A new therapeutic approach prevents metastatic tumor growth in mice by placing cancer cells in a dormant mode and preventing them to proliferate. The study, which was published on November 23 in the Journal of Experimental Medicine ( JEM) could provide new treatments to stop the recurrence or spreading of various types of cancer, including breast cancer and the head and neck squamous cell carcinoma (HNSCC).
Many cancer patients experience a relapse after treatment. They develop new tumors in the same region or spread to other parts of their body. Secondary tumors are typically resistant and are typically caused by individual tumor cells. They can remain dormant for long periods of time before they are activated to multiply again. Researchers may be able stop relapses by finding a way to keep the remaining cancerous cells dormant.
In a prior study, Maria Soledad Sosa from the Icahn School of Medicine at Mount Sinai and Julio A. Aguirre-Ghiso, now at the Albert Einstein College of Medicine discovered that the capacity of cancer cells to rest is controlled by a protein known as NR2F1. This receptor protein is able to enter the cell’s nucleus to turn on or off several genes and activate the process that prevents cancer cells from proliferating. The levels of NR2F1 are typically low in primary tumors , but are increased in dormant cancer disseminated cells. The levels of NR2F1 protein then decline yet again when cancerous cells begin to proliferate and form recurrent or metastatic tumors.
We believed that activating NR2F1 by small molecules could be a viable clinical strategy to induce dormancy in cancer cells and prevent recurrence or metastasis.
Julio A. Aguirre-Ghiso Albert Einstein College of Medicine
In the latest JEM study, Sosa and Aguirre-Ghiso’s teams employed a computer-based screening method to identify a drug, named C26, that activates the NR2F1. The researchers discovered that treating patients’ HNSCC cells with C26 increased the levels of NR2F1 and stopped cell proliferation.
The researchers then investigated whether C26 would prevent metastasis in mice. Patients-derived HNSCC cells are often implanted into animals to create large primary tumors. The tumors can are able to spread to the lungs after the primary tumor was removed. C26 treatment decreased the size of primary tumors and stopped the growth of metastatic tumors after surgery. Instead, the lungs of the rodent contained only a few dormant cancer cells that were not able to multiply even after cessation of the treatment.
Sosa and Aguirre-Ghiso’s teams determined that, by activating NR2F1, C26 forces cancer cells into a long-lived state of dormancy characterized by a unique pattern of gene activity. Cancer patients whose tumors display a similar pattern of gene activity are more likely to live longer and not relapse, suggesting that inducing this dormancy-related process using C26-type drugs could be effective in humans.
Sosa claims that drugs that activate NR2F1 might be particularly effective in breast cancer. “NR2F1 is more abundant in ER positive tumors than ER negative tumors. Thus activating NR2F1 may be able suppress the reawakening of dormant cells that are kept in a dormant state by antiestrogen treatments. However, because C26 treatment elevates the levels of NR2F1 this approach could also be beneficial for other cancers with inherently low levels of the receptor protein.
Aguirre Ghiso states, “Overall our study reveals an underlying mechanism that is rationally designed strategy for exploiting NR2F1 activated dormancy to prevent metastatic relapse.”
Khalil, B.D. and. al. (2021). An NR2F1-specific agonist inhibits metastasis and induces cancer cell dormancy. Journal of Experimental Medicine. doi.org/10.1084/jem.20210836.
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