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Triple-negative breast cancer is particularly difficult to treat. In fact, his cancer cells don’t have the marks that conventional treatments usually target. The researchers have synthesized a new molecule, called ERX-41, that is able to bind to a protein from the endoplasmic reticulum, to induce the death of breast cancer cells. This approach offers new hope for treating patients with multiple solid tumors.
Triple-negative breast cancer cells (TNBC) do not have estrogen receptor (ER-) or progesterone receptor (PR-), or even cell proliferation-regulating protein receptor (HER2-)—hence the term ‘triple negative’. They account for about 15% of new breast cancer diagnoses. Chemotherapy remains the primary treatment option for patients, as the absence of these signs precludes the use of more effective targeted therapies.
CSTN affects young women, under the age of 40. It is the most lethal type of breast cancer and has a high relapse rate. It is therefore necessary to develop new, more targeted therapies. The goal is to find a component that distinguishes cancerous cells, but is not observed in healthy cells. The fact that CSTN has a high degree of molecular heterogeneity unfortunately complicates matters. However, a team from the University of Texas at Dallas has found a way to exploit a defect in these cancer cells.
Significant reduction in tumor growth
Dr. Jung Moo Ahn, associate professor of chemistry and biochemistry at UT Dallas, has been working for more than a decade designing small molecules that can disrupt critical protein-protein interactions to improve cancer treatment. He and his team have already developed two types of oligobenzamides (D2 and ERX-11) that bind respectively to the androgen receptor and the estrogen receptor; Both are potential therapeutic candidate compounds for prostate (D2) and treatment-resistant breast cancer (ERX-11).
While seeking to improve these therapeutic agents, they mistakenly obtained another molecule (ERX-41), with potent activity against several molecular subtypes of TNBC. This molecule was first tested on isolated cells: In 21 cell lines, representing all molecular subtypes of TNBC, ERX-41 showed potent antiproliferative activity. Write researchers. The molecule also did not have a significant effect against normal human breast epithelial cells.
” Live cell imaging studies indicated that ERX-41 significantly (>90%) induced TNBC cell death within 30 h of treatment. “The compound was also tested on human cancer tissue and on mouse models of human cancers: it significantly reduced tumor growth and the mice showed no signs of toxicity (body weight remained unchanged, as did tissues of major organs),” says the team. ERX-41 does not kill healthy cells, but it does kill cancer cells whether or not they have estrogen receptors. Ahn said in a statement.
Cell death due to too much stress
In light of the results, the researchers believed that this molecule necessarily targets something other than the estrogen receptor – which was clearly not the discriminatory factor observed during the experiments. Taking a closer look at the ERX-41 molecule, Ahn and his collaborators eventually discovered that it binds to a cellular protein called lysosomal acid lipase A (LIPA). LIPA is found in a cell organelle called the endoplasmic reticulum – the cell transport system responsible for, among other things, protein folding.
For a cancer cell to grow quickly, it needs to make a lot of protein, which creates stress in the endoplasmic reticulum, Ahn says. Therefore, cancer cells produce much more LIPA than healthy cells. By binding to LIPA, ERX-41 inhibits protein processing in the endoplasmic reticulum, which leads to stress. ” Persistent and severe stress of the endoplasmic reticulum kills cancer cells by inducing autophagy, apoptosis, necrosis, or immune cell death. ‘, explained the researchers.
In a way, ERX-41 exacerbates the underlying stress caused by CSTN itself, which is why it has no effect on healthy cells. ” Triple-negative breast cancer is particularly malignant: it affects women at an early age, is aggressive and resistant to treatment. I’m really glad we discovered something that has the potential to make a huge difference for these patients. Clinical trials for ERX-41 are expected to begin in the first quarter of 2023,” Ahn said.
This molecule has shown good results in the case of CSTN, but it can be used to treat other cancers that are particularly difficult to treat. Researchers have already found that ERX-41 is effective in other cancers associated with increased stress on the endoplasmic reticulum, such as pancreatic cancer, hard-to-treat ovarian cancer, and glioblastoma, a highly aggressive brain cancer.
Source: X. Liu et al., Nature Cancer
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