Rhabdomyosarcoma (RMS) is a rare type of cancer that forms in soft tissue. RMS can occur at any age, but it most often affects children. Treatment usually involves chemotherapy, surgery, and radiation procedures. Now, new research by scientists at Cold Spring Harbor Laboratory demonstrates differentiation therapy as a new treatment option for RMS.

The findings are published in the journal Proceedings of the National Academy of Sciences in an article titled, “Myo-differentiation reporter screen reveals NF-Y as an activator of PAX3–FOXO1 in rhabdomyosarcoma.”

“Every successful medicine has its origin story. And research like this is the soil from which new drugs are born,” said Cold Spring Harbor Laboratory professor Christopher Vakoc, MD, PhD.

“Recurrent chromosomal rearrangements found in RMS produce the PAX3–FOXO1 fusion protein, which is an oncogenic driver and a dependency in this disease,” the researchers wrote. “One important function of PAX3–FOXO1 is to arrest myogenic differentiation, which is linked to the ability of RMS cells to gain an unlimited proliferation potential. Here, we developed a phenotypic screening strategy for identifying factors that collaborate with PAX3–FOXO1 to block myo-differentiation in RMS.”

For six years, Vakoc’s lab has been on a mission to transform sarcoma cells into regularly functioning tissue cells.

Vakoc and his team created a new genetic screening technique. Using genome-editing technology, they hunted down genes that, when disrupted, would force RMS cells to become muscle cells. That’s when a protein called NF-Y emerged. With NF-Y impaired, the scientists witnessed an astonishing transformation.

“The cells literally turn into muscle,” Vakoc said. The tumor loses all cancer attributes. They’re switching from a cell that just wants to make more of itself to cells devoted to contraction. Because all its energy and resources are now devoted to contraction, it can’t go back to this multiplying state.”

This newfound relationship between NF-Y and RMS may set off the chain reaction needed to bring differentiation therapy to patients. And the mission doesn’t stop at RMS. The technology could be applicable to other cancer types. If so, scientists may someday work out how to turn other tumors into healthy cells.

“This technology can allow you to take any cancer and go hunting for how to cause it to differentiate,” Vakoc explained. “This might be a key step toward making differentiation therapy more accessible.”

Previously, Vakoc and his team succeeded in transforming Ewing sarcoma cells into healthy tissue cells.

The new findings may offer patients a new treatment option and may lead to further studies using differentiation therapy.

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