RT Journal Article
SR Electronic
T1 uPAR Immuno-PET in Pancreatic Cancer, Aging, and Chemotherapy-Induced Senescence
JF Journal of Nuclear Medicine
JO J Nucl Med
FD Society of Nuclear Medicine
SP jnumed.124.268278
DO 10.2967/jnumed.124.268278
A1 Pratt, Edwin C.
A1 Mezzadra, Riccardo
A1 Kulick, Amanda
A1 Kaminsky, Spencer
A1 Samuels, Zachary V.
A1 Loor, Angelique
A1 de Stanchina, Elisa
A1 Lowe, Scott W.
A1 Lewis, Jason S.
YR 2024
UL http://jnm.snmjournals.org/content/early/2024/10/03/jnumed.124.268278.abstract
AB 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.