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Scientists have long known that when a cancerous clump of cells starts to starve, that’s when things can get dangerous. Searching for nutrients, the cancer can begin to spread throughout the body, enabled by certain proteins in a family known as transcription factors. But for decades, efforts to make a drug to target those transcription factors—and thus stop the growth of tumors—had failed.
A study from the University of Chicago, however, tested a new way to target those “undruggable” transcription factors by building a new kind of synthetic molecule.
The first results, published in Nature Chemical Biology, are promising; the scientists hope to be able to use the invention as a tool to learn more about the basic rules that govern cancer cells and biology. But they also hope that, years down the road, the approach could form the basis of a new set of treatment options for cancer.
“The idea of targeting transcription factors is like leaving the solar system for humans—it’s been at the top of the list for cancer therapies for a long time,” said Raymond Moellering, professor of chemistry at UChicago and co-senior author on the study. “While there’s a long way to go, this is an entirely new approach and we’re very excited about what we’ve seen so far.”
Tumors and transcription
All cells, including tumor cells, need oxygen and nutrients. For a time, a tumor survives on nearby blood vessels. But because it is programmed to expand no matter the cost, at some point the tumor outgrows what those blood vessels can provide.
“The distress triggers a set of proteins called hypoxia-inducible transcription factors, which normally help cells respond when they’re oxygen-deprived,” explained Marsha Rosner, the Charles B. Huggins Distinguished Service Professor in the Ben May Department of Cancer Research at UChicago and co-senior author on the study. “But in this case, the transcription factors enable the tumor cells to spread to other locations in the body, which is what we call metastasis.”
Cancer scientists have known this for decades, and they would love to have a treatment to stop this process by blocking the relevant transcription factors, known as HIFs. But designing a drug to stop transcription factors has been fiendishly difficult.
That was, until Moellering’s team came up with a revolutionary approach in 2022.
Normally, when researchers are trying to make a drug to target a protein involved in disease, they try to design a drug to target the protein itself. But this had proved difficult because transcription factors have an unusual configuration that makes them hard to bind to. So Moellering’s lab took a different tack.
They knew that in order to work, transcription factors have to latch onto a particular stretch of DNA, which they do with a little set of molecular “claws.” So, the team built a synthetic molecule consisting of a mimic of the claws, which allows the molecule to latch onto the same stretch of DNA as the natural transcription factor does. This blocks the rogue proteins from altering cell instructions.
The scientists had tested this approach on other kinds of transcription factors, but they now tried applying this to the particular transcription factors that respond to cell starvation.
They built a new molecule that specifically targeted a well-known factor involved in cancer, called XBP-1, and tested it in mice against triple-negative breast cancer, which is a particularly aggressive type of cancer with fewer current treatments available.
The molecule successfully shrunk the tumors and reduced metastasis, with no noticeable toxic side effects.
Unlocking a new strategy
The approach turned out to have even more benefits than originally planned, explained Long Nguyen, a postdoctoral researcher in Rosner’s lab at UChicago and co-first author of the paper along with Zeyu Qiao (Ph.D’24).
“There are multiple transcription factors. We saw that if this molecule was sitting on DNA, it blocked all transcription factors from carrying out their functions at those DNA sites,” he said.
“We know that transcription factors can stand in for each other, so a drug that just hits one could turn into whack-a-mole. But if we can block the spot where they both bind, that’s a different approach,” said Moellering.
Many steps remain before the drug could be used in humans, but the results are encouraging, the scientists said. And in the meantime, they hope to use the molecules in experiments to discover more information about how transcription factors work in cancer—and other diseases.
“HIFs are responsible for responding to low oxygen levels, such as what happens in the brain during oxygen deprivation, so they are really fundamental parts of the cell,” said Rosner. “This is a valuable tool for understanding that process.”
Additional authors on the paper were UChicago researchers Dongbo Yang, Christopher Dann, Deborah Thomas, Madeline Henn, Andrea Valdespino, Colin Swenson, and Scott Oakes.
Citation: “Direct inhibition of tumor hypoxia response with synthetic transcriptional repressors.” Qiao and Long et al, Nature Chemical Biology, Aug. 30, 2024.
Funding: U.S. Department of Defense, University of Chicago Comprehensive Cancer Center, National Institutes of Health, Fitch Scholarship Fund, V Foundation for Cancer Research, American Cancer Society, Ullman Family Team Science Award.
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