Greenman Michelle, Demirkiran Cem, Bellone Stefania, Hartwich Tobias M P, McNamara Blair, Ettorre Victoria M, Santin Niccolo G, Sethi Namrata, Yang-Hartwich Yang, Papatla Katyayani, Ratner Elena, Santin Alessandro D
Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut.
Cancer Res Commun. 2025 May 1;5(5):774-782. doi: 10.1158/2767-9764.CRC-25-0057.
Uterine serous carcinoma (USC) is a rare subset of endometrial cancer with a poor prognosis and high recurrence rate. Datopotamab deruxtecan (Dato-DXd) is a novel antibody-drug conjugate (ADC). The objective of this study was to evaluate the preclinical activity of Dato-DXd in USC in vitro against primary USC cell lines with various trophoblast cell-surface antigen 2 (TROP2) expression and in vivo in TROP2-overexpressing cell line-derived mice xenografts. USC primary tumor cell lines were treated with Dato-DXd and a control ADC (CTL ADC) to evaluate cell viability following exposure. Antibody-dependent cell-mediated cytotoxicity against TROP2-overexpressing and -nonexpressing cell lines was evaluated using a 4-hour chromium release assay. USC xenografts in mice were treated with Dato-DXd, CTL ADC, datopotamab, and vehicle to assess the in vivo effects via retro-orbital Dato-DXd administration. We found USC cell lines with TROP2 overexpression to be significantly more sensitive to killing induced by Dato-DXd compared with CTL ADC in vitro (e.g., IC50: 0.11 µmol/L vs. 30.07 µmol/L, P = 0.0074 and 0.11 µmol/L vs. 48.95 µmol/L, P = 0.0127, respectively). Dato-DXd induced antibody-dependent cell-mediated cytotoxicity in the presence of peripheral blood lymphocytes from healthy donors. TROP2-nonexpressing cell lines demonstrated minimal killing by Dato-DXd; however, when admixed with TROP2-overexpressing cells, a significant bystander effect was appreciated. In vivo, mice xenografts overexpressing TROP2 treated with Dato-DXd demonstrated tumor growth suppression and longer overall survival compared with CTL ADC-treated xenografts. These data demonstrate Dato-DXd to be highly active against TROP2-overexpressing USC in vitro and in vivo. Our preclinical activity results warrant future clinical trials for patients with advanced or recurrent USC.
Targeted treatment of USC using the biomarker TROP2 represents a significant opportunity for further treatment options for patients already resistant to other lines of treatment. In this study, we present data showing preclinical evidence of effectiveness of this biomarker-targeted therapy in USC.
子宫浆液性癌（USC）是子宫内膜癌中一种罕见的亚型，预后较差且复发率高。德曲妥珠单抗（Dato-DXd）是一种新型抗体药物偶联物（ADC）。本研究的目的是评估Dato-DXd在体外对具有不同滋养层细胞表面抗原2（TROP2）表达的原发性USC细胞系以及在体内对TROP2过表达细胞系衍生的小鼠异种移植物的临床前活性。用Dato-DXd和对照ADC（CTL ADC）处理USC原发性肿瘤细胞系，以评估暴露后的细胞活力。使用4小时铬释放试验评估对TROP2过表达和未过表达细胞系的抗体依赖性细胞介导的细胞毒性。通过眶后注射Dato-DXd，用Dato-DXd、CTL ADC、德曲妥珠单抗和赋形剂处理小鼠中的USC异种移植物，以评估体内效果。我们发现，与CTL ADC相比，TROP2过表达的USC细胞系在体外对Dato-DXd诱导的杀伤更为敏感（例如，IC50分别为0.11 μmol/L对30.07 μmol/L，P = 0.0074；以及0.11 μmol/L对48.95 μmol/L，P = 0.0127）。在健康供体的外周血淋巴细胞存在的情况下，Dato-DXd诱导抗体依赖性细胞介导的细胞毒性。TROP2未过表达的细胞系对Dato-DXd的杀伤作用最小；然而，当与TROP2过表达的细胞混合时，可观察到明显的旁观者效应。在体内，与CTL ADC处理的异种移植物相比，用Dato-DXd处理的TROP2过表达的小鼠异种移植物表现出肿瘤生长抑制和更长的总生存期。这些数据表明Dato-DXd在体外和体内对TROP2过表达的USC具有高度活性。我们的临床前活性结果为晚期或复发性USC患者的未来临床试验提供了依据。
使用生物标志物TROP2对USC进行靶向治疗为已经对其他治疗方案耐药的患者提供了进一步的治疗选择。在本研究中，我们展示的数据显示了这种生物标志物靶向治疗在USC中的临床前有效性证据。
