New drug target for Ewing’s sarcoma discovered

Scientists at Cold Spring Harbor Laboratory (CSHL) have discovered a new drug target for Ewing’s sarcoma, a rare type of cancer commonly diagnosed in children and young adults. Their experiments show that the cells causing this cancer can be reprogrammed with the flick of a genetic switch.

Turning off one protein forces cancer cells to assume a new identity and act like normal connective tissue cells, a radical change that limits their growth. This discovery suggests that researchers may be able to stop Ewing’s sarcoma by developing a drug that blocks a protein known as ETV6.

Ewing’s sarcoma causes tumors to grow in the bones or soft tissues around them. Once a tumor begins to spread to other parts of the body, it can be very difficult to stop the progression of the disease. Even for patients who have positive results, treatment for Ewing’s sarcoma often causes toxic side effects. New therapies are badly needed, says CSHL professor Christopher Vacock, who led the research on ETV6.

Vakoc and colleagues got excited about ETV6 when their experiments revealed that Ewing’s sarcoma cells appear to be uniquely dependent on this protein.

This protein is present in all cells. But when you scramble the protein, most normal cells don’t care. The process by which sarcomas form turns this ETV6 molecule—this relatively harmless, harmless protein that doesn’t do much—into something that now controls the cancer cell’s decision to die. “

Christopher Vakok, CSHL Professor

Postdoctoral researcher Yuan Zhao works in Vakuk’s lab. When GAO blocked ETV6 in lab-grown Ewing’s sarcoma cells, they experienced dramatic transformation. “The sarcoma cell becomes a normal cell again,” she says. “The shape of the cell changes. The behavior of the cells changes. A lot of cells will stop growing. It’s really an explosive effect.”

Vakoc and Gao hope other researchers will use what they’ve learned to begin exploring potential treatments for Ewing’s sarcoma that work by turning off ETV6. They say their biochemical analyses, which identify specific points in the ETV6 protein that are central to its function in cancer cells, could help guide drug development. Since their experiments showed that most cells are not affected by the loss of ETV6 activity, they are optimistic that such a drug might be able to eradicate cancer cells while causing few, if any, side effects.


Journal reference:

Gao, Y. et al. (2023) Dependence of ETV6 in Ewing’s sarcoma by enhanced anti-activation mediated by EWS-FLI1. Nature Cell Biology.

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