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Hindering Metastasis with an FDA-Approved Drug

For cancer to spread, it needs a hospitable environment in distant organs. This fertile “soil” can provide a home to circulating malignant cells. Recent research has shown that cancer cells from the primary tumor can help ready this soil by sending out small vesicles that contain a cocktail of molecules that “educate” healthy cells to prepare the target tissues for cancer cells to seed and thrive. Blocking this process offers one strategy to stop metastasis.

New research from Penn’s School of Veterinary Medicine has identified an FDA-approved drug that, when used with surgery, hampers metastasis in an animal model.

Originally developed and approved nearly 65 years ago to control blood pressure, the medication reserpine prevents what are known as tumor-derived extracellular vesicles (TEVs) from fusing to healthy cells and sharing their cargo of disease-promoting molecules, the research team found.

To understand how TEVs influenced the reprogramming of healthy cells to contribute to a metastatic soil, they used a mouse model possessing a protein resistant to degradation. These mice, they found, resisted uptake of TEV, and did not develop lung metastases from melanoma tumors. The team discovered that healthy cells from these mice were less likely to take up the TEVs because the lipid membrane of the vesicle did not efficiently fuse with the lipid membrane of the cell.

“At that point, we started thinking that this continuous swallowing of vesicles by healthy cells is important for the ‘education’ of normal cells,” said Serge Fuchs, professor of cell biology. “That suggested to us that any event that would interrupt this continuous uptake of the vesicles by normal cells might be able to disrupt their reprogramming, and might be antimetastatic.”

The researchers found success in pretreating cells with 25-hydroxycholesterol (25HC), a compound that is induced by interferon and has been shown to disrupt fusion of lipid membranes. But 25HC degrades quickly in the body. The scientists then landed on reserpine.

While reserpine given alone to mice with a melanoma tumor appeared to have little effect on tumor growth and survival, mice that received the reserpine treatment before and after surgery seemed to disrupt the reprogramming of healthy cells. Overall survival of these animals significant improved, and the treatment “virtually eliminated” evidence of lung metastases, the researchers report.

“We are eager to get this into the hands of medical and veterinary oncologists,” Dr. Fuchs said.

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