Cell motility refers to a cell’s ability to migrate between different locations.
When it comes to cancer cells, their increased motility contributes to cancer’s ability to spread through the body, or metastasize, and form new tumors in sometimes remote locations.
Researchers from six institutions — including the Oregon Health and Science University (OHSU) in Portland, Xiamen University in China, the University of Chicago in Illinois, and Northwestern University in Evanston, IL — have spent years trying to find a drug that inhibits cancer cells’ motility without affecting the surrounding healthy cells.
As Dr. Raymond Bergan, of the OHSU, explains, “For the vast majority of cancer — breast, prostate, lung, colon, and others — if it is detected early when it is a little lump in that organ and it has not spread, you will live.”
“And generally, if you find it late, after it has spread throughout your body, you will die,” he adds, explaining that this is why targeting cancer cells’ ability to move is crucial.
“Movement is key,” he goes on, explaining, “[T]he difference is black and white, night and day. If cancer cells spread throughout your body, they will take your life. We can treat it, but it will take your life.”
In 2011, Dr. Bergan and colleagues found a drug called KBU2046 that was able to inhibit motility in human cell models of breast, prostate, lung, and colon cancer in vitro.
In a paper recently published in the journal Nature Communications, the researchers describe their work with KBU2046 on mouse models of cancer, and how they verified whether the drug had a targeted effect, attacking cancer cells only.
In search of a precision drug
The researchers explain that collaborative work across departments and institutions is, ultimately, what allowed them to identify the compound.
Scientists in the chemistry laboratory of Prof. Karl Scheidt, the director of the Center for Molecular Innovation and Drug Discovery at Northwestern University, designed new molecules that might fit the bill.
In turn, Dr. Bergan and his team analyzed these compounds, testing for side effects and assessing whether they would be able to inhibit the movement of cancer cells without affecting their healthy neighbors.
“We’ve taken a clue provided by nature,” notes Prof. Scheidt, “and through the power of chemistry created an entirely new way to potentially control the spread of cancer. It’s been a truly rewarding experience working together as a team toward ultimately helping cancer patients.”
Developing the drug was a gradual process, in which the researchers kept improving on the initial compound, since the team wanted it to act with as much precision as possible.
“We started off with a chemical that stopped cells from moving, then we increasingly refined that chemical until it did a perfect job of stopping the cells with no side effects,” says Prof. Scheidt.
“All drugs have side effects,” he explains, “so you look for the drug that is the most specific as possible. This drug does that.”
A refined mechanism
KBU2046 works by interacting with heat shock proteins, which play vital roles in cell function and can help to protect them from degradation. The compound developed by the research team very specifically influences the proteins’ action so that they can prevent cell motility.
“The way the drug works is that it binds to these cleaner proteins to stop cell movement, but it has no other effect on those proteins,” as Dr. Bergan notes, which is what makes KBU2046’s activity such a promising therapeutic strategy.
Developing such a precise drug, explains Dr. Bergan, required tremendous effort, and it “took [the scientists] years to figure out.”
The team also encountered other stumbling blocks, such as an initial lack of funding due to the unusual nature of the research at the time when the investigators first decided to undertake it.
“Initially, nobody would fund us. We were looking into a completely different way of treating cancer,” Dr. Bergan says.
‘Preventing later-stage disease’
The drug has not yet been tested in humans, but the researchers are hoping that they will be able to conduct trials eventually.
However, they believe that doing so will require a large amount of money — around $5 million — and that it will take about 2 years until they reach a point at which they are satisfied with their preliminary work on the compound.
For now, the researchers are trying to get funds that will allow them to conduct investigational new drug studies, which are a required step in preparation for clinical trials.
“The eventual promise of this research is that we’re working toward developing a therapeutic that can help manage early stage disease, preventing patients from getting the more incurable later-stage disease,” says study co-author Ryan Gordon, of the OHSU.
So far, the researchers are pleased with the results they have obtained, and with the fact that they persisted in pushing forward with an approach that has not always been popular.
“We used chemistry to probe biology to give us a perfect drug that would only inhibit the movement of cancer cells and wouldn’t do anything else. That basic change in logic led us to do everything we did.”
Dr. Raymond Bergan
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