Breast cancer therapy

A new approach to treating breast cancer kills 95-100% of cancer cells in mouse models of human estrogen-receptor-positive breast cancers and their metastases in bone, 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 Urbana-Champaign, the research team reports the findings in the journal Science Translational Medicine. “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,” said U. of I. biochemistry professor David Shapiro, who led the research with Illinois chemistry professor Paul Hergenrother. “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,” Shapiro said.  The activity of ErSO depends on a protein called the 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 anticipatory Unfolded Protein Response, or a-UPR, spurs the production of proteins that protect the cell from harm.

“Because this pathway is already on in cancer cells, it’s easy for us to overactivate it, to switch the breast cancer cells into lethal mode,” said graduate student Darjan Duraki, who shares first-author status on the new report with graduate student Matthew Boudreau. While the original compound prevented breast cancer cells from growing, it did not rapidly kill them, and it had undesirable side effects. He researchers focused on a search for a much more potent small molecule that would target the a-UPR. Their analysis led to the discovery of ErSO, a small molecule that had powerful anticancer properties without detectable side effects in mice, further tests revealed. “This anticipatory UPR is estrogen-receptor dependent,” Hergenrother said. “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. But it’s super-potent against estrogen-receptor-positive cancer cells.”

Further studies in mice showed 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 efficacy, the researchers found.

Source: University of Illinois Urbana-Champaign news release