Two-Drug Combination Effective Against Ewing Sarcoma
Patients with Ewing sarcoma typically receive a 5-drug cocktail that can result in nerve damage.
An investigational drug plus an FDA-approved chemotherapy were observed to stop the growth of Ewing sarcoma in both cell lines and animal models, according to a study published by Science Signaling.
The authors report that this finding should pave the way for clinical trials to investigate whether the combination therapy could effectively treat patients with this rare bone cancer.
In the study, the authors examined whether investigational YK-4-279 plus vincristine, a drug used to treat the condition, could inhibit Ewing sarcoma in cell and mice models.
“Each of the 2 drugs impacts the cancer cell’s ability to survive, but they do it in a way that magnifies their effectiveness compared to if they were used alone. It’s like a left hook followed by an uppercut,” said senior investigator, Jeffrey Toretsky, MD.
Each year in the United States, 500 children and young adults are diagnosed with Ewing sarcoma. While the 5-year survival rate is up to 70%, many patients experience latent side effects from treatment. Current therapy includes a combination of 5 chemotherapy drugs, which can result in nerve damage.
Ewing sarcoma is caused by DNA exchanged between 2 chromosomes, which results in the creation of the EWSR1-FLI1 gene. This gene produces a fusion protein, EWS-FLI1, that drives cancer growth, according to the study.
Previously, the team of researchers discovered that EWS-FLI1 binds to the RNA helicase A, a protein crucial for disease progression.
YK-4-279 is an inhibitor of EWS-FLI1. The authors also developed TK216, a first-in-class small molecule being tested in a clinical trial for patients with relapsed or refractory Ewing sarcoma, according to the study.
In the study, the authors discovered that YK-4-279 worked well with vincristine to inhibit Ewing sarcoma. The combination therapy resulted in severe structural damage to cancer cells.
Treatment with the drugs resulted in a “microtubule catastrophe,” which affected the structure of cells and their ability to pull apart chromosomes when they divide, according to the study.
“Cancer needs to grow, and to do that, the cells need to divide and multiply. This is the step both drugs target, but in different ways,” Dr Toretsky said.
The dual mechanism of action offers a novel way to destroy cancer cells that may be less damaging than current therapies. However, clinical trials and additional studies are needed to confirm the combination’s efficacy.
The team of researchers is planning to test TK216 plus vincristine in patients with Ewing sarcoma, according to the study.