A recently discovered molecule kills hard-to-treat cancers

The analysis was performed on remoted cells, human most cancers tissue and human cancers grown in mice.

The new compound, known as ERX-41, kills a variety of hard-to-treat cancers.

A new molecule created by a University of Texas at Dallas researcher exploits a weak spot in cells to kill a wide range of hard-to-treat cancers, together with triple-negative breast most cancers, that aren’t focused by current medication.

The examine was performed utilizing remoted cells, human most cancers tissue, and human most cancers grown in mice. Cancer by nature.

Corresponding creator of the examine and affiliate professor of chemistry and biochemistry on the University of Texas at Dallas School of Natural Sciences and Mathematics, Dr. Jung-Mo Ahn has spent greater than a decade growing small molecules that focus on protein-protein interactions in cells. He beforehand created potential therapeutic candidate compounds for treatment-resistant prostate most cancers and breast most cancers utilizing a method known as structure-based rational drug design.

Jung Mo Ahn

Dr. Jung-Mo Ahn, an affiliate professor of chemistry and biochemistry on the University of Texas at Dallas, has synthesized a brand new compound known as ERX-41 that kills a variety of hard-to-treat cancers, together with triple-negative breast most cancers. Weakness in cells not beforehand focused by different medication. Credit: University of Texas at Dallas

In the present work, An and his colleagues examined a brand new compound he synthesized, known as ERX-41, for its results on breast most cancers cells, each these containing and people missing estrogen receptors (ERs). Although there are efficient therapies for sufferers with ER-positive breast most cancers, there are few therapy choices for sufferers with triple-negative breast most cancers (TNBC), which lack receptors for estrogen, progesterone, and human epidermal progress issue 2. TNBC is extra frequent in ladies underneath the age of 40 and has poorer outcomes than different forms of breast most cancers.

“The ERX-41 compound did not kill the wholesome cells, however it did kill the tumor cells, despite the fact that the most cancers cells had estrogen receptors,” An stated. “In truth, it killed triple-negative breast most cancers cells higher than it killed ER-positive cells.

“It shocked us on the time. “We knew it was focusing on one thing aside from the estrogen receptors on TNBC cells, however we did not know what it was.”

An’s collaborators to check the ERX-41 molecule, together with corresponding authors Drs. Ganesh Raj, professor of urology and pharmacology on the Harold Simmons Comprehensive Cancer Center at UT Southwestern Medical Center, and Dr. Ratna Vadlamudi, professor of obstetrics and gynecology at UT Health San Antonio. Dr. Tae-Kyung Lee, a former UTD researcher in An’s Bio-Organic/Medicinal Chemistry Laboratory, synthesized the compound.

The researchers discovered that ERX-41 binds to a mobile protein known as a lysosome[{” 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.

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