Ewing sarcoma tumours disappeared and did not return in more than 70 percent of mice treated with combination therapy that included drugs from a family of experimental agents developed to fight breast cancer, reported St. Jude Children's Research Hospital scientists.
The study will appear in the November 6 edition of the scientific journal Cell Reports.
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 tumours. EWS is a cancer of the bone and soft tissue that strikes primarily adolescents and young adults.
The tumour is diagnosed in about 250 U.S. residents each year, making it the second most common bone tumour in children and adolescents.
Long-term survival for EWS patients whose disease has not spread remains stalled at about 75 to 80 percent, 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 percent for patients whose disease has spread or comes back after treatment," said co-corresponding author Michael Dyer, Ph.D., a Howard Hughes Medical Institute (HHMI) investigator and a member of the St. Jude Department of Developmental Neurobiology.
This study builds on earlier research from other investigators who reported that EWS cells growing in the laboratory were sensitive to the PARP inhibitor olaparib.
The latest report includes the St. Jude 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.
St. Jude researchers conducted 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, randomised study.
EWS disappeared and had not returned in more than four months in 71 percent 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 percent of the 16 mice treated.
"Our preclinical results suggest Ewing sarcoma is particularly sensitive to this combination therapy, a possible indication that the tumour's DNA repair defect provides us with a much needed advantage to knock out tumour cells," Shelat said.
"There is some evidence that this type of defect is present in other paediatric tumours, and we are actively investigating drug sensitivity in those cancers."
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