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Scientists Discover Therapy Against Aggressive Breast Cancer

This approach affects a triply resistant cancer variety.

Breast cancerBreast cancer
 

Publishing in Nature, scientists from the University of Texas report the discovery of a small molecule that can stop an especially aggressive subtype of breast cancer [1].

The deadliest kind

Breast cancer remains the fourth deadliest type of cancer, claiming more than 40 thousand victims a year, almost exclusively women, in the US alone. Like other cancers, breast cancer has various subtypes, with triple-negative breast cancer (TNBC) being especially aggressive and insensitive to treatment. The name means that this subtype tests negative for estrogen receptors, progesterone receptors, and HER2 protein. Consequently, TNBC’s growth is not fueled by these proteins, and they cannot be used as therapeutic targets [2]. TNBC constitutes around 15% of all breast cancer cases, but it has the highest mortality rate of all subtypes and results in about 150,000 deaths annually worldwide.

A fortuitous discovery

This group of researchers had previously identified several small molecules that target estrogen and progesterone receptors, which TNBC lacks. While working on optimizing those molecules, the researchers made what they candidly call “a serendipitous discovery”: a molecule that surprisingly showed effectiveness against TNBC.

The researchers tested the molecule, ERX-41, in vitro on 21 cell lines representing all molecular subtypes of TNBC and showed that it significantly impairs the proliferation of these cancer cells but does not affect normal human mammary epithelial cells. Within 30 hours after the treatment, ERX-41 induced death in more than 90% of all TNBC cells.

The researchers found that ERX-41 had no clear signs of toxicity in mice and could be administered both intraperitoneally and orally. The molecule significantly reduced the growth of xenografts (human tumors grown in mice) of all TNBC subtypes but did not affect the mice’s weight – another sign of it being relatively safe. Histological analysis of various organs did not show any significant changes, suggesting that ERX-41 does not catalyze an immune response.

How does it work?

To understand the mechanism behind the obvious effect of ERX-41, the researchers performed RNA sequencing in two TNBC cell subtypes. It revealed that the genes most upregulated by ERX-41 relate to endoplasmic reticulum (ER) stress. The ER has numerous functions in the cell, most notably facilitation of protein folding [3].

It didn’t take the scientists long to confirm, using electron microscopy, that ERX-41 does indeed induce severe ER stress in TNBC cells but not in healthy cells. Being very aggressive, TNBC relies on fast growth, and it needs to produce proteins in large quantities to support this growth.

To identify the molecular target of ERX-41, the researchers performed a knockout screen: they used the CRISPR-Cas9 system to knock out specific genes and discover which mutant cells were best at resisting ERX-41. The LIPA gene that encodes the LAL protein turned out to be the only one fitting the profile.

LAL was previously thought to be a lysosomal acid lipase – i.e., a protein that facilitates the breakdown of lipids in lysosomes. However, this could not explain its ERX-41-related activity, which clearly affected the endoplasmic reticulum. The researchers were able to show that LAL is mostly present in the ER and not in lysosomes, which calls for a re-evaluation of the current view of this protein.

The researchers then showed that LAL was significantly overexpressed in most TNBC tumors compared to normal breast tissue. In multiple tissues, including the uterus, liver, kidney, heart, lung, and spleen, LAL levels were also much lower than in tumor tissue.

Gene ontogeny and proteomic analyses showed that binding LAL with ERX-41 specifically affects the protein maturation and folding function of the ER and drastically reduces protein production, leading to cellular death. The lipase function of LAL was neither affected by ERX-41 nor required for its anti-tumor activity.

ERX-41 remained effective when tested on actual human primary TNBC tumors in so-called patient-derived explant (PDE) cultures. Those cultures retain the native tissue architecture and better recapitulate the heterogeneity of human TNBC.

Importantly, the researchers tested ERX-41 in vitro on several other cancer cell lines, including glioblastoma, pancreatic, and ovarian cancer, and in vivo on xenografts of estrogen receptor-positive breast cancer and ovarian cancer. In all cases, the cancers showed strong response to ERX-41, proving that the molecule’s therapeutic potential is not limited to TNBC.

Conclusion

In our age of increasingly complex anti-cancer therapies, the world of small molecules can still surprise us with serendipitous discoveries such as this one. If confirmed, the anti-tumor action of ERX-41 can become a game changer for certain cancer types and save countless lives. More generally, it also shows that inducing ER stress is a plausible anti-cancer strategy worth further exploration.

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Literature

[1] Liu, X., Viswanadhapalli, S., Kumar, S., Lee, T. K., Moore, A., Ma, S., … & Raj, G. V. (2022). Targeting LIPA independent of its lipase activity is a therapeutic strategy in solid tumors via induction of endoplasmic reticulum stress. Nature Cancer, 1-19.

[2] Foulkes, W. D., Smith, I. E., & Reis-Filho, J. S. (2010). Triple-negative breast cancer. New England journal of medicine363(20), 1938-1948.

[3] Schwarz, D. S., & Blower, M. D. (2016). The endoplasmic reticulum: structure, function and response to cellular signaling. Cellular and molecular life sciences73(1), 79-94.

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About the author
Arkadi Mazin

Arkadi Mazin

Arkadi is a seasoned journalist and op-ed author with a passion for learning and exploration. His interests span from politics to science and philosophy. Having studied economics and international relations, he is particularly interested in the social aspects of longevity and life extension. He strongly believes that life extension is an achievable and noble goal that has yet to take its rightful place on the very top of our civilization’s agenda – a situation he is eager to change.
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