An experimental treatment could prevent metastasis ‘sleeping’ to cancer cells

A new therapeutic approach prevents the growth of metastatic tumors in mice by forcing cancer cells into a state of torpor in which they are unable to proliferate. The study, published in the Journal of Experimental Medicine, could lead to new treatments that prevent the reappearance or spread of various types of Cancersuch as breast and head and neck squamous cell carcinoma (HNSCC).

Many cancer patients relapse, often years or decades after their initial treatment, and develop (spread) to other parts of the body.

These secondary tumors are usually resistant to treatment and are produced by individual tumor cells that can remain dormant for long periods before reactivate to begin proliferating again. Therefore, relapse of patients could be prevented if researchers could find a way to

In an earlier study, María Soledad Sosa, from the Icahn del Monte Sinai School of Medicine, and Julio A. Aguirre-Ghiso, now at the Albert Einstein School of Medicine, discovered that the ability of cancer cells to remain dormant

This receptor protein can enter the nucleus of the cell and turn numerous genes on or off to activate a program that prevents cancer cells from proliferating. NR2F1 levels are usually low in primary tumors but are high in latent disseminated cancer cells. Levels of the NR2F1 protein decline again when cancer cells begin to proliferate again and form recurrent or metastatic tumors.

“Therefore, we think that the activation of NR2F1 by a small molecule could be an attractive clinical strategy forand prevent recurrence [recurrencia] and metastasis ”, Aguirre-Ghiso explains.

In this new study, the Sosa and Aguirre-Ghiso teams used a computer screening method to identify a drug, called C26, that activates NR2F1. The researchers found that treatment of HNSCC cells derived from patients with C26 increased NR2F1 levels and stopped cell proliferation.

Next,. Animals injected with patient-derived HNSCC cells often form large primary tumors that spread to the lungs after surgical removal of the original tumor.

Treatment with C26 reduced the size of the primary tumors and, after surgery, new doses of C26 completely blocked the growth of metastatic tumors. In contrast, the rodents’ lungs contained only a few inactive, disseminated cancer cells, unable to proliferate even after treatment was stopped.

The Sosa and Aguirre-Ghiso teams determined that, by activating the long-lasting NR2F1, characterized by a unique pattern of gene activity.

Cancer patients whose tumors show a similar pattern of gene activity tend to go longer without relapse, suggesting that inducing this latency program with C26 drugs might be effective in humans.

“Drugs that activate NR2F1 could be especially useful in breast cancer. NR2F1 is highly enriched in ER-positive tumors compared to ER-negative ones, and the activation of NR2F1 could be able to suppress the awakening of latent cancer cells maintained in this state by anti-estrogen therapies ”, says Sosa.

However, since C26 treatment raises NR2F1 levels, the approach could also be useful for other cancers with inherently low levels of the receptor protein. “Overall, our study reveals a rationally designed, mechanism-based strategy to exploit NR2F1-activated latency as a therapeutic option to prevent metastatic relapse.” Aguirre-Ghiso concludes.

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