Identifying cancer therapy resistance is a key time-saving tool for physicians. Part of chemotherapy resistance includes senescence, a persistent state without cell division or cell death. Chemically inducing senescence with the combination of trametinib and palbociclib (TP) yields several tumorigenic and prometastatic factors in pancreatic cancer models with many potential antibody-based targets. In particular, urokinase plasminogen activator receptor (uPAR) has been shown to be a membrane-bound marker of senescence in addition to an oncology target. Methods: Here, 2 antibodies against murine uPAR and human uPAR were developed as immuno-PET agents to noninvasively track uPAR antigen abundance. Results: TP treatment increased cell uptake both in murine KPC cells and in human MiaPaCa2 cells. In vivo, subcutaneously implanted murine KPC tumors had high tumor uptake with the antimurine uPAR antibody independently of TP in young mice, yet uPAR uptake was maintained in aged mice on TP. Mice xenografted with human MiaPaCa2 tumors showed a significant increase in tumor uptake on TP therapy when imaged with the antihuman uPAR antibody. Imaging with either uPAR antibody was found to be more tumor-selective than imaging with [¹⁸F]FDG or [¹⁸F]F-DPA-714. Conclusion: The use of radiolabeled uPAR-targeting antibodies provides a new antibody-based PET imaging candidate for pancreatic cancer imaging as well as chemotherapy-induced senescence.

识别癌症治疗耐药性是医生节省时间的关键工具。化疗耐药的部分包括衰老，这是一种没有细胞分裂或细胞死亡的持续状态。曲美替尼和 palbociclib （TP） 联合使用化学诱导衰老，在胰腺癌模型中产生多种致瘤和促转移因子，具有许多潜在的基于抗体的靶点。特别是，尿激酶纤溶酶原激活物受体 （uPAR） 已被证明是除肿瘤靶标外的衰老膜结合标志物。方法：在这里，开发了 2 种针对小鼠 uPAR 和人 uPAR 的抗体作为免疫 PET 试剂，以无创跟踪 uPAR 抗原丰度。结果：TP 处理增加了小鼠 KPC 细胞和人 MiaPaCa2 细胞中的细胞摄取。在体内，皮下植入的小鼠 KPC 肿瘤在年轻小鼠中与抗鼠 uPAR 抗体无关，具有很高的肿瘤摄取，但在 TP 上的老年小鼠中 uPAR 摄取维持。当使用抗人 uPAR 抗体成像时，用人 MiaPaCa2 肿瘤异种移植的小鼠在 TP 治疗后显示肿瘤摄取显着增加。发现使用 uPAR 抗体进行成像比使用 [¹⁸F]FDG 或 [¹⁸F]F-DPA-714 成像更具肿瘤选择性。结论：放射性标记的 uPAR 靶向抗体的使用为胰腺癌成像以及化疗诱导的衰老提供了一种新的基于抗体的 PET 成像候选者。