Scientists Have Discovered a New Molecule That Kills Even the Deadliest Cancer

Recently, a small group of people with rectal cancer saw their disease disappear after an experimental treatment.

It was a very small trial by doctors at Memorial Sloan Kettering Cancer Center in New York, in which patients took a drug called dostarlimab for six months. At the end of their trial, each of their tumors disappeared.

Now, in another breakthrough, a new compound synthesized by Dr. Jung-Mo Ahn, a researcher at the University of Texas at Dallas, has been shown to kill a wide range of hard-to-treat cancers, including cancer. triple-negative breast, leaving healthy cells unscathed.

It exploited a weakness in cells that were previously not targeted by other drugs.

The study, which was performed in isolated cells, both from human cancer tissue and from human cancers cultured in mice, was published in the journal nature cancer.

Ahn, co-corresponding author of the study and associate professor of chemistry and biochemistry at UT Dallas in the School of Natural Sciences and Mathematics, has worked for more than a decade on small molecules that target protein interactions. -protein in cells. Previously, he had developed potential therapeutic candidate compounds for treatment-resistant breast cancer and prostate cancer.

In his current research, Ahn and his colleagues tested a new compound he synthesized called ERX-41 for its effects on breast cancer cells – those that contained estrogen receptors (ER) and those that did not. not.

Today, 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 killed tumor cells, whether or not the cancer cells had estrogen receptors,” Ahn said. “It actually killed triple-negative breast cancer cells better than ER-positive cells.

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

Dr. Jung-Mo Ahn, an associate professor of chemistry and biochemistry at UT Dallas, has synthesized a new compound called ERX-41 that has shown promise in killing cancer cells. Source: UT Dallas

No adverse effects in healthy mice

Soon, researchers discovered that ERX-41 binds to lysosomal acid lipase A (LIPA), a cellular protein. LIPA is found in a cellular 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 protein, which puts stress on the endoplasmic reticulum,” Ahn said. “Cancer cells significantly overproduce LIPA, far more than healthy cells. By binding to LIPA, ERX-41 blocks protein processing in the endoplasmic reticulum, which becomes swollen, 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 research exactly which protein was affected by ERX-41. That was the hardest part. We chased many dead ends, but we didn’t give up,” Ahn said.

“Triple negative breast cancer is particularly insidious – it targets younger women; it is aggressive and resistant to treatment. I’m really happy that we discovered something that has the potential to make a significant difference for these patients,” says Ahn.

Can defeat the deadliest cancer

The researchers then gave the compound to mice with human forms of cancerous tumors, and they grew smaller.

The molecule also killed cancer cells in human tissue taken from patients whose tumors had been removed.

There is more.

They found that ERX-41 is effective against other cancer types with high endoplasmic reticulum stress, including hard-to-treat pancreatic and ovarian cancers and glioblastoma, the “most common primary brain cancer”. most aggressive and most deadly”.

To study the ERX-41 molecule, Ahn worked with collaborators including co-corresponding authors Dr. Ganesh Raj, professor of urology and pharmacology at UT Southwestern Medical Center’s Harold C. Simmons Comprehensive Cancer 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 at Ahn’s Bio-Organic/Medicinal Chemistry Laboratory, was also involved in synthesizing the compound.

Ahn is co-holder of issued and pending patents on ERX-41 and related compounds, which have been licensed to Dallas-based startup EtiraRX, a company co-founded in 2018 by Ahn, Raj and Vadlamudi. The company announced that it plans to begin clinical trials of ERX-41 as early as the first quarter of 2023, raising hopes for new effective treatments.

Summary: Triple-negative breast cancer (TNBC) has a poor clinical outcome, due to a lack of actionable therapeutic targets. Here, we define lysosomal acid lipase A (LIPA) as a viable molecular target in TNBC and identify a stereospecific small molecule (ERX-41) that binds to LIPA. ERX-41 induces endoplasmic reticulum (ER) stress leading to cell death, and this effect is on target, as evidenced by LIPA resistance mutations. Importantly, we demonstrate that ERX-41 activity is independent of LIPA lipase function but depends on its ER localization. Mechanically, ERX-41 binding of LIPA decreases the expression of several ER-resident proteins involved in protein folding. This targeted vulnerability has a wide therapeutic window, with no adverse effects either on normal mammary epithelial cells or in mice. Our study involves a targeted strategy for solid tumors including breast, brain, pancreas, and ovary, in which orally bioavailable small molecules targeting LIPA protein folding block, induce ER stress, and lead to death tumor cells.

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