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C26 treatment (right panel) reduced the number of metastatic tumors in the lungs of mice injected with HSNCC cells compared to controls (left panel)
.
A new treatment stops the growth of metastatic tumors in mice by forcing cancer cells into a dormant state where they cannot proliferate
.
The research, published in the Journal of Experimental Medicine (JEM), could lead to new treatments to prevent the recurrence or spread of various types of cancer, including breast cancer and head and neck squamous cell carcinoma (HNSCC).
Many cancer patients recur years or decades after initial treatment and develop new tumors that regrow in the same location or metastasize to other parts of the body
.
These secondary tumors are often resistant to treatment and arise from individual tumor cells that may lie dormant for extended periods of time before being activated and proliferating
In a previous study, Maria Soledad Sosa of the Icahn School of Medicine at Mount Sinai and Julio Aguirre-Ghiso, now of the Einstein College of Medicine, found that the ability of cancer cells to remain dormant is controlled by a protein called NR2F1
.
The receptor protein can enter the nucleus and turn many genes on or off, activating a program that stops cancer cells from proliferating
"We therefore believe that activation of NR2F1 using small molecules may be an attractive clinical strategy to induce dormancy in cancer cells and prevent recurrence and metastasis," explains Aguirre-Ghiso
.
In the new JEM study, Sosa and Aguirre-Ghiso's team used a computer-based screening method to identify a drug called C26, which activates NR2F1
.
The researchers found that treating patient-derived HNSCC cells with C26 increased levels of NR2F1 and prevented cell proliferation
The researchers then tested whether C26 could prevent metastasis in mice
.
Animals injected with patient-derived HNSCC cells often develop large primary tumors that spread to the lungs after the primary tumor has been surgically removed
Sosa and Aguirre-Ghiso's team determined that by activating NR2F1, C26 forces cancer cells into a long-term dormant state characterized by a unique pattern of gene activity
.
Tumors from cancer patients showed similar patterns of gene activity and tended to persist for longer without recurrence, suggesting that inducing this dormant program with the C26 drug might be effective in humans
"Drugs that activate NR2F1 may be particularly useful in breast cancer," Sosa said
.
"ER-positive tumors have higher levels of NR2F1 compared to ER-negative tumors, and activating NR2F1 may be able to inhibit the reawakening of dormant cancer cells that were kept in this state by anti-estrogen therapy
"Overall, our study reveals a mechanism-based and rationally designed strategy to exploit NR2F1-activated dormancy as a therapeutic option to prevent metastatic relapse," said Aguirre-Ghiso
.
Reference: "An NR2F1-specific agonist suppresses metastasis by inducing cancer cell dormancy" by Bassem D.
Khalil, Roberto Sanchez, Tasrina Rahman, Carolina Rodriguez-Tirado, Stefan Moritsch, Alba Rodriguez Martinez, Brett Miles, Eduardo Farias, Mihaly Mezei, Ana Rita Nobre, Deepak Singh, Nupura Kale, Karl Christoph Sproll, Maria Soledad Sosa and Julio A.
Aguirre-Ghiso, 23 November 2021, Journal of Experimental Medicine .
DOI: 10.
1084/jem.