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Broad Spectrum of Hard-to-Treat Cancers Killed by Novel Molecule That Targets Protein-Protein Interactions

The UT-Dallas team discovered that ERX-41 binds to a cellular protein called lysosomal acid lipase A (LIPA), which is found in the endoplasmic reticulum,…

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Researchers at the University of Texas at Dallas have synthesized a new molecule that kills a broad spectrum of hard-to-treat cancers, including triple-negative breast cancer, by exploiting a weakness in cells not previously targeted by other drugs. A study “Targeting LIPA independent of its lipase activity is a therapeutic strategy in solid tumors via induction of endoplasmic reticulum stress” describing the research, which was carried out in isolated cells, in human cancer tissue, and in human cancers grown in mice, appears in Nature Cancer.

Jung-Mo Ahn, PhD, 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, has been designing small molecules that target protein-protein interactions in cells for over a decade. Using a structure-based rational drug design method, he previously developed potential therapeutic candidate compounds for treatment-resistant breast cancer and prostate cancer.

Structure-based rational drug design was used to develop potential therapeutic candidate compounds for treatment-resistant breast cancer and prostate cancer. [Valax/Getty Images]
In the current work, Ahn and his colleagues tested a novel compound he synthesized called ERX-41 for its effects against breast cancer cells, both those that contain estrogen receptors (ERs) and those that do not. While there are effective treatments available for patients with ER-positive breast cancer, there are few treatment options for patients with triple-negative breast cancer (TNBC), which lacks receptors for estrogen, progesterone, and human epidermal growth factor 2. TNBC generally affects women under 40 and has poorer outcomes than other types of breast cancer.

“Triple-negative breast cancer (TNBC) has a poor clinical outcome, due to a lack of actionable 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,” write the investigators.

“ERX-41 induces endoplasmic reticulum (ER) stress resulting in cell death, and this effect is on target as evidenced by specific LIPA mutations providing resistance. Importantly, we demonstrate that ERX-41 activity is independent of LIPA lipase function but dependent on its ER localization.” “Mechanistically, ERX-41 binding of LIPA decreases expression of multiple ER-resident proteins involved in protein folding. This targeted vulnerability has a large therapeutic window, with no adverse effects either on normal mammary epithelial cells or in mice.

“Our study implicates a targeted strategy for solid tumors, including breast, brain, pancreatic and ovarian, whereby small, orally bioavailable molecules targeting LIPA block protein folding, induce ER stress and result in tumor cell death.”

“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 said. “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 investigate the ERX-41 molecule, Ahn worked with collaborators, including co-corresponding authors Ganesh Raj, MD, PhD, professor of urology and pharmacology at the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern Medical Center, as well as Ratna Vadlamudi, PhD, professor of obstetrics and gynecology at UT Health San Antonio. Tae-Kyung Lee, PhD, a former UTD research scientist in Ahn’s Bio-Organic Medicinal Chemistry Lab,  was involved in synthesizing the compound.

The researchers discovered that ERX-41 binds to a cellular protein called lysosomal acid lipase A (LIPA), which is found in 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,” noted Ahn. “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,” continued Ahn. “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.”

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 reported that it plans to begin clinical trials of ERX-41 as early as the first quarter of 2023.

The post Broad Spectrum of Hard-to-Treat Cancers Killed by Novel Molecule That Targets Protein-Protein Interactions appeared first on GEN - Genetic Engineering and Biotechnology News.

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