uPAR Immuno-PET in Pancreatic Cancer, Aging, and Chemotherapy-Induced Senescence.

Edwin C Pratt, Riccardo Mezzadra, Amanda Kulick, Spencer Kaminsky, Zachary V Samuels, Angelique Loor, Elisa de Stanchina, Scott W Lowe, Jason S Lewis
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Abstract

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.

胰腺癌、衰老和化疗诱导衰老中的 uPAR 免疫 PET
对医生来说,识别癌症耐药性是一项节省时间的重要工具。化疗耐药性的一部分包括衰老,这是一种没有细胞分裂或细胞死亡的持续状态。在胰腺癌模型中,曲美替尼和帕博西尼(TP)的化学诱导衰老作用产生了几种致瘤和促转移因素,其中有许多潜在的抗体靶点。特别是,尿激酶纤溶酶原激活物受体(uPAR)已被证明是衰老的膜结合标志物,同时也是肿瘤靶点。方法:在此,我们开发了两种针对鼠uPAR和人uPAR的抗体作为免疫PET制剂,以非侵入性追踪uPAR抗原的丰度。结果TP处理可增加小鼠KPC细胞和人类MiaPaCa2细胞的摄取量。在体内,皮下植入的小鼠 KPC 肿瘤在抗uPAR 抗体的作用下有较高的肿瘤摄取率,而年轻小鼠的摄取率与 TP 无关。用抗人类 uPAR 抗体对异种移植了人类 MiaPaCa2 肿瘤的小鼠进行 TP 治疗后,肿瘤摄取量显著增加。与[18F]FDG或[18F]F-DPA-714成像相比,使用uPAR抗体成像更具有肿瘤选择性。结论:使用放射性标记的uPAR靶向抗体为胰腺癌成像和化疗诱导衰老提供了一种新的基于抗体的PET成像候选方法。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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