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.
โEven 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,โ said U. of I.ย biochemistryย professorย David Shapiro, who led the research with Illinoisย chemistryย professorย Paul Hergenrother. โIt 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,โ Shapiro said. (Watch aย videoย about the results.)
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.
โThe a-UPR is already on, but running at a low level, in many breast cancer cells,โ Shapiro said. โIt turns out that this pathway shields cancer cells from being killed off by anti-cancer drugs.โ
Shapiro and former U. of I. medical scholar Neal Andruska first identified the a-UPR pathway in 2014 andย reportedย the development of a compound that pushed the a-UPR pathway into overdrive to selectively kill estrogen-receptor-containing breast cancer cells.
โBecause this pathway is already on in cancer cells, itโs easy for us to overactivate it, to switch the breast cancer cells into lethal mode,โ 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. For the new research, Shapiro and Hergenrother worked together 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.
โThis anticipatory UPR is estrogen-receptor dependent,โ Hergenrother said. โThe unique thing about this compound is that it doesnโt touch cells that lack the estrogen receptor, and it doesnโt affect healthy cells โ whether or not they have an estrogen receptor. But itโs super-potent against estrogen-receptor-positive cancer cells.โ
ErSO is nothing like the drugs that are commonly used to treat estrogen-responsive cancers, Shapiro said.
โThis is not another version of tamoxifen or fulvestrant, which are therapeutically used to block estrogen signaling in breast cancer,โ he said. Even though it binds to the same receptor that estrogen binds, it targets a different site on the estrogen receptor and attacks a protective cellular pathway that is already turned on in cancer cells, he said.
โSince about 75% of breast cancers are estrogen-receptor positive, ErSO has potential against the most common form of breast cancer,โ Boudreau said. โThe amount of estrogen receptor needed for ErSO to target a breast cancer is very low, so ErSO may also work against some breast cancers not traditionally considered to be ER-positive.โ
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.
ErSO also worked quickly, even against advanced, human-derived breast cancer tumors in mice, the researchers report. Often within a week of exposure to ErSO, advanced human-derived breast cancers in mice shrank to undetectable levels.
โMany of these breast cancers shrink by more than 99% in just three days,โ Shapiro said. โErSO is fast-acting and its effects on breast cancers in mice are large and dramatic.โ
The pharmaceutical company Bayer AG hasย licensed the new drugย and will explore its potential for further study in human clinical trials targeting estrogen-receptor-positive breast cancers, the researchers said. The researchers will next explore whether ErSO is effective against other types of cancers that contain estrogen receptor.
Study co-authors at the U. of I. also includeย veterinary clinical medicineย professorย Timothy Fan,ย molecular and integrative physiologyย professorย Erik Nelson, and professor emeritus ofย pathologyย Edward Roy. Fan, Hergenrother, Nelson, Shapiro and Roy are affiliates of theย Cancer Center at Illinois. Fan, Hergenrother and Nelson also are affiliated with theย Carl R. Woese Institute for Genomic Biologyย at Illinois and Hergenrother and Fan are faculty in theย Carle Illinois College of Medicineย at the U. of I.
Funders of this work include the University of Illinois, the U.S. Department of Defense, the National Institutes of Health, and Systems Oncology. The U. of I. has filed patents on some compounds described in the study.
Editorโs notes:
To reach David Shapiro, emailย [email protected].
To reach Paul Hergenrother, emailย [email protected].
The paper โA small-molecule activator of the unfolded protein response eradicates human breast tumors in miceโ is availableย onlineย and from theย U. of I. News Bureau.
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