New approach eradicates breast cancer in mice

wallycat

https://www.sciencedaily.com/releases/2021/07/2107...

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.

"The a-UPR is already on, but running at a low level, in many breast cancer cells," Shapiro said. "It turns out that this pathway shields cancer cells from being killed off by anti-cancer drugs."

Shapiro and former U. of I. medical scholar 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 estrogen-receptor-containing breast cancer cells.

"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. 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.

"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."

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

"This is not another version of tamoxifen or fulvestrant, which are therapeutically used to block estrogen signaling in breast cancer," 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.

"Since about 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 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."

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.

"Many of these breast cancers shrink by more than 99% in just three days," Shapiro said. "ErSO is fast-acting and its effects on breast cancers in mice are large and dramatic."

The pharmaceutical company Bayer AG has licensed 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 next explore whether ErSO is effective against other types of cancers that contain estrogen receptor.

Study co-authors at the U. of I. also include veterinary clinical medicine professor Timothy Fan, molecular and integrative physiology professor Erik Nelson, and professor emeritus of pathology Edward Roy. Fan, Hergenrother, Nelson, Shapiro and Roy are affiliates of the Cancer Center at Illinois. Fan, Hergenrother and Nelson also are affiliated with the Carl R. Woese Institute for Genomic Biology at Illinois and Hergenrother and Fan are faculty in the Carle Illinois College of Medicine 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.

PiperKay

Wow. This does not seem real. Let's hope the results are replicated.

mommamonaster

Apparently it works on very low levels of ER positivity, so even some cancer that are treated as ER negative could still benefit from it.

elenas401

the BBC article on ErSO said if all goes well, it will available in a DECADE!!! Seriously!!?? Why should it take so long?They got a vaccine out for a novel coronavirus in less than a year. Why not do an emergency approval for this like they did the vaccine and let people who have no options try it. It should not drag out so long.

exbrnxgrl

elenas401,

The mRNA technology that went into the Covid19 vaccines had been developed and used for other viruses many years ago. The “new" part was adjusting it to fit COVID19. So much of the foundation for this vaccine already existed and the fact that it just needed tweaking was what allowed for it's rapid development. Over 600,000 folks have died from it in the US alone which more than justified it's emergency use authorization. Although losing 40,000. a year to bc is awful, it doesn't come close to emergency status.

As I mentioned, mRNA technology is not new which is what makes it very different from something that shows promise in mouse trials. I am also stage IV so completely understand your frustration but comparing the rapidity of the development of a COVID19 vaccine to mouse model trials is not really valid. Don't forget that COVID19 has been identified as the virus which causes the disease. It's still not clear what causes breast cancer.

I am sorry to sound like a Debbie Downer over this. Mouse trials are just the beginning and a cause for hope. Finding out if the same thing works in humans is a different ball of wax. Here is an article (Harvard) that speaks to this:

https://sitn.hms.harvard.edu/flash/2020/why-drugs-tested-in-mice-fail-in-human-clinical-trials/.

elenas401

Even as I wrote what I did out of frustration, I think I kind of understood what you said about the difference between getting the virus vaccine out and a new treatment for MBC. Hopefully things will go well developing ErSO. Thanks you for your thoughts. I wish you well in dealing with your Stage 4.

kathabus

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Over 9 million people die of cancer each year. It’s okay to get frustrated. Our lives are on the line. I think many of us have had the same wonder if we could be doing more as a country about OUR pandemic. I know it’s complicated and not straightforward. 😔

While I understand the odds might be low for the success of ErSO…..here’s to hoping!!! Even if it fails I hope it brings us closer to something that is a success. ✌🏼