Three-drug combo kills Ewing sarcoma in mice

Anang Shelat, assistant member of the St. Jude Department of Chemical Biology and Therapeutics

A new triple-drug combination therapy tested in mice may provide a new treatment avenue for Ewing sarcoma, a rare bone cancer that primarily affects children and adolescents.

Scientists at St. Jude Children's Research Hospital combined two chemotherapy drugs currently used to treat Ewing sarcoma with experimental drugs called poly (ADP-ribose) polymerase (PARP) inhibitors that interfere with DNA repair. PARP inhibitors are currently being tested in clinical trials to treat breast and ovarian cancers as well as other solid tumors.

Previous research showed that Ewing sarcoma cells growing in a lab setting were sensitive to the PARP inhibitor olaparib. The latest research from St. Jude found that Ewing sarcoma cells have a defect in DNA damage repair.

Working off these discoveries, researchers used Ewing sarcoma cell lines and mouse models to find that this defect in Ewing sarcoma could be exploited by combining a DNA-damaging chemotherapy with a PARP inhibitor. PARP inhibitors work by interfering with activity of an important DNA-repair enzyme.

When tested in a mouse model, the three-drug combination therapy--which included the chemotherapy drugs irinotecan and temozolomide and the PARP inhibitor olaparib--caused tumors to disappear. In 71% of treated mice, tumors did not return. The results were even better when investigators combined irinotecan and temozolomide with a different PARP inhibitor, talazoparib. That combination led to a complete remission in 88% of the treated mice. The findings were published online Oct. 23 by the journal Cell Reports.

St. Jude is planning to test the second combination therapy in a clinical trial slated to open later this year for adolescents and young adults with Ewing sarcoma whose tumors have not disappeared with standard therapy or have returned after treatment. St. Jude will collaborate with the Dana-Farber/Harvard Cancer Center in Boston for the trial, which will test the PARP inhibitor olaparib with irinotecan and temozolomide.

"Our preclinical results suggest Ewing sarcoma is particularly sensitive to this combination therapy, a possible indication that the tumor's DNA repair defect provides us with a much needed advantage to knock out tumor cells," said Anang Shelat, an assistant member of the St. Jude Department of Chemical Biology and Therapeutics, in a statement. "There is some evidence that this type of defect is present in other pediatric tumors, and we are actively investigating drug sensitivity in those cancers."

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