Recently, a small group of people with rectal cancer saw their disease disappear after experimental treatment.
It was a very small test done by doctors at Memorial Sloan Kettering Cancer Center in New York, where the patients took a drug called dostarlimab for six months. At the end of their trial, all their tumors disappeared.
utilities, in another breakthrougha new compound synthesized by Dr. Jung-Mo Ahn, a researcher from the University of Texas at Dallas, was found to kill a broad spectrum of difficult-to-treat cancers, including triple-negative breast cancer, leaving healthy cells unharmed.
He took advantage of a weakness in cells that had previously not been targeted by the other drugs.
The study, which was conducted in isolated cells both in human cancer tissue and in human cancers cultured in mice, was published in the magazine Nature Cancer†
Ahn, a co-corresponding author of the study and a UT Dallas associate professor of chemistry and biochemistry in the School of Natural Sciences and Mathematics, worked on small molecules that have focused on protein-protein interactions in cells for more than a decade. He had previously developed potential therapeutic candidate compounds for treatment-resistant breast cancer and prostate cancer.
In his current study, Ahn and his colleagues tested a new compound he synthesized, called ERX-41, for its effects on breast cancer cells — those that contain estrogen receptors (ERs) and those that don’t.
Now there are effective treatments for patients with ER-positive breast cancer, but there are only a few treatment options for patients with triple-negative breast cancer (TNBC). It lacks receptors for estrogen, progesterone and human epidermal growth factor 2. TNBC is known to affect women under 40 and has worse outcomes than other types of breast cancer.
“The ERX-41 compound didn’t kill healthy cells, but it destroyed 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 the ER-positive cells.
“This was a mystery to us at the time. We knew it had to be something other than estrogen receptors in the TNBC cells, but we didn’t know what that was.”
No adverse effects in healthy mice
The researchers soon discovered that ERX-41 binds to lysosomal acid lipase A (LIPA), a cellular protein. LIPA is found in a cell structure called the endoplasmic reticulum, an organelle that processes and folds proteins.
“In order for a tumor cell to grow quickly, it has to produce a lot of proteins, and this puts stress on the endoplasmic reticulum,” Ahn said. “Cancer cells produce a significant overproduction of LIPA, much more than healthy cells. By binding to LIPA, ERX-41 blocks protein processing in the endoplasmic reticulum, which becomes inflated, leading to cell death.”
The team tested the molecule in healthy mice and noted that there were no ill effects.
“It took us several years to figure out exactly which protein was affected by ERX-41. That was the hard part. We hunted a lot of dead ends, but we didn’t give up,” Ahn said.
†Triple-negative breast cancer is particularly insidious – it targets women at a younger age; it is aggressive and resistant to handling. I’m really pleased that we discovered something that has the potential to make a significant difference for these patients,” Ahn said.
Can beat the deadliest cancer
The researchers then fed the compound to mice with human cancers, and they got smaller.
The molecule also killed cancer cells in human tissue collected from patients whose tumors had been removed.
There is more.
They found that ERX-41 is effective against other cancer types with increased endoplasmic reticulum stress, including: difficult to treat pancreatic and ovarian cancer and glioblastomathe most “aggressive and deadly primary brain cancer.”
To investigate the ERX-41 molecule, Ahn collaborated with collaborators, including co-corresponding authors Dr. Ganesh Raj, professor of urology and pharmacology at 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 researcher in Ahn’s Bio-Organic/Medicinal Chemistry Lab, was also involved in the synthesis of the compound.
Ahn is a co-holder of issued and pending patents on ERX-41 and related compounds, which are licensed to the Dallas-based startup EtiraRX, a company co-founded in 2018 by Ahn, Raj and Vadlamudi. The company has announced that it plans to begin clinical trials of ERX-41 as early as the first quarter of 2023, offering hope for effective new treatments.
Abstract: Triple-negative breast cancer (TNBC) has a poor clinical outcome due to a lack of useful therapeutic targets. Herein, we define lysosomal acid lipase A (LIPA) as a viable molecular target in TNBC and identify a stereospecific small molecule (ERX-41) that binds LIPA. ERX-41 induces endoplasmic reticulum (ER) stress resulting in cell death, and this effect is on the target as evidenced by specific LIPA mutations that give rise to resistance. Importantly, we show that ERX-41 activity is independent of LIPA lipase function, but dependent on its ER localization. Mechanistically, LIPA ERX-41 binding reduces the expression of multiple ER-resident proteins involved in protein folding. This targeted vulnerability has a large therapeutic window, with no adverse effects on normal mammary epithelial cells or in mice. Our study implies a targeted strategy for solid tumors, including breast, brain, pancreas and ovary, where small, orally bioavailable molecules targeting LIPA block protein folding, induce ER stress and result in tumor cell death.
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