Lacalle-Gonzalez Carlos, Florez-Cespedes Maria, Sanz-Criado Lara, Ochieng' Otieno Michael, Ramos-Muñoz Edurne, Fernandez-Aceñero Maria Jesus, Ortega-Medina Luis, Garcia-Foncillas Jesus, Martinez-Useros Javier
Department of Medical Oncology, Fundación Jiménez Díaz University Hospital, 28040 Madrid, Spain.
Faculty of Engineering, Imperial College, London SW7 2AZ, UK.
Biomedicines. 2023 Oct 17;11(10):2812. doi: 10.3390/biomedicines11102812.
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive neoplasm with very poor patient survival outcomes despite available treatments. There is an urgent need for new potential treatment options and novel biomarkers for these patients. Delta-like canonical Notch ligand 3 (DLL3) interacts with the Notch receptor and causes inhibition of Notch signaling, which confers a survival advantage to PDAC cells. Thus, DLL3 expression could affect cell survival, and its inhibition could increase a patient's survival. To test this hypothesis, a survival analysis was conducted using the progression-free and overall survival from two independent datasets of PDAC patients, with one using mRNA z-score levels and the other using the Hscore protein expression level; both were carried out using a log-rank test and plotted using Kaplan-Meier curves. DLL3 at the mRNA expression level showed an association between high mRNA expression and both a longer progression-free survival (PFS) and overall survival (OS) of patients. Then, we designed a retrospective study with resected PDAC samples. Our primary objective with this dataset was to assess the relationship between PFS and OS and DLL3 protein expression. The secondary assessment was to provide a rationale for the use of anti-DLL3-based treatments in combination with immunotherapy that is supported by the link between DLL3 and other factors that are involved in immune checkpoints. The survival analyses revealed a protective effect of high DLL3 protein expression levels in both PFS and OS. Interestingly, high DLL3 protein expression levels were significantly correlated with PD-L1/2 and negatively correlated with NOTCH1. Therefore, DLL3 could be considered a biomarker for better prognosis in resectable PDAC patients as well as a therapeutic biomarker for immunotherapy response. These facts set a rationale for testing anti-DLL3-based treatments either alone or combined with immunotherapy or other NOTCH1 inhibitors.
胰腺导管腺癌（PDAC）是一种侵袭性肿瘤，尽管有可用的治疗方法，但患者的生存结果仍然很差。迫切需要为这些患者提供新的潜在治疗选择和新型生物标志物。Delta样经典Notch配体3（DLL3）与Notch受体相互作用并导致Notch信号传导受到抑制，这赋予了PDAC细胞生存优势。因此，DLL3的表达可能影响细胞存活，抑制其表达可能会提高患者的生存率。为了验证这一假设，我们使用来自两个独立的PDAC患者数据集的无进展生存期和总生存期进行了生存分析，一个数据集使用mRNA z评分水平，另一个使用Hscore蛋白表达水平；两者均使用对数秩检验进行，并使用Kaplan-Meier曲线进行绘制。mRNA表达水平的DLL3显示高mRNA表达与患者更长的无进展生存期（PFS）和总生存期（OS）之间存在关联。然后，我们设计了一项对切除的PDAC样本的回顾性研究。我们对该数据集的主要目标是评估PFS、OS与DLL3蛋白表达之间的关系。次要评估是为基于抗DLL3的治疗与免疫疗法联合使用提供理论依据，这一依据由DLL3与免疫检查点相关的其他因素之间的联系所支持。生存分析显示，高DLL3蛋白表达水平在PFS和OS方面均具有保护作用。有趣的是，高DLL3蛋白表达水平与PD-L1/2显著相关，与NOTCH1呈负相关。因此，DLL3可被视为可切除PDAC患者预后较好的生物标志物，以及免疫治疗反应的治疗生物标志物。这些事实为单独或联合免疫疗法或其他NOTCH1抑制剂测试基于抗DLL3的治疗提供了理论依据。
