Most promising breakthroughs: Drug candidate for breast cancer will start clinical trials

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Most promising breakthroughs: Drug candidate for breast cancer will start clinical trials

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Most promising breakthroughs: Drug candidate for breast cancer will start clinical trials.

Nature sub-journal: The strongest breast cancer drug candidate will start clinical trials early next year.

Breast cancer is one of the serious diseases that threaten women’s health. Most breast cancers have a good prognosis, but about 15% of breast cancers are triple negative breast cancer ( TNBC ) .

Named after the lack of human epidermal growth factor receptor (PR) and human epidermal growth factor receptor-2 (HER-2), triple-negative breast cancer is the most aggressive breast cancer, more likely to spread, metastasize, and recur, and due to the lack of therapeutic targets , The limited treatment of drugs has always been a difficult point in breast cancer treatment, also known as ” the most aggressive breast cancer “.

In 2018 alone, more than 150,000 people worldwide died of triple-negative breast cancer.

Therefore, there is an urgent need to discover effective therapeutic targets.

Recently, Ganesh Raj of the University of Texas Southwestern Medical Center , Jung-Mo Ahn of the University of Texas at Dallas, and Ratna Vadlamudi of the University of Texas Health Science Center , etc. published a title in Nature Cancer , a sub-journal of Nature : Targeting Research paper on LIPA independent of its lipase activity is a therapeutic strategy in solid tumors via induction of endoplasmic reticulum stress .

The research team synthesized a new small-molecule compound, ERX-41 , that kills cancer cells by exploiting a cellular weakness previously not targeted by other drugs.

ERX-41 can successfully target a variety of solid tumors, including triple-negative breast cancer, as demonstrated in multiple types of cancer cells and animal models .

The discovery could lead to the development of new treatments for cancer patients with few treatments .

The research team says this is one of the most promising breakthroughs in triple-negative breast cancer to date, and clinical trials could begin as soon as the first quarter of 2023.

The ideal targeted therapy exploits the unique weaknesses of cancer cells.

However, triple-negative breast cancer (TNBC) has multiple biologically distinct subtypes whose molecular heterogeneity, immune cell composition, and genetic and drug vulnerabilities limit the activity of individual targeted therapies.

In 2017, Jung-Mo Ahn et al. synthesized the compound ERX-11, which targets the estrogen receptor (ER) protein that drives most breast cancers.

During lead compound optimization, they stumbled upon the small-molecule compound ERX-41 that killed both estrogen receptor-positive and triple-negative breast cancer cells in a petri dish.

In this latest study, the research team found that ERX-41 binds to the lysosomal acid lipase A (LIPA) protein, which is present in the endoplasmic reticulum, an organelle in cells that processes and folds proteins .

For rapid tumor growth, cancer cells often overproduce LIPA, which leads to endoplasmic reticulum stress (ER stress) .

Endoplasmic reticulum stress is one of the hallmarks of inflammation and is widely involved in the disease process.

Cells under ER stress must rapidly restore protein-folding capacity to meet protein-folding demands if they are to survive.

In the presence of high levels of misfolded proteins in the ER, an intracellular signaling pathway called the unfolded protein response (UPR) induces a series of transcriptional and translational events to restore ER homeostasis.

In mouse tumor model experiments, the research team observed that a single dose of ERX-41 administered orally or intraperitoneally significantly inhibited tumor progression and reduced tumor growth in xenografts derived from four different triple-negative breast cancer patients.

Importantly, mouse body weight did not change before and after treatment. This suggests that ERX-41 has no apparent toxic effect.

Histological evaluation after ERX-41 treatment showed no significant histological changes in multiple organs including heart, lung, spleen, liver, kidney, uterus and pancreas.

Likewise, in mice, there were no significant histological changes or immune infiltration in multiple organs, including the spleen, suggesting that ERX-41 is not immunogenic.

Jung-Mo Ahn said that regardless of whether the cancer cells have estrogen receptors (ER) , ERX-41 does not kill healthy cells, it only destroys tumor cells.

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

The research team found that by binding to LIPA, ERX-41 induces endoplasmic reticulum stress, shuts down protein de novo synthesis, blocks the proliferation of triple-negative breast cancer cells , and induces their apoptosis, a series of actions that are targeted Furthermore, the activity of ERX-41 is independent of LIPA lipase function, but is dependent on endoplasmic reticulum localization.

Mechanistically, binding of ERX-41 to LIPA reduces the expression of multiple endoplasmic reticulum-resident proteins involved in protein folding, a vulnerability that targets cancer cells with a large therapeutic window.

Furthermore, gene enrichment analysis revealed that the major pathways upregulated after 4 hours of ERX-41 treatment were associated with induction of endoplasmic reticulum stress and compensatory unfolded protein response (UPR) pathways.

Further experiments found that ERX-41 was also effective against pancreatic, brain and ovarian tumors. Therefore, LIPA is also a viable molecular target in other cancers.

In conclusion, this study demonstrates a targeting strategy for solid tumors , including breast , glioblastoma , pancreatic , and ovarian cancers , that orally bioavailable small molecules targeting LIPA block protein folding , induces endoplasmic reticulum stress, which in turn leads to tumor cell death.

Ratna Vadlamudi , co-corresponding author of the study, said the findings were encouraging.

The safety profile and high therapeutic index of ERX-41 are particularly remarkable, indicating good prospects for clinical translation.

The three corresponding authors of the paper, Ganesh Raj , Jung-Mo Ahn and Ratna Vadlamudi , founded a startup called EtiraRX , and on EtiraRX’s website, they describe ERX-41 as follows:

• The only drug with cytotoxic activity against metastatic breast cancer cells;
• The first treatment for most breast cancers;
• The only drug shown to be active against most metastatic breast cancers (estrogen receptor positive or negative breast cancer, triple negative breast cancer) ;
• The first therapy to induce sustained and uncompensated endoplasmic reticulum stress leading to cell death.
• The drug kills the cancer, other drugs only stop or slow the growth of the cancer

The company said it will begin clinical trials of ERX-41 as early as the first quarter of 2023.

Paper link :
https://www.nature.com/articles/s43018-022-00389-8

https://www.etirarx.com/erx-41/

Most promising breakthroughs: Drug candidate for breast cancer will start clinical trials

(source:internet, reference only)

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