A new molecule made by a University of Texas at Dallas researcher kills a wide range of hard-to-treat cancers, including triple-negative breast cancer, by exploiting a weakness in cells that were not previously targeted by other drugs.
A study describing the research — conducted in isolated cells, in human cancer tissue and in human cancers grown in mice — was published online June 2 in the journal. nature cancer.
Jung-Mo Ahn, study co-author and associate professor of chemistry and biochemistry at UT Dallas in the College of Natural Sciences and Mathematics, has been passionate about his work designing small molecules that target protein-protein interactions in cells for more than a decade. Using an approach called Rational Structure-Based Design, he previously developed potential therapeutic candidate compounds for treatment-resistant breast cancer and prostate cancer.
In the current work, Ahn and colleagues tested a new compound he made called ERX-41 for its effects against breast cancer cells, both those with estrogen receptors (ERs) and those without. While there are effective treatments available for patients with ER-positive breast cancer, there are few treatment options for patients with triple-negative breast cancer (TNBC), who lack the estrogen, progesterone, and human epidermal growth factor receptor 2. TNBC generally affects women under 40 It has worse results than other types of breast cancer.
“ERX-41 does not kill healthy cells, but it does kill cancer cells regardless of whether the cancer cells have estrogen receptors or not,” said Ann. “In fact, it killed triple negative breast cancer cells better than hospital positive cells.
“This was baffling us at the time. We knew it must be targeting something other than the estrogen receptors in TNBC cells, but we didn’t know what that was.”
To investigate the ERX-41 molecule, Ahn worked with collaborators, including interview co-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 the Ahn’s Laboratory of Organic/Medical Chemistry, was involved in manufacturing the compound.
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 cancer cell to grow quickly, it has to produce a lot of proteins, and that creates stress on the endoplasmic reticulum,” Ahn said. “Cancer cells significantly overproduce LIPA, much more than healthy cells. By binding to LIPA, ERX-41 impairs protein processing in the endoplasmic reticulum, which becomes swollen, leading to cell death.”
The research team also tested the compound in healthy mice and did not notice any adverse effects.
“It took us several years to hunt down exactly the protein that was affected by ERX-41. That was the hard part. We chased many dead ends, but we didn’t give up,” Ahn said.
“Triple-negative breast cancer is particularly malignant – it targets women at a younger age; it’s aggressive; and it’s treatment-resistant. I’m really glad we’ve discovered something that has the potential to make a huge difference for these patients.”
The researchers fed mice the compound with human forms of carcinomas, and the tumors got smaller. The molecule also proved effective in killing cancer cells in human tissue collected from patients whose tumors had been removed.
They also found that ERX-41 is effective against other types of cancer with high pressure on the endoplasmic reticulum, including hard-to-treat pancreatic and ovarian cancer and glioblastoma, the most aggressive and deadly primary brain cancer.
“As a chemist, I’m kind of isolated from patients, so this success is an opportunity for me to feel that what I’m doing can be good for society,” Ahn said.
Ahn is a joint holder of patents issued and pending on ERX-41 and related compounds, which have been licensed to Dallas-based startup EtiraRX, a company founded in 2018 by Ahn, Raj and Vadlamudi. The company recently announced that it plans to begin clinical trials of ERX-41 as early as the first quarter of 2023.
Ahn’s research in this project is supported by the National Cancer Institute, part of the National Institutes of Health (1R01CA223828); the Texas Cancer Prevention and Research Institute; The Welch Foundation.
In addition to researchers from UT Southwestern and UT Health San Antonio, other study authors from the Janelia Research Campus of Howard Hughes Medical Institute, Northwest A&F University in China, and Xiamen University College of Medicine in China contributed.