A new study from the University of Notre Dame shows drugs used to treat high cholesterol could interfere with the way breast cancer cells adapt to the microenvironment in the brain, preventing the cancer from taking hold. Patients with breast cancer who experience this type of metastasis typically survive for only months after the diagnosis.
Statins, a group of drugs commonly prescribed for those with high cholesterol, were shown to interfere with a pathway that allows a cancer cell to recycle cell surface proteins in ways that make it easier to live within the brain.
“It normally takes a decade to develop new medications. Instead of waiting, we can repurpose medications people are already taking,” said Siyuan Zhang, the Dee Associate Professor in the Department of Biological Sciences and the Mike and Josie Harper Cancer Research Institute, and principal investigator of the study published in Nature Communications. “Statins are relatively safe drugs, and they can even be given, if doctors choose, to try to prevent metastasis.”
The protein Rab11b brings “recycled” proteins back to the surface like a fast-moving Ferris wheel, Zhang said. Statins suppress breast cancer survival in the brain by inhibiting the ability of Rab11b to recycle surface proteins. The surface of the metastatic tumor cell then becomes less sticky because of this reduced recycling. This limits the survival of cancer cells, and ultimately slows the rate of tumor colonization in the brain microenvironment.
To complete the research, Zhang’s lab completed gene profiling to screen for genes that were functionally important in inhibiting the way tumor cells adapted to the brain, Zhang said. Then, they used a fruit fly (Drosophilia melanogaster) tumor model to perform a genetic tumor growth screen, allowing the team to quickly narrow down a subset of genes that might be important for tumor formation in the brain.
“We knew Rab11b sits downstream of an enzyme that is important for cholesterol synthesis, so once we recognized its role, we thought that statins could knock Rab11b back from its role in pushing the other proteins up to the surface in metastatic breast cancer in the brain,” said Zhang.
Zhang seeks uses of already-FDA-approved drugs to target cancer metastasis because they are already known to be safe, which allows for quicker testing without waiting several years for new therapeutics to be developed and tested.
Collaborators on the study include lead author Erin Howe, a postdoctoral fellow in Zhang’s lab; Jeremiah J. Zartman, associate professor of Chemical and Biomolecular Engineering, Crislyn D’Souza-Schorey, the Morris Pollard Professor in the Department of Biological Sciences, and Jun Li, associate professor in the Department of Applied and Computational Mathematics and Statistics at Notre Dame; Victoria Hedrick and Uma K. Aryal at Purdue University; Ian Guldner, Alicia Lamere and James Clancy; former Notre Dame graduate students Miranda Burnette and Patricia M. Schnepp; and former Notre Dame undergraduate student Melanie Justice.
Funding for the project was provided through an Advancing Basic Cancer Research Grant from the Walther Cancer Foundation, the Department of Defense and the National Institutes of Health.