Researchers create molecule that kills hard-to-treat cancers

DALLAS — Researchers from two North Texas universities have created a molecule that kills a spectrum of hard-to-treat cancers, including an aggressive form of breast cancer. Their work was published in the journal Nature Cancer.

The researchers tested the molecule in isolated cells, human cancer tissue and in mice, with a goal to test in humans by mid-2023. They hope their work could eventually lead to treatments that make a difference in the lives of patients that suffer from these cancers.

“What motivates me now is, it’s not just [that] we understand a particular thing scientifically,” said Jung-Mo Ahn, an associate chemistry professor at the University of Texas at Dallas and an author on the study. “We realize that this molecule could be very useful, and it can help other people’s lives.”

Ahn worked with UT Southwestern Medical Center professor Dr. Ganesh Raj and Ratna Vadlamudi from the University of Texas Health Science Center at San Antonio on the research.

A tale of two elephants

In his lab at UTD, Ahn creates tiny molecules that can have a large impact on how our bodies fight diseases like cancer. He tries to prevent molecular “handshakes” between proteins that lead to uncontrollable cell growth and cancer spread.

“It’s almost like two elephants are hugging each other,” he said, “and you’re throwing a pebble to stop them.”

Triple-negative breast cancer, or TNBC, is an aggressive form of breast cancer that comprises about 15% of new breast cancer diagnoses. Most breast cancer cells have receptors for hormones like estrogen that scientists can target to kill the cancer cells. TNBCs lack those receptors, making chemotherapy one of the only viable treatments.

Several years ago, Ahn’s lab created a tiny molecule that could inhibit protein handshakes in prostate cancers and modified it to work in breast cancers.

The researchers altered the molecule’s structure and tested it on breast cancer cells, using TNBC cells as a baseline. They weren’t expecting it to work on the TNBCs – after all, the molecule wasn’t designed to kill those cells.

When Ahn and his team checked their results, they were surprised. Their molecule had reduced tumor growth in the TNBCs and killed the cancer cells, even though it wasn’t supposed to.

Molecular traffic jams

Ahn and his team were determined to find out how their molecule wiped out TNBC cells. Their answer lurked in a part of the cell called the “endoplasmic reticulum” – a “highway” that guides newly-created proteins to their final cellular destinations.

“What our molecule does is stop the traffic, and stop the highway,” Ahn said.

ERX-41, the molecule Ahn and his team created, binds to a specific protein in the endoplasmic reticulum called LIPA. This causes “traffic jams” in the endoplasmic reticulum, stressing out the cell and initiating its self-destruct protocol.

Healthy cells have less LIPA compared to TNBC cells. The researchers found that ERX-41 successfully killed human cancer cells in mice without significantly harming healthy cells.

The idea to kill cancer cells by stressing out the endoplasmic reticulum isn’t new. However, ERX-41 does so by binding to LIPA in a way that is not well-studied.

Juan del Valle, an associate professor at the University of Notre Dame who studies endoplasmic reticulum stress, said Ahn’s research has uncovered both a potential treatment for TNBC and a target within the endoplasmic reticulum that other researchers can study to create new cancer therapies.

“I think what was really fascinating was that it was almost a serendipitous discovery of a new target that might be a viable target for therapeutics in cancer,” said del Valle, who was not involved with the study.

Ahn and his co-authors are working to develop ERX-41 into a treatment that could be tested in animals, and eventually human patients. The Dallas-based startup EtiraRX, created by Ahn, Raj and Vadlamudi in 2018, has licensed the tech with plans to start clinical trials next year.

Since the research was published, Ahn has received phone calls and emails from TNBC patients, sharing their stories with him and encouraging him to continue with the work. Ahn, who comes from a family of cancer patients, said the response pushes him forward. His team’s unexpected discovery proved to be a valuable one.

“Sometimes, life throws a curveball,” Ahn said. “But when you seize the moment … you could actually track it down to the bottom of the pit and then find out there was a treasure waiting to be found.”