Kaul Marilyn, Sanin Ahmed Y, Shi Wenjie, Janiak Christoph, Kahlert Ulf D
Institute for Inorganic and Structural Chemistry, Heinrich-Heine-University Düsseldorf, 40204, Düsseldorf, Germany.
Molecular and Experimental Surgery, University Clinic for General-, Visceral-, Vascular- and Transplant Surgery, Faculty of Medicine, Otto-Von-Guericke-University Magdeburg, 39120, Magdeburg, Germany.
Pharmacol Rep. 2024 Aug;76(4):793-806. doi: 10.1007/s43440-024-00600-w. Epub 2024 May 13.
Pancreatic ductal adenocarcinoma (PDAC) is one of the most difficult to treat tumors. The Src (sarcoma) inhibitor dasatinib (DASA) has shown promising efficacy in preclinical studies of PDAC. However, clinical confirmation could not be achieved. Overall, our aim was to deliver arguments for the possible reinitiating clinical testing of this compound in a biomarker-stratifying therapy trial for PDAC patients. We tested if the nanofunctionalization of DASA can increase the drug efficacy and whether certain Src members can function as clinical predictive biomarkers.
Methods include manufacturing of poly(vinyl alcohol) stabilized gold nanoparticles and their drug loading, dynamic light scattering, transmission electron microscopy, thermogravimetric analysis, Zeta potential measurement, sterile human cell culture, cell growth quantification, accessing and evaluating transcriptome and clinical data from molecular tumor dataset TCGA, as well as various statistical analyses.
We generated homo-dispersed nanofunctionalized DASA as an AuNP@PVA-DASA conjugate. The composite did not enhance the anti-growth effect of DASA on PDAC cell lines. The cell model with high LYN expression showed the strongest response to the therapy. We confirm deregulated Src kinetome activity as a prevalent feature of PDAC by revealing mRNA levels associated with higher malignancy grade of tumors. BLK (B lymphocyte kinase) expression predicts shorter overall survival of diabetic PDAC patients.
Nanofunctionalization of DASA needs further improvement to overcome the therapy resistance of PDAC. LYN mRNA is augmented in tumors with higher malignancy and can serve as a predictive biomarker for the therapy resistance of PDAC cells against DASA. Studying the biological roles of BLK might help to identify underlying molecular mechanisms associated with PDAC in diabetic patients.
胰腺导管腺癌（PDAC）是最难治疗的肿瘤之一。Src（肉瘤）抑制剂达沙替尼（DASA）在PDAC的临床前研究中显示出有前景的疗效。然而，未能实现临床验证。总体而言，我们的目的是为在针对PDAC患者的生物标志物分层治疗试验中重新启动该化合物的临床试验提供依据。我们测试了DASA的纳米功能化是否能提高药物疗效，以及某些Src成员是否可作为临床预测生物标志物。
方法包括制备聚乙烯醇稳定的金纳米颗粒及其药物负载、动态光散射、透射电子显微镜、热重分析、Zeta电位测量、无菌人类细胞培养、细胞生长定量、从分子肿瘤数据集TCGA获取和评估转录组及临床数据，以及各种统计分析。
我们制备了均一分散的纳米功能化DASA，即AuNP@PVA-DASA共轭物。该复合物并未增强DASA对PDAC细胞系的抗生长作用。LYN表达高的细胞模型对该疗法显示出最强反应。通过揭示与肿瘤更高恶性程度相关的mRNA水平，我们证实Src激酶组活性失调是PDAC的一个普遍特征。BLK（B淋巴细胞激酶）表达可预测糖尿病PDAC患者较短的总生存期。
DASA的纳米功能化需要进一步改进以克服PDAC的治疗抗性。LYN mRNA在恶性程度较高的肿瘤中增加，可作为PDAC细胞对DASA治疗抗性的预测生物标志物。研究BLK的生物学作用可能有助于确定与糖尿病患者PDAC相关的潜在分子机制。
