The RAGE Inhibitor TTP488 (Azeliragon) Demonstrates Anti-Tumor Activity and Enhances the Efficacy of Radiation Therapy in Pancreatic Cancer Cell Lines.

Document Type

Article

Publication Date

12-24-2024

Publication Title

Cancers (Basel)

Abstract

Pancreatic cancer is the third leading cause of cancer-related mortality in the United States, with rising incidence and mortality. The receptor for advanced glycation end products (RAGE) and its ligands significantly contribute to pancreatic cancer progression by enhancing cell proliferation, fostering treatment resistance, and promoting a pro-tumor microenvironment via activation of the nuclear factor-kappa B (NF-κB) signaling pathways. This study validated pathway activation in human pancreatic cancer and evaluated the therapeutic efficacy of TTP488 (Azeliragon), a small-molecule RAGE inhibitor, alone and in combination with radiation therapy (RT) in preclinical models of pancreatic cancer. Human (Panc1) and murine (Pan02) pancreatic cancer cell lines exhibited elevated levels of RAGE and its ligands compared to normal pancreatic tissue. In vitro, Azeliragon inhibited RAGE-mediated NF-κB activation and ligand-mediated cell proliferation in pancreatic cancer cell lines. Target engagement of Azeliragon was confirmed in vivo, as determined by decreased NF-κB activation. Azeliragon demonstrated significant growth delay in mouse models of pancreatic cancer and additive effects when combined with RT. Additionally, Azeliragon modulated the immune suppressive tumor microenvironment in pancreatic cancer by reducing immunosuppressive cells, including M2 macrophages, regulatory T cells, and myeloid-derived suppressor cells, while enhancing CD8+ T cell infiltration. These findings suggest that Azeliragon, by inhibiting RAGE-mediated signaling and modulating immune response, may serve as an effective anti-cancer agent in pancreatic cancer.

Volume

17

Issue

1

First Page

17

DOI

10.3390/cancers17010017

ISSN

2072-6694

PubMed ID

39796649

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