Study Identifies Potential Drug Combination for Ewing Sarcoma

November 9, 2017, by NCI Staff

Ewing sarcoma cells with gene fusions (arrows) involving the EWS gene.
Credit: Zhang N, et al. PLOS ONE April 2016. https://doi.org/10.1371/journal.pone.0153546CC BY 4.0

Researchers have identified a two-drug combination that slows the growth of Ewing sarcoma tumors in mice better than either drug alone.

One of the drugs, vincristine, is a chemotherapyagent that is part of the standard treatment for patients with Ewing sarcoma. The other, YK-4-279, is an experimental drug that targets an abnormality, called a fusion protein, that is commonly found in Ewing sarcoma tumors.

The researchers’ findings, published October 3 in Science Signaling, showed that, when combined, the two drugs work together to kill more cancer cellsthan either treatment alone.

“It is essentially like the old boxing analogy of giving a one-two punch,” said Jeffrey Toretsky, M.D., of Georgetown University, the study’s senior investigator.

The drug combination potentially could be an effective treatment for patients with Ewing sarcoma, the researchers wrote.

“There’s a lot of excitement about agents that target the fusion protein,” said Christine Heske, M.D., a researcher in the Pediatric Oncology Branch of NCI’s Center for Cancer Research, who was not involved in the study.

Researchers are also excited, she continued, about “studying these drugs in combination with other drugs so that we can make rational decisions about how to bring them into standard therapy.”

Combining Drugs to Kill More Cancer Cells

Ewing sarcoma is a type of cancer that forms in bone or surrounding soft tissue, most often in teenagers and young adults. Most patients with Ewing sarcoma that has not spread respond well to treatment with a combination of chemotherapies.

But for patients whose cancer has spread to distant locations or has come back after initial treatment, the chance of survival is low, Dr. Heske explained.

The growth of nearly all Ewing sarcoma tumors is driven by a fusion protein (the product of a fusion gene), most commonly by one called EWS-FLI1.

For many years, scientists considered EWS-FLI1 “undruggable” because it is not an enzyme—proteins that tend to be easier to target. EWS-FLI binds to other proteins to affect gene expression. In 2009, Dr. Toretsky and his colleagues discovered YK-4-279, a compound that prevents EWS-FLI1 from controlling gene expression.

Although YK-4-279 kills Ewing sarcoma cells in lab experiments, “there are very few drugs that, by themselves, cure patients,” said Dr. Toretsky. Different drugs are often combined to have a stronger effect, he explained.

For their new study, the researchers treated Ewing sarcoma cells with 69 different cancer drugs, both alone and in combination with YK-4-279. They analyzed how well each combination killed the cancer cells, compared with the individual drugs.

The researchers looked specifically for combinations that had far more than just an additive effect—that is, the combination was synergistic.

YK-4-279 was synergistic with 19 different drugs, the investigators found. They noted that three of the 19 stop cancer growth by interfering with cell division. They also tested other drugs that block cell division in a slightly different way, but they were not synergistic with YK-4-279.

“We saw a nice pattern in the synergy and the drugs’ mechanism, and to us that warranted further investigation,” Dr. Toretsky explained. Of those three drugs, they focused on vincristine because it is part of the standard treatment for patients with Ewing sarcoma.

In a mouse model of Ewing sarcoma, treatment with vincristine plus YK-4-279 slowed tumor growth and improved survival better than either drug alone, the investigators found.

From more detailed experiments, the researchers determined that YK-4-279 and vincristine worked together to disrupt cell division and lower the threshold for cell death in Ewing sarcoma cells. “It seems to be that combination gives us the opportunity to enhance tumor shrinkage,” Dr. Toretsky explained.

Aiming for Less Toxic Treatments

Later in life, people who had Ewing sarcoma often develop significant long-term side effects (called late effects) from their cancer treatment. For example, vincristine can damage the nervous system.

These late effects are a result of harsh treatments and the young age at which patients receive the treatments, Dr. Heske explained. For that reason, she said, finding less toxic therapies for Ewing sarcoma is a major goal.

When combined with YK-4-279, a significantly lower dose of vincristine was required to kill eight different Ewing sarcoma cell lines, the researchers found.

“That means we potentially could get more mileage out of the vincristine dose we use, or we may be able to use a much lower dose and get significantly less toxicity, which will require testing in a future clinical trial,” said Dr. Toretsky.

Moving From the Lab to the Clinic

In 2014, a biotech startup company (of which Dr. Toretsky is a cofounder) began to search for a compound that was similar to YK-4-279 but better at blocking EWS-FLI1. With the help of chemists, the company developed a compound, called TK216, that fit the bill.

TK216 is now being tested in a first-in-human clinical trial for patients with Ewing sarcoma. “It is the first drug that has been used in the clinic that directly targets EWS-FLI1,” Dr. Toretsky noted.

“Because it is the first drug to specifically target the fusion protein, everybody is anxiously waiting to see how it will do in the patient setting,” Dr. Heske said.

If TK216 appears to be safe in patients, the new study findings provide a rationale for combining it with vincristine “to reduce side effects through dose reduction,” the researchers wrote.

But, Dr. Heske cautioned, “when new drugs are discovered, it’s a little bit tricky to figure out all of the different ways they affect cancer cells. TK216 is believed to target the fusion protein, but it may have other effects as well.”

Dr. Toretsky and his team are investigating other drug combinations including YK-4-279 that could potentially kill more Ewing sarcoma cells and are trying to anticipate ways that the cells may resist the effects of the treatment.

And because they have evidence to show that YK-4-279 and TK216 have the same effects on Ewing sarcoma cells, they believe their laboratory studies with YK-4-279 could help inform clinical studies of TK216.