Researchers are developing a new “cancer killer” molecule

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Triple negative breast cancer is particularly difficult to treat. In fact, his cancer cells don’t have the markers that traditional treatments usually target. Researchers have synthesized a new molecule called ERX-41 that is able to bind to a protein in the endoplasmic reticulum to induce breast cancer cell death. This approach offers new hope for the treatment of patients with multiple solid tumors.

Triple-negative breast cancer (TNBC) cells lack estrogen (ER) or progesterone (PR) receptors, or even receptors for the protein that regulates cell proliferation (HER2-)—hence the term “triple negative.” They account for about 15% of new breast cancer diagnoses. Chemotherapy remains the most important treatment option for patients because the lack of these markers prevents the use of more effective targeted therapies.

CSTN affects young women under the age of 40. It is the deadliest breast cancer subtype and has a high recurrence rate. There is therefore an urgent need to develop new, more targeted therapies. The aim is to find an element that characterizes cancer cells but does not occur in healthy cells. Unfortunately, the fact that CSTN exhibits high molecular heterogeneity complicates matters. However, a team from the University of Texas at Dallas found a way to exploit a flaw in these cancer cells.

Significantly reduced tumor growth

dr Jung-Mo Ahn, associate professor of chemistry and biochemistry at UT Dallas, has spent more than a decade developing small molecules that can disrupt protein-protein interactions critical to improving cancer treatment. He and his team have already developed two oligobenzamides (D2 and ERX-11) that bind to the androgen receptor and the estrogen receptor, respectively; both are potential therapeutic candidate compounds for prostate cancer (D2) and treatment-resistant breast cancer (ERX-11).

While attempting to optimize these therapeutics, they inadvertently obtained another molecule (ERX-41) with robust activity against multiple TNBC molecular subtypes. This molecule was first tested on isolated cells: ” ERX-41 showed potent antiproliferative activity in 21 cell lines representing all molecular subtypes of TNBC write the researchers. The molecule also had no significant effect against normal human mammary epithelial cells.

In mice, ERX-41 significantly reduced the volume and mass of tumors without affecting the animal’s body weight. © X. Liu et al.

Live cell imaging studies showed that ERX-41 significantly (>90%) induced TNBC cell death within 30 hours after treatment ‘ says the team. The compound was also tested on human cancer tissue and mouse models of human cancers: it significantly reduced tumor growth and the mice showed no signs of toxicity (body weight remained unchanged, as did the histology of the major organs). ” The compound ERX-41 didn’t kill healthy cells, but it did kill tumor cells, whether or not they had estrogen receptors Ahn said in a statement.

Cell death from too much stress

Given the results, the researchers thought this molecule was bound to target something other than estrogen receptors – which apparently weren’t the discriminating factor observed during the experiments. Ahn and his collaborators took a closer look at the ERX-41 molecule and eventually discovered that it binds to a cellular protein called lysosomal acid lipase A (LIPA). LIPA is located in a cell organelle, the endoplasmic reticulum – the cell transport system that is responsible for protein folding, among other things.

For a tumor cell to grow quickly, it needs to produce 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 blocks protein processing in the endoplasmic reticulum, leading to stress. ” Prolonged and severe endoplasmic reticulum stress kills cancer cells by inducing their autophagy, apoptosis, necroptosis, or immunogenic cell death ‘ the researchers explain.

Somehow, ERX-41 exacerbates the baseline stress induced by CSTN itself, which is why it has no effect on healthy cells. ” Triple-negative breast cancer is particularly insidious: it affects women earlier, is aggressive and resistant to therapy. I am very pleased that we have discovered something that has the potential to make a significant difference for these patients. ‘ said Ahn. Clinical trials of ERX-41 are expected to begin in the first quarter of 2023.

This molecule has shown good results in the case of CSTN, but could also be used to treat other types of cancer that are particularly difficult to treat. Indeed, researchers have found that ERX-41 is effective in other cancers associated with increased stress on the endoplasmic reticulum, such as:

Source: X. Liu et al., Nature Cancer

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