New approach kills breast cancer in mice

A new approach to treating breast cancer kills 95-100% of cancer cells in mouse models of estrogen receptor positive human breast cancers and their metastases to bones, brain, liver and lungs. The newly developed drug, called ErSO, quickly shrinks even large tumors to undetectable levels.

Led by scientists at the University of Illinois at Urbana-Champaign, the research team reports the findings in the journal Scientific translational medicine.

“Even when a few breast cancer cells survive, allowing tumors to grow back over several months, the tumors that grow back remain completely responsive to reprocessing with ErSO,” said biochemistry professor David Shapiro, who led the research with the chemistry of Illinois. professor Paul Hergenrother. “It is striking that ErSO caused the rapid destruction of most lung, bone and liver metastases and dramatic narrowing of brain metastases, as tumors that have spread to other sites in the body are responsible for most of the breast cancer deaths, ”Shapiro said.

The activity of ErSO depends on a protein called estrogen receptor, which is present in a high percentage of breast tumors. When ErSO binds to the estrogen receptor, it upregulates a cellular pathway that prepares cancer cells for rapid growth and protects them from stress. This pathway, called the unfolded protein anticipatory response, or a-UPR, stimulates the production of proteins that protect the cell from damage.

“A-UPR is already activated, but works at a low level, in many breast cancer cells,” Shapiro said. “It turns out that this pathway prevents cancer cells from being killed by anti-cancer drugs.”

Shapiro and the former medical researcher at the University of I. Neal Andruska first identified the a-UPR pathway in 2014 and reported the development of a compound that pushed the a-UPR pathway into overdrive to selectively kill breast cancer cells containing estrogen receptors.

“Because this pathway is already activated in cancer cells, it is easy for us to over-activate it, to put breast cancer cells into lethal mode,” said graduate student Darjan Duraki, who shares the status of premier author of the new report with graduate student Matthew Boudreau.

While the parent compound prevented breast cancer cells from growing, it did not kill them quickly and had unwanted side effects. For the new research, Shapiro and Hergenrother worked together to find a much more potent small molecule that would target a-UPR. Their analysis led to the discovery of ErSO, a small molecule that had potent anticancer properties with no detectable side effects in mice, further tests revealed.

“This anticipated UPR is estrogen receptor dependent,” Hergenrother said. “The peculiarity of this compound is that it does not affect cells lacking an estrogen receptor and does not affect healthy cells, whether or not they have an estrogen receptor. But it’s super potent against estrogen receptor positive. cancer cells.”

ErSO is nothing like drugs commonly used to treat estrogen receptor positive cancers, Shapiro said.

“This is not another version of tamoxifen or fulvestrant, which are used therapeutically to block estrogen signaling in breast cancer,” he said. Even though it binds to the same receptor as estrogen, it targets a different site on the estrogen receptor and attacks a protective cellular pathway that is already activated in cancer cells, he said.

“Since approximately 75% of breast cancers are estrogen receptor positive, ErSO has potential against the most common form of breast cancer,” Boudreau said. “The amount of estrogen receptors required for ErSO to target breast cancer is very low, so ErSO may also work against some breast cancers that are not traditionally considered ER-positive.”

Other studies in mice have shown that exposure to the drug had no effect on their reproductive development. And the compound was well tolerated in mice, rats and dogs given doses much higher than required for therapeutic effectiveness, the researchers found.

ErSO also worked quickly, even against advanced human breast cancer tumors in mice, the researchers report. Often within a week of exposure to ErSO, advanced human breast cancers in mice have decreased to undetectable levels.

“A lot of these breast cancers are reduced by over 99% in just three days,” Shapiro said. “ErSO is fast acting and its effects on breast cancer in mice are significant and dramatic.”

Pharmaceutical company Bayer AG has cleared the new drug and will explore its potential for further study in human clinical trials targeting estrogen receptor positive breast cancers, the researchers said. The researchers will then examine whether ErSO is effective against other types of cancer containing estrogen receptors.