Researchers at Georgetown University’s Lombardi Comprehensive Cancer Center, in collaboration with scientists at the University of Miami, have made a breakthrough in understanding how the experimental drug TTP488 (azeliragon) impairs the metastasis of aggressive, triple-negative breast cancer at the cellular level. The findings, published in Nature Breast Cancer on July 13, 2023, shed light on the signaling pathways and cellular mechanisms controlled by a receptor called the receptor for advanced glycation end-products (RAGE), which is found on the surface of triple-negative breast cancer cells.
Triple-negative breast cancers (TNBCs) make up approximately 10-15% of all diagnosed breast cancers and are characterized by the absence of estrogen and progesterone receptors, as well as a low production of the HER2 protein. TNBCs are more prevalent in women under the age of 40 and in Black women, and the five-year survival rate for metastatic TNBC is only 12%.
For decades, effective treatment options for TNBC have been elusive. However, this recent discovery has identified key pathways and cellular mechanisms through which RAGE regulates the metastatic spread of TNBC. Armed with this knowledge, the researchers were able to evaluate the efficacy of TTP488 in both laboratory experiments and mice, demonstrating its potential as a beneficial drug for human use.
The study marks the first time TTP488 has been shown to inhibit breast cancer metastasis in both cells and animal models. As the only RAGE inhibitor approved for human use, TTP488 holds significant promise for clinical trials targeting triple-negative breast cancers.
Barry Hudson, Ph.D., associate professor of oncology at Georgetown Lombardi and the corresponding author of the study, emphasized the direct connection between the preclinical research on RAGE inhibitors conducted at the University of Miami and the ongoing clinical trial at Lombardi and other cancer centers. The current clinical trial is a direct outcome of this collaborative research effort.
RAGE was initially discovered in 1992 as a potential factor in vascular complications associated with diabetes. Subsequent research has implicated RAGE in various diseases due to its ability to bind to multiple molecules and induce inflammation.
TTP488 was originally developed in the 2000s as a treatment for Alzheimer’s disease. Although initial trial results were inconclusive, recent advancements in understanding its biology and effects, coupled with its wide availability across different biological systems and its favorable safety profile, have positioned TTP488 as a promising candidate for clinical trials.
During the study, researchers examined two RAGE inhibitors: TTP488 and FPS-ZM1. Both inhibitors demonstrated the ability to impede spontaneous and experimental metastasis of triple-negative breast cancer in mice. However, after extensive investigation in the laboratory and animal models, TTP488 emerged as the more effective drug, prompting further exploration and consideration for use in human clinical trials. Nonetheless, TTP488 still needs to undergo larger and more advanced clinical trials to establish its true effectiveness before becoming available to women outside of the trial cohorts.
The research team also identified three significant pathways affected by RAGE inhibition: Pyk2, STAT3, and Akt. This discovery offers valuable insights into the mechanisms underlying RAGE-driven metastasis, potentially facilitating the development of combination therapies targeting RAGE and these specific pathways.
The researchers are currently evaluating different combinations of TTP488 with other anti-cancer therapies to determine if RAGE inhibitors can enhance treatment outcomes synergistically. With these recent advancements, the outlook for effectively treating triple-negative breast cancers has become increasingly promising.