Targeting a Killer

University of Maryland engineering researchers have developed a way to treat a particularly aggressive form of breast cancer that currently lacks a modern, targeted therapy option, forcing patients to rely on chemotherapy.

Researchers from the Fischell Department of Bioengineering, working with colleagues from four other universities, have outlined a therapeutic strategy to treat triple-negative breast cancer (TNBC)—a potential first. The group’s research was published yesterday in Nature Nanotechnology, centering on nanotechnology-based precision targeting of a gene linked to cancer cell survival.

About 10 to 20 percent of breast cancers are considered triple-negative, which means that, unlike most breast cancers, they’re not fueled by the hormones estrogen or progesterone, nor by the HER2 protein. While treatments for most other forms of breast cancer work by targeting one of these three avenues, TNBC does not respond to modern hormonal therapies or medicines that target HER2 protein receptors.

TNBC patients often face a poorer prognosis compared to those with other types of breast cancer, said bioengineering Professor Xiaoming (Shawn) He, corresponding author of the paper.

“While we have seen dramatic advancements in breast cancer treatment in recent decades, TNBC patients are typically treated with conventional chemotherapy that is often associated with adverse side effects, drug resistance and even cancer relapse or recurrence,” said He, who is also a faculty member of the Robert E. Fischell Institute for Biomedical Devices and the University of Maryland Medical System’s Marlene and Stewart Greenebaum Comprehensive Cancer Center.

All cancers originate as the result of changes within the genes of a cell or group of cells. In the case of triple-negative breast cancer, a critical gene known as TP53 is most frequently deleted or mutated.

That gene provides instructions for making a protein called p53 that helps prevent the development of tumors by stopping cells with mutated or damaged DNA from growing and dividing uncontrollably. Although many researchers have considered techniques to restore p53 activity, no such therapy has been translated into the clinic, owing to the complexity of p53 signaling.

He and his research team took a different approach, focusing on POLR2A, an essential neighboring gene of TP53. The group chose this route because genomic alterations tend to be large regional events in the body. Most cancers that lead to the loss of a particular tumor suppressor gene also lead to the partial loss of nearby genes such as POLR2A, a gene that is essential for any cell to survive.

Although cancer cells can survive a partial loss of POLR2A, they become weakened and vulnerable to POLR2A inhibition. Knowing this, He and his research team hypothesized that targeted inhibition of POLR2A could potentially kill TNBC cells while sparing normal cells.

Fischell Department of Bioengineering researchers Jiangsheng Xu (co-first author), Hai Wang, Samantha Stewart and Yuntian Zhang contributed to the paper, along with researchers from Indiana University, the Ohio State University, and the University of Science and Technology of China.