- The most common type of breast cancer is incurable if it spreads to other parts of the body.
- A study in mice suggests that a drug candidate called ErSO not only kills primary breast tumors but also secondary, or metastatic, cancer in bone and the brain, liver, and lungs.
- The cancer cells do not appear to become resistant to ErSO, unlike current drug treatments.
- The new drug works by overactivating a cellular mechanism that usually protects the cells.
Every year, around 255,000 women and 2,300 men in the United States receive a diagnosis of breast cancer.
Approximately three-quarters of cases are a type called estrogen receptor-positive, in which the cancer cells have a receptor in their membranes that binds to the sex hormone estrogen. This type of breast cancer is incurable if it spreads.
The problem with current drug treatments, such as tamoxifen, is that the cancer cells can develop resistance.
Scientists from the University of Illinois Urbana-Champaign are working on a new type of drug that could prevent the development of resistance.
The drug, called ErSO, works by overactivating a stress response mechanism that normally protects cancer cells from harm. When the mechanism goes into overdrive, however, it kills the cells.
In mouse models of estrogen receptor-positive breast cancer, the drug rapidly killed 95–100% of primary cancer cells and their metastases in the brain, liver, lungs, and in bone.
“Even when a few breast cancer cells do survive, enabling tumors to regrow over several months, the tumors that regrow remain completely sensitive to retreatment with ErSO,” says David Shapiro, Ph.D., a professor of biochemistry, who co-led the research with chemistry professor Paul Hergenrother, Ph.D.
“It is striking that ErSO caused the rapid destruction of most lung, bone, and liver metastases and dramatic shrinkage of brain metastases, since tumors that have spread to other sites in the body are responsible for most breast cancer deaths,” Prof. Shapiro adds.
In previous research, another drug candidate that activates the same stress response mechanism caused undesirable side effects in mice.
However, ErSO killed cancer cells more quickly than the other drug and was well-tolerated in mice, rats, and dogs.
The researchers report their findings in Science Translational Medicine.
Overactive stress response
Breast cancer cells with receptors for estrogen prepare for the stresses of rapid growth by activating a pathway called the anticipatory unfolded protein response.
This stress response pathway can help breast tumors develop resistance to conventional anticancer drugs, which work by blocking or inhibiting the estrogen receptor.
But the new drug, ErSO, binds to a different part of the estrogen receptor. This has the effect of overactivating the stress response pathway, with fatal consequences for the cells.
Crucially, the drug appears to be selective, only killing cancer cells and not healthy cells.
“The unique thing about this compound is that it doesn’t touch cells that lack the estrogen receptor, and it doesn’t affect healthy cells — whether or not they have an estrogen receptor,” says Prof. Hergenrother.
“But it’s super potent against estrogen receptor-positive cancer cells,” he adds.
In mice, advanced breast cancers derived from human cells often shrank to undetectable levels within a week of treatment with ErSO.
“Many of these breast cancers shrink by more than 99% in just 3 days,” says Prof. Shapiro. “ErSO is fast-acting, and its effects on breast cancers in mice are large and dramatic.”
Protein production line
The unfolded protein response is a regulatory mechanism that kicks in when unfolded proteins start to accumulate in the endoplasmic reticulum. This is a structure within cells that works like a production line to fold newly created proteins into their final shapes.
Normally, after the stress response has reduced the number of unfolded proteins, it shuts down once again.
In breast cancer cells with estrogen receptors, however, the stress response remains switched on in preparation for rapid growth and protein production.
The researchers found that ErSO works by further cranking up the stress response to a degree that is fatal for the cancer cells.
Specifically, one of the effects of ErSO on cancer cells is to release a flood of calcium ions from the endoplasmic reticulum within minutes of exposure to the drug.
“This release of calcium triggers the strong and sustained activation of the stress response pathway but does not itself kill the cancer cells,” Prof. Shapiro told Medical News Today.
“It is the subsequent loss of energy in the cancer cell and the inability to produce new proteins that play key roles in the death of the cancer cells after exposure to ErSO,” he explained.
In further preclinical studies, the research team at the University of Illinois plans to investigate whether ErSO is effective against other types of cancer cell that have estrogen receptors in their membranes.
The scientists report that the drug company Bayer now has exclusive rights to develop ErSO as a cancer therapy.
Only clinical trials will reveal whether the drug is an effective and safe treatment for metastatic breast cancer in humans.
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