RAGE inhibitor TTP488 (Azeliragon) suppresses metastasis in triple-negative breast cancer

by Selleckchem | Dec 12 2023

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.

Comments:

The research findings you described highlight a promising avenue for the treatment of triple-negative breast cancer (TNBC) using RAGE inhibitors, specifically TTP488 (Azeliragon). Here's a summary of the key points from the research study you outlined:

### Research Hypothesis:
- **Target:** Receptor for Advanced Glycation End-products (RAGE) signaling in TNBC.
- **Intervention:** Small molecule RAGE inhibitors (TTP488/Azeliragon and FPS-ZM1).

### Experimental Results:
- **Metastasis Inhibition:** Both TTP488 and FPS-ZM1 impaired spontaneous and experimental metastasis of TNBC models.
- **Efficacy:** TTP488 was more effective, significantly reducing metastasis compared to FPS-ZM1.
- **Gene and Protein Changes:** Transcriptomic analysis revealed significant changes in gene and protein expression in primary xenograft tumor and metastatic tissue with both drugs. TTP488 showed greater potency against metastatic driver pathways.
- **Cellular Mechanisms:** RAGE inhibition impaired TNBC cell adhesion to various extracellular matrix proteins (collagens, laminins, fibronectin), migration, and invasion. It did not affect cellular viability, proliferation, or cell cycle in vitro.
- **Proteomic Changes:** Proteomic analysis of serum from tumor-bearing mice revealed alterations in cytokines and growth factors, key drivers of metastasis.
- **Signaling Pathways:** Phospho-proteomic analysis demonstrated that RAGE inhibition led to decreased signaling through critical breast cancer metastatic driver mechanisms, including Pyk2, STAT3, and Akt.

### Implications and Conclusion:
- **Clinical Potential:** TTP488 displays a favorable safety profile in human studies.
- **Rationale for Clinical Trials:** The study provides a strong rationale for evaluating TTP488 in clinical trials to treat or prevent metastatic TNBC.
- **Targeted Pathways:** The research clarifies the signaling and cellular mechanisms through which RAGE mediates metastasis in TNBC.

### Significance:
- **Clinical Translation:** This research suggests a potential targeted therapy for a highly aggressive and metastatic subtype of breast cancer, where treatment options are currently limited.
- **Safety Profile:** The safety profile of TTP488 in human studies enhances its potential as a viable candidate for clinical trials.

These findings provide important insights into the molecular mechanisms of TNBC metastasis and offer hope for the development of effective therapies in the future. The emphasis on TTP488's favorable safety profile suggests a promising direction for clinical research and potential treatments for metastatic TNBC patients.