PO.CL01.05 · 临床研究
claudin-3(CLDN3)和B7-H3(CD276)的显著共表达可作为神经内分泌癌靶向治疗的潜在生物标志物
The significant co-expression of claudin-3(CLDN3) and B7-H3(CD276) as a potential biomarker for targeted therapy in neuroendocrine carcinomas
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
尽管神经内分泌癌(SCLC和LCNEC;大细胞神经内分泌癌)的死亡率较高,但由于不可靶向的驱动突变占主导地位,新型治疗靶点的开发受到了限制。因此,识别可行的治疗靶点变得日益重要,Claudin-3(CLDN3)和B7-H3等蛋白正成为靶向治疗的有前景的候选者。CLDN3是上皮细胞和内皮细胞紧密连接的关键组成部分,在各种癌症中经常发生失调。尽管CLDN3也存在于正常组织中,但其在肿瘤细胞中增强的表面可及性凸显了其作为治疗靶点的潜力。近期研究表明,CLDN3在大多数神经内分泌肿瘤中高表达,其阳性与透明细胞肾细胞癌的不良预后相关。同样,B7-H3作为神经内分泌肿瘤(尤其是SCLC)中有前景的靶点也受到了关注。B7-H3的高表达在SCLC各分子亚型中保持一致,支持其在蛋白水平特征分析和新型治疗策略开发中的相关性。在此背景下,本研究的目的是使用经过验证的多重免疫组织化学(IHC)平台评估CLDN3和B7-H3作为治疗靶点生物标志物。共回顾性收集了94例经手术切除或活检获得的福尔马林固定石蜡包埋组织。所有病例均诊断为神经内分泌癌,包括SCLC、LCNEC或复合型神经内分泌癌。已开发出一种基于酪胺信号放大的7重IHC检测panel,用于评估治疗靶点生物标志物。CLDN3的表达水平通过两种不同方法获得:单一IHC和多重IHC检测。这些方法经分析显示出93.3%的高灵敏度,受试者工作特征(ROC)曲线下面积(AUC)为0.964。在使用经过验证的7重IHC方法分析的四个靶点生物标志物中,CLDN3和B7-H3被确定为神经内分泌癌的潜在治疗靶点生物标志物。这一经过验证的多重IHC panel可作为支持神经内分泌癌治疗开发的有用平台。
查看英文原文 English abstract
Despite the elevated mortality rate associated with neuroendocrine carcinomas (SCLC and LCNEC; large cell neuroendocrine carcinomas), the development of novel therapeutic targets has been limited by the predominance of non-targetable driver mutations. Consequently, the identification of viable therapeutic targets has become increasingly important, with proteins such as Claudin-3 (CLDN3) and B7-H3 emerging as promising candidates for targeted therapy. CLDN3, a key component of tight junctions in epithelial and endothelial cells, is frequently dysregulated in various cancers. Although CLDN3 is also present in normal tissues, its enhanced surface accessibility in tumor cells highlights its potential as a therapeutic target. Recent studies have demonstrated that CLDN3 is highly expressed in most neuroendocrine neoplasms, and its positivity has been linked to poor prognosis in clear cell renal cell carcinoma. Similarly, B7-H3 has gained attention as a promising target in neuroendocrine tumors, particularly SCLC. The high expression of B7-H3 is consistent across molecular subtypes in SCLC, supporting its relevance for protein-level characterization and the development of novel therapeutic strategies. In this context, the purpose of the present study was to evaluate CLDN3 and B7-H3 as therapeutic target biomarkers using a validated multiplex immunohistochemistry (IHC) platform. A total of 94 cases of formalin-fixed, paraffin-embedded tissues obtained from surgical resection or biopsy were retrospectively collected. All cases were diagnosed as neuroendocrine carcinoma, including SCLC, LCNEC, or combined neuroendocrine carcinoma. A tyramide signal amplification-based 7-plex IHC assay panel has been developed for the evaluation of therapeutic target biomarkers. The expression levels of CLDN3 were elicited by two different methods: single IHC and multiplex IHC assay. These were analysed with a high sensitivity of 93.3% and an area under the curve (AUC) of 0.964 under the receiver operating characteristic (ROC) curve. Among the four targeted biomarkers analyzed using a validated 7-plex IHC method, CLDN3 and B7-H3 were identified as potential therapeutic target biomarkers for neuroendocrine carcinomas. This validated multiplex IHC panel serves as a useful platform for supporting therapeutic development in neuroendocrine carcinomas.
利益披露 Disclosure
J. Nam,
Logone Bio-Convergence Research Foundation Employment.
J. Kim,
Logone Bio-Convergence Research Foundation Employment.
J. Choi, None.
M. Sung,
Samsung Medical Center Employment.
J. Kang, None..
H. Yang, None..
Y. Choi, None..
Y. Shin, None.