建立高级别子宫内膜癌患者来源的异种移植模型的综合小组：分子亚型，遗传改变和治疗目标分析

IF 4.8 2区医学 Q1 Biochemistry, Genetics and Molecular Biology

Neoplasia Pub Date : 2025-04-07 DOI:10.1016/j.neo.2025.101158

Sho Sato , Shigehiro Yagishita , Hiroshi Yoshida , Daisuke Shintani , Aiko Ogasawara , Tadaaki Nishikawa , Masanori Yasuda , Keiji Furuuchi , Toshimitsu Uenaka , Akinobu Hamada , Kosei Hasegawa

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引用次数: 0

摘要

背景：高级别子宫内膜癌（EC）预后不良，但基于分子分类的治疗提供了新的治疗机会。抗体-药物偶联物（ADC）是一种很有前景的工具，但对抗原动力学、最佳治疗序列和耐药机制的深入了解是必不可少的。本研究探讨了患者源性异种移植（PDX）模型作为EC临床前平台的效用，评估了患者和PDX肿瘤的分子亚型和ADC靶点表达。方法：我们建立了一个完整的分子表征的EC患者PDX模型，代表了不同的组织学类型。利用测序和免疫组织化学分析分子亚型和基因改变。ADC靶点包括人表皮生长因子受体2、滋养细胞表面抗原2、B7-H4、叶酸受体α和钙粘蛋白6。结果成功建立了31个EC-PDX模型，与患者肿瘤保持组织学保真度和93.1%的分子亚型一致性。值得注意的是，80.6%的PDX模型表现出至少一个ADC靶点的高表达（2+/3+），54.8%的模型表现出多个靶点的高表达。值得注意的是，9.7%的人表现出所有靶标的高表达，同时也表现出基因突变。同时，78.8%的患者肿瘤至少一种ADC靶点高表达（2+/3+），63.6%的患者肿瘤多个靶点高表达。结论分子分类的EC- pdx面板，丰富了详细的抗原谱和遗传数据，为研究新的ADC疗法和高级别EC的精确治疗策略提供了一个强大的平台。

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Establishing a comprehensive panel of patient-derived xenograft models for high-grade endometrial carcinoma: molecular subtypes, genetic alterations, and therapeutic target profiling

Background

High-grade endometrial cancer (EC) has a poor prognosis, but molecular classification-based treatments present new therapeutic opportunities. Antibody-drug conjugates (ADC) emerge as promising tools, yet a deeper understanding of antigen dynamics, optimal therapeutic sequencing, and resistance mechanisms is essential. This study investigates the utility of patient-derived xenograft (PDX) models for EC as preclinical platforms, evaluating molecular subtypes and the ADC targets expression of patient and PDX tumors.

Methods

We developed a comprehensive panel of molecularly characterized PDX models from patients with EC representing various histological types. Molecular subtypes and gene alterations were analyzed using sequencing and immunohistochemistry. ADC targets, including human epidermal growth factor receptor 2, trophoblast cell-surface antigen 2, B7-H4, folate receptor alpha, and cadherin-6, were profiled.

Results

Thirty-one EC-PDX models were successfully established, maintaining histological fidelity and 93.1 % molecular subtype consistency with the patient tumors. Notably, 80.6 % of the PDX models exhibited high expression (2+/3+) of at least one ADC target, and 54.8 % displayed high expression of multiple targets. Remarkably, 9.7 % showed high expression of all targets, with gene mutations also characterized. Meanwhile, patient tumors, 78.8 % showed high expression (2+/3+) of at least one ADC target, and 63.6 % showed high expression of multiple targets.

Conclusion

The molecularly classified EC-PDX panel, enriched with detailed antigen profiles and genetic data, provides a robust platform for investigating novel ADC therapies and precision treatment strategies for high-grade EC.

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来源期刊

Neoplasia 医学-肿瘤学

CiteScore

9.20

自引率

2.10%

发文量

审稿时长

26 days

期刊介绍： Neoplasia publishes the results of novel investigations in all areas of oncology research. The title Neoplasia was chosen to convey the journal’s breadth, which encompasses the traditional disciplines of cancer research as well as emerging fields and interdisciplinary investigations. Neoplasia is interested in studies describing new molecular and genetic findings relating to the neoplastic phenotype and in laboratory and clinical studies demonstrating creative applications of advances in the basic sciences to risk assessment, prognostic indications, detection, diagnosis, and treatment. In addition to regular Research Reports, Neoplasia also publishes Reviews and Meeting Reports. Neoplasia is committed to ensuring a thorough, fair, and rapid review and publication schedule to further its mission of serving both the scientific and clinical communities by disseminating important data and ideas in cancer research.