背景:卵巢癌仍然是美国最致命的妇科癌症。治疗策略的进展有限,总体生存率显着提高。因此,必须继续开发和验证新的治疗策略和标志物,以确定将从新策略中获益的患者.在这份报告中,我们试图进一步验证新型人源化抗唾液酸Tn抗体-药物偶联物(抗STn-ADC)在卵巢癌中的应用.
方法:我们旨在进一步测试唾液酸-Tn(STn)阳性和阴性卵巢癌细胞系中的人源化抗STn-ADC,患者来源的类器官(PDO),和患者来源的异种移植(PDX)模型。此外,我们试图确定血清STn水平是否能反映肿瘤样本中的STn阳性,使我们能够确定抗STn-ADC策略最有效的患者.我们开发了一种具有高特异性和敏感性的定制ELISA,用于评估循环STn水平是否与阶段相关,无进展生存期,总生存率,及其在增强CA-125作为诊断方面的价值。最后,我们评估了血清水平是否反映了通过免疫组织化学分析在一部分肿瘤样本中观察到的结果.
结果:我们的体外实验进一步定义了抗STn-ADC的特异性。卵巢癌PDO,和PDX模型为靶向卵巢癌的基于抗STn-ADC的策略提供了额外的支持。定制血清ELISA在STn水平升高的患者的潜在分类中提供了信息。然而,它的敏感性不足以增加现有CA-125水平的诊断价值.虽然ELISA鉴定了低CA-125水平的非浆液性卵巢肿瘤,样本量太小,无法提供STnELISA对CA-125有意义地增加诊断的置信度.
结论:我们的临床前数据支持抗STn-ADC可能是治疗STn水平升高患者的可行选择。此外,我们的基于STn的ELISA可以补充IHC,以识别基于抗STn的策略可能更有效的患者。
BACKGROUND: Ovarian cancer remains the deadliest of the gynecologic cancers in the United States. There have been limited advances in treatment strategies that have seen marked increases in overall survival. Thus, it is essential to continue developing and validating new treatment strategies and markers to identify patients who would benefit from the new strategy. In this report, we sought to further validate applications for a novel humanized anti-Sialyl Tn antibody-drug conjugate (anti-STn-ADC) in ovarian cancer.
METHODS: We aimed to further test a humanized anti-STn-ADC in sialyl-Tn (STn) positive and negative ovarian cancer cell line, patient-derived organoid (PDO), and patient-derived xenograft (PDX) models. Furthermore, we sought to determine whether serum STn levels would reflect STn positivity in the tumor samples enabling us to identify patients that an anti-STn-ADC strategy would best serve. We developed a custom ELISA with high specificity and sensitivity, that was used to assess whether circulating STn levels would correlate with stage, progression-free survival, overall survival, and its value in augmenting CA-125 as a diagnostic. Lastly, we assessed whether the serum levels reflected what was observed via immunohistochemical analysis in a subset of tumor samples.
RESULTS: Our in vitro experiments further define the specificity of the anti-STn-ADC. The ovarian cancer PDO, and PDX models provide additional support for an anti-STn-ADC-based strategy for targeting ovarian cancer. The custom serum ELISA was informative in potential triaging of patients with elevated levels of STn. However, it was not sensitive enough to add value to existing CA-125 levels for a diagnostic. While the ELISA identified non-serous ovarian tumors with low CA-125 levels, the sample numbers were too small to provide any confidence the STn ELISA would meaningfully add to CA-125 for diagnosis.
CONCLUSIONS: Our preclinical data support the concept that an anti-STn-ADC may be a viable option for treating patients with elevated STn levels. Moreover, our STn-based ELISA could complement IHC in identifying patients with whom an anti-STn-based strategy might be more effective.