免疫荧光分析，对 CEACAM5 和其他临床相关抗原的表达进行了描述。建立了一种遗传定义的神经内分泌转化分化测定法，以评估 NEPC 中 CEACAM5 调节的机制。在 CEACAM5 前列腺癌细胞系和患者来源的异种移植模型中，确定了 labetuzumab govitecan 的特异性和疗效。
结果
与其他 mCRPC 亚型相比，CEACAM5 在 NEPC 中的表达更为丰富，与前列腺特异性膜抗原、前列腺干细胞抗原和滋养细胞表面抗原 2 的表达最小重叠。我们重点研究了 与 之间表达的相关性，以确定 ASCL1 可以驱动前列腺癌的神经内分泌重编程，这与 核心启动子的染色质可及性增加和 CEACAM5 的表达有关。Labetuzumab govitecan 在 CEACAM5 前列腺癌细胞系中诱导 DNA 损伤，并在包括化疗耐药性 NEPC 在内的 CEACAM5 CRPC 异种移植模型中引起明显的抗肿瘤反应。
结论
我们的研究结果提供了关于前列腺癌中 CEACAM5 表达的范围和调控的深入了解，并为 labetuzumab govitecan 治疗 NEPC 的临床研究提供了有力支持。
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