Cancer: a new molecule targets aggressive tumors, according to a study


A new lab-engineered molecule that exploits a weakness in cells can kill a wide range of hard-to-treat cancers, according to a new US study in human cancer tissue and human cancer cultured in mice.


The study, published June 2 in the peer-reviewed journal Nature Cancer, found that the compound, ERX-41, was able to kill cancer cells, including breast cancer cells that lack receptors. to estrogen, without killing healthy cells.


Estrogen and progesterone receptors and a receptor for a protein called HER2 are commonly present in breast cancer. These receptors are like “locks” that certain treatments, or “keys,” can open to kill cancer cells. But about 10-15% of all breast cancers are triple-negative breast cancer (TNBC), an aggressive form of the disease that is more likely to have already spread by the time it’s discovered, according to the American CancerSociety. The name “triple negative” comes from the fact that these cancer cells test negative for all three receptors, making them much more difficult to treat, with chemotherapy being the primary option for most patients. Those under 40 who are black have the highest risk of developing TNBC, which also has the highest mortality rate among the different types of breast cancer.


“Compound ERX-41 did not kill healthy cells, but it killed tumor cells, whether or not the cancer cells had estrogen receptors,” said Dr. Jung-Mo Ahn, associate professor of chemistry. and biochemistry at the University of Texas at Dallas. who synthesized the new molecule, said in a statement.


In fact, it killed triple-negative breast cancer cells better than ER-positive cells.


Ahn said he and his research team were initially intrigued by the results and unsure what the molecule might be targeting.


After several years of searching for a number of dead ends, scientists finally determined that ERX-41 binds to a cellular protein called lysosomal acid lipase A (LIPA).


“For a tumor cell to grow rapidly, it has to produce a lot of protein, which puts stress on the endoplasmic reticulum,” Ahn explained.


“Cancer cells significantly overproduce LIPA, much 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 endoplasmic reticulum (ER) is a network of sac-like structures and tubes in the gel-like cytoplasm inside a cell. Proteins and other molecules move through this network.


“Using a variety of biochemical and ultrastructural studies, we have shown that ERX-41 induces ER stress,” the authors wrote in the paper, adding that the molecule shuts down a certain type of protein synthesis, blocks the proliferation and causes apoptosis, or a type of cell death.


“Our results suggest that ERX-41 aggravates this system already engaged in TNBC to exhaust its protective functions and induce apoptosis. In normal cells and tissues, ERX-41 does not induce ER stress.


The compound has been shown to be effective in killing cancer cells in human tissue taken from cancer patients, as well as in mice bearing human forms of cancerous tumors, with the tumors shrinking. No adverse effects were observed in mice.


“Importantly, ERX-41 treatment did not show overt signs of toxicity, as evidenced by the unchanged body weights of the treated mice,” the authors wrote.


“Histological evaluation after ERX-41 treatment showed no significant changes in macroscopic histology of multiple organs including heart, lungs, spleen, liver, kidneys, uterus, and pancreas. .”


According to the researchers, the molecule also appears to work against other types of cancer that exhibit high levels of endoplasmic reticulum stress, including difficult-to-treat pancreatic and ovarian cancers, as well as the brain tumor glioblastoma. aggressive and fast growing.


The authors said ERX-41 could be useful in treating patients with multiple solid tumors.


EtiraRX, a startup co-founded by Ahn and co-authors Dr. Ganesh Raj, professor of urology and pharmacology at UT Southwestern Medical Center, and Dr. Ratna Vadlamudi, professor of obstetrics and gynecology at UT Health San Antonio , announced plans to begin clinical trials of ERX-41 as an oral drug as early as the first quarter of 2023.


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

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