Experimental breast cancer drug holds promise in combination therapy for Ewing sarcoma

Ewing sarcoma tumors disappeared and did not return in more than 70% of mice treated with combination therapy that included drugs from a family of experimental agents developed to fight breast cancer, according to a newly published study.

The treatment paired two chemotherapy drugs currently used to treat Ewing sarcoma (EWS) with experimental drugs called poly-ADP ribose polymerase (PARP) inhibitors that interfere with DNA repair. PARP inhibitors are currently in clinical trials for the treatment of certain breast and ovarian cancers as well as other solid tumors. EWS is a cancer of the bone and soft tissue that strikes primarily adolescents and young adults.

A clinical trial using the three-drug combination therapy detailed in this research is expected to open later this year for adolescents and young adults with EWS whose tumors have not disappeared with standard therapy or have returned after treatment. The trial is a collaboration of researchers at St. Jude Children's Hospital in Memphis, Tennessee, and the Dana-Farber/Harvard Cancer Center in Boston, Massachusetts. The therapy will pair the PARP inhibitor olaparib with the chemotherapy drugs irinotecan (IRN) and temozolomide (TMZ).

The study is one of two clinical trials St. Jude plans to open soon combining IRN and TMZ with PARP inhibitors for the treatment for EWS. The tumor is diagnosed in about 250 US residents each year, making it the second most common bone tumor in children and adolescents.

Long-term survival for EWS patients whose disease has not spread remains stalled at about 75% to 80%, and the outcome for patients with metastatic disease is dismal.

"During the past 20 years there has been no significant improvement in the cure rate for Ewing sarcoma, and survival is just 15% to 20% for patients whose disease has spread or comes back after treatment," said co-corresponding author Michael Dyer, PhD, of St. Jude.

The latest report, published in Cell Reports (2014; doi:10.1016/j.celrep.2014.09.028), includes the discovery that EWS cells have a defect in DNA damage repair. Working with EWS cells grown in the laboratory and mice, investigators showed the EWS defect could be exploited to help patients by combining DNA-damaging chemotherapy with a PARP inhibitor. PARP inhibitors work by interfering with activity of an important DNA-repair enzyme.

The study involved a series of mouse experiments designed to mirror the human phase I, II, and III studies that gauge the safety and effectiveness of experimental treatment in humans. The research showed that PARP inhibitors work synergistically with IRN and TMZ to kill EWS.

The Phase III study included 274 mice with EWS treated in a double-blind, placebo-controlled, randomized study. The study included 15 different treatment groups using different combinations and doses of IRN, TMZ, and three PARP inhibitors currently in development for pediatric cancer treatment.

EWS disappeared and had not returned in more than 4 months in 71% of mice treated with IRN, TMZ, and the PARP inhibitor olaparib. The results were even better when IRN and TMZ were combined with the PARP inhibitor talazoparib. The combination led to a durable, complete remission in 88% of the 16 mice treated.

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