Synapse - TROP2 expression and therapeutic targeting in uterine carcinosarcoma

TROP2 expression and therapeutic targeting in uterine carcinosarcoma Journal Article

Authors:	Moufarrij, S.; Dopeso, H.; Brown, D. N.; Green, H.; Gill, K.; Tengelin, J.; Brodeur, M. N.; Zammarrelli, W. A. 3rd; Varice, N.; Wu, M.; Jungbluth, A.; Zhu, Y.; Chen, X.; Da Cruz Paula, A.; Basili, T.; de Stanchina, E.; Abu-Rustum, N. R.; Aghajanian, C.; Ellenson, L. H.; Chui, M. H.; Weigelt, B.
Article Title:	TROP2 expression and therapeutic targeting in uterine carcinosarcoma
Abstract:	Objective: 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. Methods: 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). Results: 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 IC50 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). Conclusions: 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. © 2025 Elsevier Inc.
Keywords:	immunohistochemistry; clinical article; controlled study; human tissue; protein expression; cancer surgery; unclassified drug; area under the curve; nonhuman; endometrial cancer; animal cell; mouse; gene expression; tumor volume; animal experiment; animal model; cell differentiation; tumor xenograft; protein p53; messenger rna; tumor protein; informed consent; dna extraction; rna extraction; carcinosarcoma; uterine carcinosarcoma; human; female; article; ic50; antibody drug conjugate; real time reverse transcription polymerase chain reaction; sacituzumab govitecan; antibody–drug conjugate; organoid model; trop2 protein
Journal Title:	Gynecologic Oncology
Volume:	197
ISSN:	0090-8258
Publisher:	Elsevier Inc.
Date Published:	2025-06-01
Start Page:	129
End Page:	138
Language:	English
DOI:	10.1016/j.ygyno.2025.04.590
PUBMED:	40344963
PROVIDER:	scopus
PMCID:	PMC12160578
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-105004464634&doi=10.1016%2fj.ygyno.2025.04.590&partnerID=40&md5=a5329c990d20e488641ffc30212dc03b
Notes:	Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PDF -- MSK corresponding author is Britta Weigelt -- Source: Scopus