文章：

RAGE抑制剂TTP488（阿泽利拉贡）在胰腺癌细胞系中展示抗肿瘤活性并增强放射治疗效果

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

原文发布日期：24 December 2024

DOI: 10.3390/cancers17010017

类型: Article

开放获取: 是

英文摘要：

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.

摘要翻译： 

胰腺癌是美国癌症相关死亡的第三大原因，其发病率和死亡率呈上升趋势。晚期糖基化终末产物受体（RAGE）及其配体通过激活核因子κB（NF-κB）信号通路，显著促进胰腺癌进展，包括增强细胞增殖、诱导治疗抵抗以及营造促肿瘤微环境。本研究验证了该通路在人类胰腺癌中的激活情况，并在临床前胰腺癌模型中评估了小分子RAGE抑制剂TTP488（Azeliragon）单用及联合放射治疗（RT）的疗效。与正常胰腺组织相比，人源（Panc1）和小鼠源（Pan02）胰腺癌细胞系中RAGE及其配体水平升高。体外实验表明，Azeliragon能抑制胰腺癌细胞系中RAGE介导的NF-κB激活及配体介导的细胞增殖。体内实验通过NF-κB激活水平降低证实了Azeliragon的靶点结合作用。在胰腺癌小鼠模型中，Azeliragon显著延缓肿瘤生长，且与RT联用产生叠加效应。此外，Azeliragon通过减少免疫抑制细胞（包括M2巨噬细胞、调节性T细胞和髓源性抑制细胞）并增强CD8+ T细胞浸润，调节了胰腺癌的免疫抑制性肿瘤微环境。这些发现表明，Azeliragon通过抑制RAGE介导的信号传导和调节免疫应答，可能成为胰腺癌的有效抗癌药物。

原文链接：

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