- 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 medicine called ErSO not only kills primary breast tumors, but also kills metastatic cancer in bone and the brain, liver, and lungs.
- The cancer cells do not appear to be resistant to ErSO, unlike current drug treatments.
- This new drug works by overactivating a cellular mechanism that usually protects the cells.
Every year, around 2.3 million women worldwide are diagnosed to have breast cancer.
Approximately three-quarters of all cases are a cancer 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 to the drug.
Scientists from the University of Illinois Urbana-Champaign are working on a new type of drug that could prevent the resistance to drug.
This drug, called ErSO, works by overactivating a stress response mechanism. This mechanism normally protects cancer cells from harm. When this mechanism goes into overdrive, however, it kills the cells.
In mouse models which have estrogen receptor-positive breast cancer, this 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 can survive and enable tumors to regrow over several months, the tumors that regrow remain completely sensitive to retreatment with ErSO,” says David Shapiro, a professor of biochemistry, who co-led this research with chemistry professor Paul Hergenrother.
“It is striking that ErSO caused the rapid destruction of most cancer metastases in lung, bone, liver, and caused dramatic shrinkage of cancer metastases in brain, because tumors that have spread to other parts in the body are responsible for most breast cancer deaths”, professor Shapiro says.
In previous research, another drug which 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 journal.
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. These drugs work by blocking or inhibiting the estrogen receptor.
But the new drug ErSO binds to a different part of the estrogen receptor. This action has the effect of overactivating the stress response pathway, with fatal consequences for the cells.
Crucially, this 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,” professor Hergenrother says.
“But this drug is super potent against estrogen receptor-positive cancer cells,” he says.
In mice, metastatic breast cancers derived from human cells often shrank to undetectable levels within a week of treatment with ErSO.
“Many of these breast tumors shrink by more than 99% in just 3 days. 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 starts 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 causes the strong and sustained activation of the stress response pathway, but does not itself kill the cancer cells,” professor Shapiro says.
“The subsequent loss of energy in the cancer cell and the inability to produce new proteins play key roles in the death of the cancer cells after exposure to ErSO,” he explained.
In further pre-clinical 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 this drug is an effective and safe treatment for metastatic breast cancer in humans.