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William J. Gradishar, MD, FACP, FASCO
William J. Gradishar, MD, FACP, FASCO
Posted: Wednesday, August 2, 2023
Barry I. Hudson, PhD, of Georgetown University Hospital, Washington, DC, and colleagues investigated the potential of the novel RAGE (receptor for advanced glycation end products) inhibitors TTP488 (azeliragon) and FPS-ZM1 to impede triple-negative breast cancer metastasis. According to the investigators, the results of this study not only support the efficacy of TTP488 in impairing triple-negative breast cancer metastasis, but also shed light on the underlying cellular and signaling mechanisms mediated by RAGE in metastasis. The results were published in Nature Breast Cancer.
“Our study is the first to show that TTP488 impairs breast cancer metastasis in cells and rodents. It is the only RAGE inhibitor that is approved for use in humans, so the implications for clinical trials are many-fold, and we hope that progress against triple-negative breast cancers will be rapid,” said Dr. Hudson at an institutional press release.
The results demonstrated that both inhibitors were successful in impairing spontaneous as well as experimental metastasis. However, TTP488 exhibited a greater influence on metastatic driver pathways compared with FPS-ZM1, the researchers reported. Transcriptomic analysis of primary xenograft tumor and metastatic tissue samples treated with both drugs revealed significant changes in gene and protein expression.
Functional cell assays were performed to validate the findings from the transcriptomic analysis. RAGE inhibition was found to impair triple-negative breast cancer cell adhesion to various extracellular matrix proteins—such as collagens, laminins, and fibronectin—and to hinder cell migration and invasion. Of note, cellular viability, proliferation, and cell cycle were unaffected by RAGE inhibition, which the investigators believe suggests a favorable safety profile. Further mechanistic studies through phosphoproteomic analysis of tumors revealed that RAGE inhibition led to reduced signaling of critical breast cancer metastatic driver mechanisms such as Pyk2, STAT3, and Akt.
Disclosure: For full disclosures of the study authors, visit nature.com/articles.
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