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Background: Triple-negative breast cancer (TNBC) is a highly aggressive breast cancer subtype with a high metastatic rate. Despite significant advances in breast cancer therapeutics, due to the lack of specific therapeutic targets in TNBC, cytotoxic chemotherapy is still the mainstay of treatment for this BC subtype. Preclinical studies have shown that the Receptor for Advanced Glycation End-products (RAGE) drives the progression and metastasis of aggressive cancer subtypes, including TNBC. RAGE plays a multifaceted role in driving tumorigenesis and metastasis through tumor cell-intrinsic mechanisms, such as cancer cell invasion, migration and epithelial-mesenchymal transition, and tumor cell-extrinsic mechanisms. This multifaceted role in cancer progression and metastasis makes RAGE a promising therapeutic target in the prevention and treatment of breast cancer. Here we tested the preclinical anti-metastasic efficacy of two small molecule RAGE inhibitors; TTP48 (Azeliragon) and FPS-ZM1. Importantly, TTP488 displays a high safety profile in human trials and has previously undergone Phase 3 clinical trials for Alzheimer’s disease. While FPS-ZM1 is a well-known RAGE inhibitor in preclinical cancer models, TTP488 has not been tested for its anti-cancer activity in breast cancer. Methods: We tested the in vitro anti-metastatic effect of TTP488 and FPS-ZM1 on cancer cell migration and invasion in Boyden chamber assays with TNBC cell lines (MDA-MB-231 and 4T-1). We used the 4175 highly metastatic MDA-MB-231 variant in xenograft studies in NSG mice to test the efficacy of the RAGE inhibitors in vivo on tumor progression and metastasis. Experimental metastasis assays were performed with tail-vein injection of 4T-1 cells into BALBc mice. We performed bulk RNA sequencing on the MDA-MB-231/4175/NSG tumors to unveil and compare the mechanism of action of the two small molecule RAGE inhibitors. Results: Our results showed that TTP488 and FPS-ZM1 impaired mechanisms of metastasis in vitro with both MDA-MB231/4175 and 4T-1 cells. TTP488 and FPS-ZM1 significantly inhibited MDA-MB231/4175 cell metastasis from the orthotopic site in NSG mice without displaying any deleterious effects on mouse health. In the syngeneic 4T-1/BALBc model, both TTP488 and FPS-ZM1 impaired metastasis in tail-vein injected experimental metastasis assays. Transcriptomic analysis of primary xenograft tumors from NSG mice revealed that TTP488 and FPS-ZM1 displayed high concordance in gene expression changes. Pathway enrichment analysis showed that both RAGE inhibitors affected metastatic pathways, including focal adhesion, ECM-receptor interaction, cell cycle, and DNA replication. Conclusions: These results show that TTP488 impairs metastasis of multiple highly aggressive TNBC models for the first time. Importantly, as TTP488 displays a high safety profile in human trials, this study provides the rationale for evaluating TTP488 in clinical trials to treat or prevent metastatic breast cancer. Citation Format: Melinda Magna, Gyong Ha Hwang, Alec McIntosh, Katherine Drews-Elger, Masaru Takabatake, Barbara Mera, Taekyoung Kwak, Philip Miller, Marc Lippman, Barry I. Hudson. Azeliragon (TTP488), an orally- available small molecule RAGE inhibitor, reduces metastasis in preclinical mouse models of breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-08-10. |
