Recently Discovered Molecule Kills Hard-To-Treat Cancers

The new compound, called ERX-41, kills a broad spectrum of difficult-to-treat cancers.

A new molecule created by a researcher at the University of Texas at Dallas kills a variety of difficult-to-treat cancers, including triple-negative breast cancer, by taking advantage of a weakness in cells not previously targeted by existing drugs.

The research, which was conducted using isolated cells, human cancer tissue, and human cancer grown from a mouse, was recently published nature cancer,

A co-corresponding author of the study and an associate professor of chemistry and biochemistry in the School of Natural Sciences and Mathematics at the University of Texas at Dallas, Dr. Jung-mo Ah devoted more than ten years of his career to small development Is. Molecules that target protein-protein interactions in cells. They previously created potential therapeutic candidate compounds for treatment-resistant prostate cancer and breast cancer using a method called structure-based rational drug design.

Dr. Jung-Mo Ah, associate professor of chemistry and biochemistry at the University of Texas at Dallas, synthesized a novel compound called ERX-41 that kills a broad spectrum of difficult-to-treat cancers, including triple-negative breast cancer. exploiting weakness in cells that had not previously been targeted by other drugs. credit: University of Texas at Dallas

In the current work, Ah and his colleagues tested a novel compound called ERX-41 for its effects against breast cancer cells, which have estrogen receptors (ERs) and those that do not. While effective treatments are available for patients with ER-positive breast cancer, there are few treatment options for patients with triple-negative breast cancer (TNBC) that lack receptors for estrogen, progesterone, and human epidermal growth factor. TNBC typically affects women under the age of 40 and has a worse outcome than other types of breast cancer.

“The ERX-41 compound does not kill healthy cells, but it does eradicate tumor cells, even though cancer cells have estrogen receptors,” Ah said. “In fact, it killed triple-negative breast cancer cells better than it killed ER-positive cells.

“It was a surprise to us at the time. We knew it must be targeting something other than estrogen receptors in TNBC cells, but we didn’t know what that was.

To investigate the ERX-41 molecule, Ah worked with colleagues, including co-corresponding author Dr. Ganesh Raj, Professor of Urology and Pharmacology, Harold C. at UT Southwestern Medical Center. Simmons Comprehensive Cancer Center, as well as Dr. Ratna Vadalmudi. , professor of obstetrics and gynecology at UT Health San Antonio. Dr. Tae-kyung Lee, a former UTD research scientist in the Ahns Bio-Organic/Medical Chemistry Lab, was involved in synthesizing the compound.

Researchers found that ERX-41 binds to a cellular protein called lysosomal[{” attribute=””>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 researchers fed the compound to mice with human forms of cancerous tumors, and the tumors got smaller. The molecule also proved effective at killing cancer cells in human tissue gathered from patients who had their tumors removed.

They also found that ERX-41 is 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.

Reference: “Targeting LIPA independent of its lipase activity is a therapeutic strategy in solid tumors via induction of endoplasmic reticulum stress” by Xihui Liu, Suryavathi Viswanadhapalli, Shourya Kumar, Tae-Kyung Lee, Andrew Moore, Shihong Ma, Liping Chen, Michael Hsieh, Mengxing Li, Gangadhara R. Sareddy, Karla Parra, Eliot B. Blatt, Tanner C. Reese, Yuting Zhao, Annabel Chang, Hui Yan, Zhenming Xu, Uday P. Pratap, Zexuan Liu, Carlos M. Roggero, Zhenqiu Tan, Susan T. Weintraub, Yan Peng, Rajeshwar R. Tekmal, Carlos L. Arteaga, Jennifer Lippincott-Schwartz, Ratna K. Vadlamudi, Jung-Mo Ahn, and Ganesh V. Raj, 2 June 2022, Nature Cancer.
DOI: 10.1038/s43018-022-00389-8

Ahn is a joint holder of patents issued and pending on ERX-41 and related compounds, which have been licensed to the Dallas-based startup EtiraRX, a company co-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.

The study was funded by the National Cancer Institute, the Cancer Prevention and Research Institute of Texas, and The Welch Foundation.