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HER2抗体 - 药物结合物对消极小圆细胞瘤具有活性

Tom Zhang^1,2, Christopher A Febres-Aldana^2,3, Zebing Liu⁴

¹New York Medical College, Valhalla, New York.

Clinical cancer research : an official journal of the American Association for Cancer Research

|August 9, 2024

概括

形小圆细胞瘤 (DSRCT) 表达ERBB2/HER2,是新疗法的标. 像T-DXd这样的HER2抗体-药物结合体 (ADC) 在缩小DSRCT瘤方面表现有前途,为这种侵袭性肉瘤提供了希望.

科学领域:

在瘤学瘤学.
分子生物学分子生物学
药理学药理学是指药理学的学科.

背景情况:

乳性小圆细胞瘤 (DSRCT) 是一种罕见的,年轻男性的侵袭性腹腔皮肉瘤.
目前的治疗方法 (手术,化疗,辐射) 由于缺乏可操作的基因组标,导致结果不佳.
EWSR1::WT1融合是已知的驱动因素,但尚未确定其他可操作的变化.

研究的目的:

评估ERBB2/HER2表达作为DSRCT中的潜在治疗标.
在DSRCT模型中评估针对HER2的抗体-药物合物 (ADC) 的疗效.

主要方法:

在临床样本和患者衍生异种移植 (PDX) 中使用RNA测序,RT-qPCR和新型HER2 IHC测定 (克隆29D8) 评估ERBB2/HER2表达.
在DSRCT PDX,细胞系和有机体模型中对HER2 ADCs (trastuzumab deruxtecan [T-DXd和trastuzumab emtansine) 的评估反应.
研究了药物内化,亡诱导 (西方涂抹,卡斯帕斯分析) 和旁观者效应.

主要成果:

在DSRCT样本中可以检测ERBB2/HER2,通过RNA测定和克隆29D8 IHC提高了灵敏度.
在DSRCT模型中,T-DXd和trastuzumab 治疗导致了显著的瘤回归.
治疗反应包括快速的HER2ADC内化,p53介导的亡,以及与HER2水平成比例的旁观者效应.

结论:

ERBB2/HER2是DSRCT的一个可行的治疗点.
HER2 ADCs代表了对这种侵袭性肉瘤的有希望的新型治疗选择.
这些发现可能会解决对更有效的DSRCT疗法的关键未满足需求.

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