Novel Drug for Triple-Negative Breast Cancer Treatment

Researchers from Georgetown University’s Lombardi Comprehensive Cancer Center collaborated with scientists from the University of Miami, Florida, to discover how TTP488 (azeliragon), an experimental drug, prevents aggressive, triple-negative breast cancer from metastasizing at the cellular level.

The discovery was published in Nature Breast Cancer on July 13, 2023.

Triple-negative breast cancers (TNBCs) account for roughly 10-15% of all diagnosed breast cancers and are made up of cancer cells that lack estrogen and progesterone receptors as well as the protein HER2. TNBCs are more common in women under the age of 40 or in people of color; the five-year survival rate for metastasizing tumors is only 12%.

TNBCs have remained untreated for decades. This research identifies some of the communication pathways and biological mechanisms by which the Receptor for Advanced Glycation End-products (RAGE) receptor on the surface of TNBC cells drives its lethal metastatic dissemination. With this information, the researchers were able to assess the efficacy of TTP488 in both the lab and on mice, demonstrating that the medicine could be beneficial to humans.

“A clinical trial that is now underway at Lombardi and other cancer centers is a direct result of this preclinical research on RAGE inhibitors that started at the University of Miami and has continued with my move to Lombardi,” says Barry Hudson, PhD, associate professor of oncology at Georgetown Lombardi and corresponding author for this article. “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 manyfold, and we hope that progress against triple-negative breast cancers will be rapid.”

RAGE was found in 1992 as a probable component in diabetic vascular problems. Because of its diabolical ability to bind many different molecules and promote inflammation, it has since been linked to a wide range of disorders. TTP488 was developed in the 2000s for Alzheimer’s disease based on this information, however trial outcomes were mixed. However, it currently appears to be a very viable candidate for clinical trials, armed with more recent knowledge about its biology and effects, including its broad availability across many biological systems and its good safety profile.

The researchers began their investigation with two RAGE inhibitors, TTP488 and FPS-ZM1, both of which inhibited spontaneous and experimental metastasis of TNBC in mice. TTP488, however, was obviously the more effective medicine and the one they investigated extensively enough to determine if it qualified for use in people in a clinical trial after significant investigation in the lab and in mice. TTP488 is still being studied in larger, more sophisticated clinical trials to demonstrate its genuine efficacy, hence it is not yet available to women who are not involved in research trials.

The researchers also identified three key pathways that could be involved in RAGE inhibition: Pyk2, STAT3, and Akt. This discovery will aid researchers in better understanding the processes through which RAGE promotes metastasis, perhaps paving the way for combination treatment methods targeting both RAGE and these pathways.

“We are currently testing different combinations of TTP488 with other anti-cancer therapies to determine if RAGE inhibitors can synergize with those therapies,” says Hudson. “I think the outlook for effectively treating triple-negative breast cancers has become much brighter of late.”

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