Researchers at Georgetown University's Lombardi Comprehensive Cancer Center have identified a mechanism that may help explain the main reason behind poor outcomes for breast cancer treatment in older adults.
The study links the role of the RAGE receptor, scientifically known as Receptor for Advanced Glycation End-products, or receptor for delayed glycation end-products of non-enzymatic reaction, which is a receptor on the surface of cells that amplifies inflammatory signals, and whose activity increases with the development of metastatic disease.
“Our study fills a major research gap by showing that aging significantly increases the spread of metastatic breast cancer, and that this effect is dependent on the RAGE receptor, a cell surface receptor that fuels inflammation,” says Dr. Barry Hudson, associate professor of oncology at Georgetown Lombardi Medical Center and lead author of the paper.
He added: "Most laboratory studies rely on young mice, which has limited our understanding of how the host environment itself changes with age, including immune function and chronic inflammatory conditions that in turn affect cancer behavior."
A key aspect of the study benefited from timing and serendipity. During the COVID-19 pandemic, due to reduced laboratory activity, some of the research team's mouse colonies aged longer than originally planned. This created a rare opportunity to study cancer in these aging animals, something that is usually difficult and expensive.
Coincidentally, this opportunity gave scientists the ability to compare tumor behavior in young mice versus older mice.
Using three different mouse models of triple-negative breast cancer, a highly aggressive form of the disease, researchers found that older mice developed significantly more lung metastases than younger mice, despite similar primary tumor growth. Furthermore, genetic deletion of the RAGE receptor in the mice almost completely eliminated this age-related increase in metastasis.
In their studies, aging led to increased levels of inflammatory molecules that activate the RAGE receptor. These included proteins S100 and HMGB1, which are found in both primary tumors and metastatic sites.
These changes made it easier for cancer cells to invade tissues and spread.
Hudson says: "These results show that aging not only increases the risk of cancer, but actively changes the body in ways that help tumors spread. The RAGE receptor appears to be a key mediator of these harmful age-related pathways."
The team also analyzed breast cancer data from more than 1,000 patients and found that high expression of the AGER gene (the gene encoding the RAGE receptor) and associated inflammatory genes was linked to worse outcomes in patients, supporting the clinical significance of these findings.
The future of RAGE is now being explored as a therapeutic target in many age-related diseases, highlighting its potential importance in cancer.
In previous work, researchers showed that the RAGE inhibitor TTP488 (aziliragon) could suppress breast cancer proliferation in preclinical models. In the current study, they also tested the drug in vitro and found that TTP488 was able to reduce serum-induced cancer cell invasion from aged mice.
Researchers are currently conducting a clinical trial at the Lombardi Center to evaluate the drug TTP488 in breast cancer patients undergoing chemotherapy, focusing on safety and cognitive outcomes. The drug has shown promising safety indicators in humans, making it an ideal candidate for further investigation.
The findings were published in the journal Communications Biology and will also be included in a special collection from the journal Nature entitled "Cancer and Aging".
