UArizona researchers are working on a less toxic treatment for deadly breast cancer

UArizona researchers are working on a less toxic treatment for deadly breast cancer

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

Researchers have developed an active ingredient that appears to stop the growth of cancer cells in so-called triple-negative breast cancer. The drug, which has not yet been tested in humans, has been shown to eliminate tumors in mice with little to no effect on normal healthy cells, making it potentially non-toxic to patients.

The therapy is based on a newly discovered way a gene known as epidermal growth factor receptor, or EGFR, leads to cancer. EGFR is a long-researched oncogene - a gene that can turn a cell into a tumor cell under certain circumstances.

The researchers' findings are published in the journal Cancer Gene Therapy, and the team is 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 approximately 10 to 15% of all breast cancers. Triple negative refers to the fact that the cancer cells test negative for the three other types of breast cancer — those driven by too much estrogen, too much progesterone or too much of a protein called HER2, according to the American Cancer Society. Triple-negative breast cancer occurs more often in women under 40 who are black or have a specific mutation in a gene called BRCA1. According to the National Institutes for Health, about half of all cases of triple-negative breast cancer overexpress the EGFR oncogene.

The UArizona researchers developed a compound that blocks EGFR from going to a part of the cell that drives cancer survival. The compound switches off the function of the EGFR protein, which works in cancer cells but not in normal cells.

Drugs often do not attack in a targeted manner and attack parts of other, healthy cells, which leads to undesirable side effects. The researchers wanted to prevent that.

"EGFR has been known as an oncogene for six decades, and there are many drugs that try to attack it, but they all had limitations that made them unsuitable as breast cancer drugs," said Joyce Schroeder, who co-authored the paper with lead author Benjamin Atwell, a postdoctoral fellow in the Department of Molecular and Cellular Biology.

Schroeder heads the university's Department of Molecular and Cellular Biology and directs the laboratory where the research for the publication was conducted. She is also a member of the BIO5 Institute and the University Cancer Center.

The first two drug technologies she and her team developed worked to kill the cancer cells, but they had problems.

eBook on laboratory diagnostics and automation

Compilation of the top interviews, articles and news from the last year. Download a copy today

In their first attempt, the researchers targeted what Schroeder called an "unstructured" part of the EGFR protein, and as a result the compound failed to work consistently and reliably.

The second attempt resulted in a compound that was too generalized and hit a part of the protein that also triggered 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 enter a cancer cell and target just the right part of the proteins produced by the EGFR gene to stop the cancer from spreading. They succeeded on the third attempt.

It was like the Goldilocks effect.”

Joyce Schroeder

She and her team knew they had to find a solution that wouldn't affect a normal cell and that would remain active in the body.

"When we tested the drug in animal models, we got this fabulous result where it not only stopped the tumors from disappearing, but caused them to regress and disappear, and we don't see any toxic side effects," she said. “We are so excited about it because it is very tumor specific.”

Like designing a key for a very specific lock, molecular and cellular biologists ideally design a drug chemistry that interacts just right with the target protein and nothing else.

“Fighting triple-negative breast cancer has been difficult because it doesn’t have one of those obvious targets,” Schroeder said. "People have known for a long time that triple-negative breast cancer cells express EGFR, but when the known EGFR drugs were thrown at them, they didn't respond."

Many researchers thought that maybe EGFR shouldn't be the target, so they looked for new ones. Schroeder, on the other hand, believes that EGFR only works in ways that researchers don't yet understand. She and her team successfully attempted to target it in novel ways.

The next step, besides human trials, is to test the drug's ability to suppress metastasis, which occurs when cancer cells spread to other parts of the body, Schroeder said.

The researchers have worked to protect the intellectual property and further invest in licensing the asset with Tech Launch Arizona, the university office that commercializes university innovations.

Funding for the work was provided by the Department of Defense as well as donations from the Ginny L. Clements Breast Cancer Fund and philanthropist Susan Greendorfer.

Source:

University of Arizona

Reference:

Atwell, B., et al. (2022) Sorting Nexin-dependent therapeutic targeting of the oncogenic epidermal growth factor receptor. Cancer gene therapy. doi.org/10.1038/s41417-022-00541-7.

.