Researchers develop ‘Goldilocks drug’ to treat triple-negative breast cancer

Các nhà nghiên cứu phát triển 'thuốc Goldilocks' để điều trị ung thư vú ba âm tính

cSNX1.3 competitively inhibits binding of EGFR to SNX1. One Ribbon drawing of the EGFR kinase domain (PDB ID 5CNO) and the SNX1 Bar domain (PDB ID 4FZS). The proposed SNX1 binding site is far from the kinase active site. REMOVE SDS site gels for the purified SNX1 Bar domain (base 301–522) and the EGFR kinase domain (base 672–998). OLD MST EGFR kinase domain binding curves (50 nM) to His-tagged fluorescent dye were titrated against the Bar domain, SNX1.3 (limited), SNX1.3, and control PTD4 peptides , as well as the BSA control. EASY Binding of SNX1.3 to the kinase domain was also measured by biological layer interferometry (Octet BLI), yielding a dissociation constant similar to the dissociation constant measured with MST. Credit: Cancer gene therapy (In 2022). DOI: 10.1038 / s41417-022-00541-7

After decades of research and two previous drug development efforts, things are looking promising for a team of University of Arizona researchers working on a less toxic treatment for a type of cancer. specific breasts.

Researchers have developed a drug compound capable of blocking cancer cells grow in what is called triple negative breast cancer. The drug, which has not been tested in humans, has been shown to eliminate tumors in mice, with little or no effect on normal healthy cells, so it is likely not toxic to patients.

The therapy is based on a newly discovered method where a gene called epidermal growth factor receptor, or EGFR, leads to cancer. EGFR is a long-studied oncogene – a gene that can, under certain circumstances, transform a cell into a tumor cell.

The researchers’ findings are published in the journal Nature Cancer gene therapyand the team are working to get approval from the Food and Drug Administration to test the compound in phase 1 human clinical trials.

Triple-negative breast cancer accounts for about 10 to 15% of all breast cancers. Triple negative refers to the fact that cancer cells test negative for three other types of breast cancer — those caused by too much estrogen, too much progesterone, or too much of a protein called HER2, according to the American Society of American Cancer. Triple-negative breast cancer is more common in women under the age of 40 who are black or who have a specific mutation in a gene called BRCA1. According to the US National Institutes of Health, about half of negative breast cancer cases overexpress the oncogene EGFR.

Researchers at UA Arizona have invented a compound that blocks EGFR from reaching the part of the cell that leads to cancer survival. This compound blocks the action of the active EGFR protein in cancer cells but not in normal cells.

Often, drugs are not targeted enough in their attack and so they attack parts of other healthy cells, leading to unwanted side effects. The researchers want to prevent that.

Joyce Schroeder, who co-wrote the paper with lead author Benjamin Atwell, a postdoctoral fellow in the Department of Molecular and Cell Biology.

Schroeder heads the university’s Department of Molecular and Cellular Biology and leads the laboratory where the research for the paper was conducted. She is also a member of the BIO5 Institute and the university’s Cancer Center.

The first two drug technologies she and her team created kill cancer cells, but they have problems.

In their first attempt, the researchers targeted what Schroeder calls the “unstructured” part of the EGFR protein, and as a result the compound was unable to work consistently and reliably. trust.

The second attempt created a compound that was too general and hit a part of the protein that also promotes normal activities in healthy cells, making the drug toxic.

To be effective, Schroeder and her team knew they had to develop a compound that could get into cancer cells and precisely target the right part of the protein made by the EGFR gene to stop cancer. spread. They succeeded on the third attempt.

“It’s like the Goldilocks effect,” says Schroeder.

She and her team knew they had to find a solution that wouldn’t affect normal cells and that would still function inside the body.

“When we tested this drug in animal models, we got this amazing result, where it really didn’t just stop the tumors from growing, but also made them regress and go away, and we didn’t see any toxic side effects,” she said. “We’re excited about this because it’s so tumor-specific.”

Like designing a key to fit a very specific key, molecular and cellular biologists ideally design drug chemistry that would interact with target protein in exactly the right way and nothing else.

“Targeting triple-negative breast cancer has been difficult because it doesn’t have one of these obvious things to target,” says Schroeder. “People have known for a long time that triple-negative breast cancer cells express EGFR, but when known EGFR drugs were thrown at it, it didn’t respond.”

Many researchers thought that perhaps EGFR shouldn’t be the target, so they looked for new ones. Schroeder, on the other hand, thinks EGFR is just working in a way that researchers don’t yet understand. She and her team tried to target it in a novel way, and succeeded.

The next step, besides human trials, is to test the drug’s ability to prevent metastasis, which occurs when cancer cells Schroeder said.

Researchers have worked to protect Intellectual Property and invest further in asset licensing with Tech Launch Arizona, the university office that commercializes university innovations.

New drug target for triple negative breast cancer

More information:
Benjamin Atwell et al., Classification of nexin-dependent therapeutic targets of the carcinogenic epidermal growth factor receptor, Cancer gene therapy (In 2022). DOI: 10.1038 / s41417-022-00541-7

Quote: Researchers developing ‘Goldilocks drug’ to treat triple negative breast cancer (2022, 25 October) retrieved 25 October 2022 from 10-goldilocks-drug-triple-negative-breast-cancer .html

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