RAGE inhibitor TTP488 (Azeliragon) suppresses metastasis in triple-negative breast cancer
Melinda Magna1,2, Gyong Ha Hwang1, Alec McIntosh2
1Sheila and David Fuente Graduate Program in Cancer Biology, University of Miami Miller School of Medicine, Miami, FL, USA.
Abstract:
Triple-negative breast cancer (TNBC) is a highly aggressive and metastatic cancer subtype, which is generally untreatable once it metastasizes. We hypothesized that interfering with the Receptor for Advanced Glycation End-products (RAGE) signaling with the small molecule RAGE inhibitors (TTP488/Azeliragon and FPS-ZM1) would impair TNBC metastasis and impair fundamental mechanisms underlying tumor progression and metastasis. Both TTP488 and FPS-ZM1 impaired spontaneous and experimental metastasis of TNBC models, with TTP488 reducing metastasis to a greater degree than FPS-ZM1. Transcriptomic analysis of primary xenograft tumor and metastatic tissue revealed high concordance in gene and protein changes with both drugs, with TTP488 showing greater potency against metastatic driver pathways. Phenotypic validation of transcriptomic analysis by functional cell assays revealed that RAGE inhibition impaired TNBC cell adhesion to multiple extracellular matrix proteins (including collagens, laminins, and fibronectin), migration, and invasion. Neither RAGE inhibitor impaired cellular viability, proliferation, or cell cycle in vitro. Proteomic analysis of serum from tumor-bearing mice revealed RAGE inhibition affected metastatic driver mechanisms, including multiple cytokines and growth factors. Further mechanistic studies by phospho-proteomic analysis of tumors revealed RAGE inhibition led to decreased signaling through critical BC metastatic driver mechanisms, including Pyk2, STAT3, and Akt. These results show that TTP488 impairs metastasis of TNBC and further clarifies the signaling and cellular mechanisms through which RAGE mediates metastasis. Importantly, as TTP488 displays a favorable safety profile in human studies, our study provides the rationale for evaluating TTP488 in clinical trials to treat or prevent metastatic TNBC.
Insights
RAGE inhibitors, TTP488 and FPS-ZM1, significantly reduced triple-negative breast cancer (TNBC) metastasis. TTP488 demonstrated greater efficacy in impairing TNBC progression and metastatic pathways.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Metastasis Research
Background:
- Triple-negative breast cancer (TNBC) is an aggressive subtype known for its high metastatic potential and limited treatment options.
- Receptor for Advanced Glycation End-products (RAGE) signaling is implicated in tumor progression and metastasis.
- Targeting RAGE offers a potential therapeutic strategy for aggressive cancers like TNBC.
Purpose of the Study:
- To investigate the efficacy of RAGE inhibitors (TTP488/Azeliragon and FPS-ZM1) in impairing TNBC metastasis.
- To elucidate the molecular mechanisms by which RAGE inhibition affects TNBC progression and metastasis.
- To provide a rationale for the clinical evaluation of TTP488 in treating or preventing metastatic TNBC.
Main Methods:
- Utilized TNBC mouse models to assess spontaneous and experimental metastasis following treatment with TTP488 and FPS-ZM1.
- Conducted transcriptomic and proteomic analyses on tumor and serum samples to identify drug-induced molecular changes.
- Performed functional cell assays (adhesion, migration, invasion) and phospho-proteomic analysis to validate transcriptomic findings and investigate signaling pathways.
Main Results:
- Both TTP488 and FPS-ZM1 significantly impaired TNBC metastasis, with TTP488 showing superior efficacy.
- RAGE inhibition reduced TNBC cell adhesion, migration, and invasion without affecting cell viability or proliferation.
- Transcriptomic and proteomic analyses revealed that TTP488 effectively targeted key metastatic driver pathways, including Pyk2, STAT3, and Akt signaling.
Conclusions:
- RAGE inhibition, particularly with TTP488, effectively impairs triple-negative breast cancer metastasis by targeting fundamental tumor progression mechanisms.
- TTP488 demonstrates a potent ability to disrupt RAGE-mediated signaling pathways critical for TNBC metastasis.
- The favorable safety profile of TTP488 in human studies supports its potential as a therapeutic agent for metastatic TNBC.
