Did We Just Cure Cancer?
June 2022 came along with the bright sun, rising temps, and a possible cure for treatment-resistant cancers. A biochemist by the name of Dr. Jung-Mo Ahn and his team at the University of Texas-Dallas discovered how to synthesize a molecule that kills a broad spectrum of hard-to-treat cancers, including triple-negative breast cancer, by exploiting a weakness in cells not previously targeted by other drugs. This fascinating finding is giving hope to patients and doctors and causing quite the stir in the scientific world.
Dr. Jung-Mo Ahn is an associate professor of chemistry and biochemistry in the School of Natural Sciences and Mathematics. Dr. Ahn has been passionate about his work designing small molecules that target protein-protein interactions in cells for over a decade. Ahn worked with collaborators, including co-corresponding authors Dr. Ganesh Raj, professor of urology and pharmacology at the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern Medical Center, as well as Dr. Ratna Vadlamudi, professor of obstetrics and gynecology at UT Health San Antonio. Dr. Tae-Kyung Lee, a former UTD research scientist in Ahn’s Bio-Organic/Medicinal Chemistry Lab, was involved in synthesizing the compound.
This compound, called ERX-41, is a novel compound the team synthesized for its effects against breast cancer cells, both those that contain estrogen receptors (ERs) and those that do not. There are effective treatments available for those with ER-positive breast cancer. However, the patient can develop resistance, making those ineffective. Even worse are patients with triple-negative breast cancer, which affects women under 40 and with far worse outcomes. However, this is the kind of situation where ERX-41 really shines.
“The ERX-41 compound did not kill healthy cells, but it wiped out tumor cells regardless of whether the cancer cells had estrogen receptors,” Ahn said. “In fact, it killed the triple-negative breast cancer cells better than it killed the ER-positive cells.
This was puzzling to us at the time. We knew it must be targeting something other than estrogen receptors in the TNBC cells, but we didn’t know what that was.”
The researchers discovered that ERX-41 binds to a cellular protein called lysosomal acid lipase A (LIPA). LIPA is found in a cell structure called the endoplasmic reticulum, an organelle that processes and folds proteins.
“For a tumor cell to grow quickly, it has to produce a lot of proteins, and this creates stress on the endoplasmic reticulum,” Ahn said. “Cancer cells significantly overproduce LIPA, much more so than healthy cells. By binding to LIPA, ERX-41 jams the protein processing in the endoplasmic reticulum, which becomes bloated, leading to cell death.”
The research team also tested the compound in healthy mice and observed no adverse effects.
“It took us several years to chase down exactly which protein was being affected by ERX-41. That was the hard part. We chased many dead ends, but we did not give up,” Ahn said. “Triple-negative breast cancer is particularly insidious — it targets women at younger ages; it’s aggressive, and it’s treatment-resistant. I’m really glad we’ve discovered something that has the potential to make a significant difference for these patients.”
The beauty of this discovery from Dr. Ahn and his team is that ERX-41 is also effective against other cancer types with elevated endoplasmic reticulum stress, including hard-to-treat pancreatic and ovarian cancers and glioblastoma, the most aggressive and lethal primary brain cancer.
"As a chemist, I am somewhat isolated from patients, so this success is an opportunity for me to feel like what I do can be useful to society," Ahn said.
Ahn's research on this project is supported by the National Cancer Institute, part of the National Institutes of Health (1R01CA223828); the Cancer Prevention and Research Institute of Texas; and The Welch Foundation.
Congratulations to Dr. Ahn and his dedicated team at the University of Texas-Dallas. Your discovery and contribution bring new hope to cancer patients and their practitioners the world over. It will be fascinating in the coming years to see how this discovery plays out in clinical trials!