The new compound referred to as ERX-41 kills a broad spectrum of hard-to-treat cancers.
A brand new molecule created by a researcher on the University of Texas at Dallas kills a wide range of difficult-to-treat cancers, together with triple-negative breast most cancers, by benefiting from a weak spot in cells that was not beforehand focused by current medication.
The analysis, which was performed utilizing remoted cells, human most cancers tissue, and mouse-grown human cancers, was not too long ago revealed in Nature Cancer.
A co-corresponding creator of the research and an affiliate professor of chemistry and biochemistry within the School of Natural Sciences and Mathematics on the University of Texas at Dallas, Dr. Jung-Mo Ahn has devoted greater than ten years of his profession to 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 technique referred to as structure-based rational drug design.
In the present work, Ahn and his colleagues examined a novel compound he synthesized referred to as ERX-41 for its results towards breast most cancers cells, each those who comprise estrogen receptors (ERs) and people that don’t. While there are efficient remedies obtainable for sufferers with ER-positive breast most cancers, there are few therapy choices for sufferers with triple-negative breast most cancers (TNBC), which lacks receptors for estrogen, progesterone, and human epidermal development issue 2. TNBC usually impacts ladies below 40 and has poorer outcomes than different forms of breast most cancers.
“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 stated. “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.”
To examine the ERX-41 molecule, Ahn labored with collaborators, together with co-corresponding authors Dr. Ganesh Raj, professor of urology and pharmacology on the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern Medical Center, in addition to Dr. Ratna Vadlamudi, professor of obstetrics and gynecology at UT Health San Antonio. Dr. Tae-Kyung Lee, a former UTD analysis scientist in Ahn’s Bio-Organic/Medicinal Chemistry Lab, was concerned in synthesizing the compound.
The researchers found that ERX-41 binds to a mobile protein referred to as 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 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.
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.