Abstract A032: Targeting pancreatic cancer senescence with ImmunoPET

Abstract

Abstract Pancreatic cancer is the fourth leading cause of cancer-related deaths for men and women, with five-year overall survival rates around 10 percent. Despite years of cancer research and new immunotherapy solutions, pancreatic cancer is still mainly treated by chemotherapies, starting with gemcitabine. Many cytostatic drug combinations have been shown, in a wide range of cancers, to induce senescence, a persistent, anti-apoptotic process characterized almost exclusively by beta galactosidase activity. Studies inducing senescence with the combination of trametinib and palbociclib (TP) have linked several tumorigenic and pro-metastatic factors in murine pancreatic cancer models to the senescence-associated secretory profile (SASP), giving rise to new antigen targets during the induction of senescence. Accordingly, senescence has recently been elevated as a new hallmark of cancer. There is thus a critical need for antigen-based tools to noninvasively identify markers of senescence in vivo. Senescence targets comprise of shed antigens (VEGF and IL-6) in the context of senescence-inducing therapy with trametinib and palbociclib (TP), when membrane bounds targets such as urokinase plasminogen activated receptor (uPAR) are potentially enriched. We show that VEGF and IL-6 targeting antibodies labeled with zirconium-89 deferoxamine (89Zr-DFO) bind cells treated with TP though in vivo, marked reduction in tumor targeting is seen. Preloading and targeting antigen shed are being actively considered as alternative imaging approaches. For membrane bound antigens associated with senescence, here we report the latest work developing uPAR immunoPET agents. First, we have shown that attachment of 89Zr-DFO preserves the binding function of both murine (muPAR) and human uPAR (huPAR) antibodies with high cross-reactivity of the murine uPAR (muPAR) antibody with huPAR. Cell uptake was increased two-fold in murine KPC cells with senescence-inducing TP treatment. In vivo, accumulation in subcutaneously implanted murine KPC pancreatic tumors was observed with TP-treated mice; however lower liver and blood activity was imaged by PET/CT and confirmed by terminal biodistribution at 144h. Human uPAR-targeting antibody in nude mice bearing flank MiaPaCa2 tumors showed strong antibody uptake by 144 h, with increased tumor uptake for mice undergoing TP therapy. Preloading studies at 10 µg, 40 µg, and 100µg at 4h prior to injection of 40µg 89Zr-DFO-huPAR showed improved tumor uptake kinetics with the highest preloading level, though overall tumor uptake was decreased at the higher radiolabeled antibody dose used, thus more optimization is needed. The development and optimization of 89Zr-DFO-uPAR antibodies for human and murine targets provides a superior means of identifying pancreatic cancer and pancreatic cancer senescence than that afforded by shed antigens. Future directions include further dose optimization and testing uptake in other pancreatic models, senescence-inducing drug combinations, and possible antibody-conjugated senolytic or endoradiotherapy strategies. Citation Format: Edwin C. Pratt, Riccardo Mezzadra, Tara Viray, Spencer Kaminsky, Scott W. Lowe, Jason S. Lewis. Targeting pancreatic cancer senescence with ImmunoPET [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr A032.