Scientists Discover New Molecule That Kills Hard-to-Treat Cancers

A new molecule synthesized by a UT Dallas researcher 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 describing the research — which was carried out in isolated cells, in human cancer tissue and in human cancers grown in mice — appears in the July 2022 issue of Nature Cancer.

Dr. Jung-Mo Ahn, a co-corresponding author of the study and associate professor of chemistry and biochemistry in the School of Natural Sciences and Mathematics, has been passionate about his work designing small molecules that target protein-protein interactions in cells for over a decade. Using an approach called structure-based rational drug design, he previously developed potential therapeutic candidate compounds for treatment-resistant breast cancer and for prostate cancer.

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).

“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.”

To investigate the ERX-41 molecule, Ahn worked with collaborators at UT Southwestern Medical Center and UT Health San Antonio. They discovered that ERX-41 binds to a cellular protein called 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,” Ahn said. “That was the hard part. We chased many dead ends, but we did not give up.”

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 pancreatic and ovarian cancers and glioblastoma.

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. The company plans to begin clinical trials in 2023.

– Amanda Siegfried