Moufarrij Sara, Dopeso Higinio, Brown David N, Green Hunter, Gill Kaitlyn, Tengelin Julia, Brodeur Melica N, Zammarrelli William A, Varice Nancy, Wu Michelle, Jungbluth Achim, Zhu Yingjie, Chen Xiaoping, Da Cruz Paula Arnaud, Basili Thais, de Stanchina Elisa, Abu-Rustum Nadeem R, Aghajanian Carol, Ellenson Lora H, Chui M Herman, Weigelt Britta
Gynecology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Gynecol Oncol. 2025 Jun;197:129-138. doi: 10.1016/j.ygyno.2025.04.590. Epub 2025 May 8.
Uterine carcinosarcoma (UCS) is a rare and aggressive type of endometrial carcinoma (EC), and novel therapeutic strategies are needed. We sought to assess TROP2 expression in archival UCSs and TROP2 antibody-drug conjugate (ADC) targeting in patient-derived UCS organoid (PDO) and xenograft (PDX) models.
TROP2 protein (immunohistochemistry) and mRNA (qRT-PCR) expression were assessed in 72 archival UCS tissues. Nine UCS PDO models were established and molecularly characterized by panel sequencing; then, TROP2 levels were determined and the efficacy of the TROP2 ADC sacituzumab govitecan (SG) defined in the UCS PDO and PDX models (n = 2).
TROP2 protein and mRNA expression were detected in ≥90 % of primary UCSs, and those with a predominant carcinomatous component or with homologous differentiation had higher TROP2 expression than those with a predominant sarcomatous component or with heterologous differentiation (p < 0.001 and p = 0.022, respectively). UCS PDOs displayed TROP2 expression and molecular profiles (median 88 %, range 50-100 % of mutation in primary UCSs present in PDOs) reflective of their respective primary UCSs. All 9 UCS PDOs responded in a dose-dependent manner to SG treatment, with a median IC of 167.7pM (range 51.4pM-3.2 nM). In addition, both UCS PDX models with high and low TROP2 protein expression had a significant reduction in tumor volume with SG treatment (p = 0.03 and p = 0.02, respectively).
We demonstrate that the majority of UCSs have detectable TROP2 expression. Our findings on the SG response in UCS PDO and PDX models warrant further studies on TROP2 targeting for patients with this aggressive disease.
子宫癌肉瘤（UCS）是一种罕见且侵袭性强的子宫内膜癌（EC）类型，需要新的治疗策略。我们试图评估存档UCS中TROP2的表达情况，以及在患者来源的UCS类器官（PDO）和异种移植（PDX）模型中TROP2抗体药物偶联物（ADC）的靶向作用。
对72份存档UCS组织进行TROP2蛋白（免疫组织化学）和mRNA（qRT-PCR）表达评估。建立了9个UCS PDO模型，并通过panel测序进行分子特征分析；然后，测定TROP2水平，并确定TROP2 ADC赛托珠单抗戈维单抗（SG）在UCS PDO和PDX模型（n = 2）中的疗效。
在≥90%的原发性UCS中检测到TROP2蛋白和mRNA表达，与主要为肉瘤成分或异源分化的UCS相比，主要为癌成分或同源分化的UCS具有更高的TROP2表达（分别为p < 0.001和p = 0.022）。UCS PDO显示出TROP2表达和分子特征（中位数88%，范围为PDO中存在的原发性UCS突变的50%-100%），反映了它们各自的原发性UCS。所有9个UCS PDO对SG治疗均呈剂量依赖性反应，中位IC为167.7pM（范围为51.4pM - 3.2 nM）。此外，TROP2蛋白表达高低不同的两个UCS PDX模型在接受SG治疗后肿瘤体积均显著减小（分别为p = 0.03和p = 0.02）。
我们证明大多数UCS具有可检测到的TROP2表达。我们在UCS PDO和PDX模型中关于SG反应的研究结果，为针对这种侵袭性疾病患者的TROP2靶向治疗的进一步研究提供了依据。
