uPAR immuno-PET in pancreatic cancer, aging, and chemotherapy-induced senescence Journal Article
| Authors: | Pratt, E. C.; Mezzadra, R.; Kulick, A.; Kaminsky, S.; Samuels, Z. V.; Loor, A.; de Stanchina, E.; Lowe, S. W.; Lewis, J. S. |
| Article Title: | uPAR immuno-PET in pancreatic cancer, aging, and chemotherapy-induced senescence |
| 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. ß 2024 by the Society of Nuclear Medicine and Molecular Imaging. |
| Keywords: | immunohistochemistry; cancer chemotherapy; human cell; nonhuman; antineoplastic agents; pyridines; pancreas cancer; pancreatic neoplasms; positron emission tomography; antineoplastic agent; ki 67 antigen; mass spectrometry; mouse; animal; metabolism; animals; mice; cell death; cell division; protein p16; immune system; signal noise ratio; animal experiment; animal model; drug effect; cell line, tumor; diagnostic imaging; cancer therapy; enzyme linked immunosorbent assay; dimethyl sulfoxide; isotope labeling; folinic acid; pancreas tumor; tumor cell line; fluorodeoxyglucose f 18; positron-emission tomography; chimeric antigen receptor; imaging; aging; pancreatic cancer; piperazines; tracer; senescence; drug therapy; piperazine derivative; surface plasmon resonance; protein p21; cell aging; thin layer chromatography; pyridine derivative; organ weight; radiochemistry; urokinase receptor; immuno-pet; cellular senescence; edetic acid; trametinib; humans; human; article; palbociclib; mia paca-2 cell line; receptors, urokinase plasminogen activator |
| Journal Title: | Journal of Nuclear Medicine |
| Volume: | 65 |
| Issue: | 11 |
| ISSN: | 0161-5505 |
| Publisher: | Society of Nuclear Medicine |
| Date Published: | 2024-11-01 |
| Start Page: | 1718 |
| End Page: | 1723 |
| Language: | English |
| DOI: | 10.2967/jnumed.124.268278 |
| PUBMED: | 39362768 |
| PROVIDER: | scopus |
| PMCID: | PMC11533913 |
| DOI/URL: | |
| Notes: | Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PubMed and PDF -- MSK corresponding author is Jason Lewis -- Source: Scopus |
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