Two new compounds suppress tumor growth in cell culture and mouse xenograft models of Ewing sarcoma, a rare pediatric cancer. These 2 compounds are similar to mithramycin, also known as picamycin.1
Ewing sarcoma is a small-round–cell tumor found in the bone or in soft tissue. Approximately 85% of Ewing sarcoma tumors are the result of a genetic translocation between chromosomes 11 and 22. Ewing sarcoma comprises 16% of all primary bone sarcomas.
Mithramycin is a drug with antineoplastic and antibiotic properties that is a known inhibitor of EWS-FLI1, a double protein only present in disease cells and that promotes tumor growth. Mithramycin inhibits RNA synthesis (transcription), and Ewing sarcoma is caused by a chromosomal translocation of EWS and Fli1. Although mithramycin inhibits EWS-FLI1, doses high enough to be effective have such high toxicity that mithramycin cannot be safely administered. The manufacture of mithramycin was discontinued in 2000.
This study, published in Clinical Cancer Research, identified 2 compounds that similarly inhibit EWS-FLI1. Both compounds inhibited EWS-FLI1 better than mithramycin and had less toxicity.
“Our current approach, a combination of chemotherapy, radiation, and surgery, is a tough road and isn’t extremely effective in patients whose cancer has spread or relapsed,” said Patrick Grohar, MD, PhD, an associate professor at Van Andel Research Institute and a pediatric oncologist at Spectrum Health Helen DeVos Children’s Hospital, Grand Rapids, Michigan, and senior author of the study.
“EWS-FLI1 is unique to Ewing sarcoma and is present in the majority of cases, which offers an excellent opportunity for developing precise therapies that combat cancer cells with less chance of affecting normal, healthy cells. At the same time, these findings lay the groundwork for devising ways to target transcription factors in other cancers, which historically has been challenging.”
Both compounds not only suppress EWS-Fli1 in cell culture but also in a mouse xenograft model of Ewing sarcoma with reasonable toxicities.
“Although we are hopeful our findings will lead to new, more effective therapies for Ewing sarcoma, we also believe they serve as a precedent for targeting transcription factors in other tumor types. We’re excited to complete the preclinical work, which will help us prioritize one of the compounds for translation into a clinical trial,” explained Grohar.
1. Osgood CL, Maloney N, Kidd CG, et al. Identification of mithramycin analogs with improved targeting of the EWS-FLI1 transcription factor [published online ahead of print March 15, 2016]. Clin Cancer Res. doi:10.1158/1078-0432.CCR-15-2624.