The RAGE Inhibitor TTP448 (Azeliragon) Demonstrates Anti-Tumor Activity and Enhances the Efficacy of Radiation Therapy in Pancreatic Cancer

Document Type

Conference Proceeding

Publication Date

6-30-2025

Publication Title

Michigan Medical Education and Health Bulletin

Abstract

Introduction: Pancreatic cancer has a poor prognosis, with a 5-year survival rate below 10%, and is projected to become the 2nd leading cause of cancer-related death by 2030. Despite advances in cancer treatment overall, pancreatic cancer outcomes have only marginally improved over the past decade. The receptor for advanced glycation end products (RAGE) is a receptor implicated in cancer, diabetes, and Alzheimer’s disease. In pancreatic cancer, RAGE activation promotes tumor progression, treatment resistance and immune suppression, primarily through NF-κB signaling. Azeliragon is an oral RAGE inhibitor, previously tested in Alzheimer’s and shown to be safe in humans – making it a promising candidate for repurposing in oncology. We evaluated Azeliragon’s effect, both alone and in combination with radiation therapy (RT) in preclinical models of pancreatic cancer. Methods: Human (Panc1) and Murine (Panc02) pancreatic cancer cell lines were cultured under standard conditions. Cell proliferation was assessed following Azeliragon treatment, and clonogenic survival was evaluated post-irradiation. Tumor models were established in C57BL/6NJ and NU/J mice, randomized into control and treatment groups receiving Azeliragon, radiation, or both. Tumor growth was monitored, and tissues were harvested for downstream analyses. Western blotting was used to assess protein expression, and flow cytometry profiled tumor-infiltrating immune cells. Appropriate controls were included in all in vitro and in vivo experiments. Statistical significance was determined using t-tests or one-way ANOVA with Tukey’s post hoc test. Results: 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. Conclusions: Azeliragon significantly delayed tumor growth and enhanced anti-tumor immunity, both alone and in combination with radiation, in preclinical pancreatic cancer models. Azeliragon’s dual anti-tumor and immunomodulatory effects gives it a unique advantage over current systemic agents in use. Additionally, its established safety profile from Alzheimer’s trials, makes it a candidate for repurposing and accelerated clinical translation. Trials of Azeliragon in pancreatic cancer are now ongoing (NCT05766748) and given its immunomodulatory effect, future studies should explore combinations with immunotherapy to further expand its therapeutic value.

Volume

3

Issue

2 Suppl

First Page

A115

Last Page

A115

Comments

Southeast Michigan Center for Medical Education (SEMCME) 47th Research Forum, May 22, 2025, Troy, MI

DOI

10.69735/001c.141316

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