Both compounds suppress the activity of EWS-FLI1, which belongs to a class of molecules called transcription factors that play key roles in gene regulation. In Ewing sarcoma, EWS-FLI1 switches certain genes 鈥渙n鈥� or 鈥渙ff鈥� incorrectly, leading to uncontrolled cellular proliferation and, ultimately, tumors. Although they are difficult to target for drug treatment because of their structure, transcription factors offer significant opportunities for developing more precise therapies that perform better and have fewer side effects.
鈥淥ur current approach鈥攁 combination of chemotherapy, radiation and surgery鈥攊s a tough road and isn鈥檛 extremely effective in patients whose cancer has spread or relapsed,鈥� said senior author , an associate professor at and a pediatric oncologist at . 鈥淓WS-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.鈥�
The new compounds are derived from mithramycin, a drug previously investigated as a potential therapy for Ewing sarcoma. Not only do they suppress EWS-FLI1 activity more effectively than mithramycin, but the new compounds also demonstrate far less toxicity, making them attractive candidates for further studies.
鈥淎lthough 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,鈥� Grohar said. 鈥淲e鈥檙e excited to complete the preclinical work, which will help us prioritize one of the compounds for translation into a clinical trial.鈥�
The study was published online in the journal Clinical Cancer Research and includes authors from , , , , , and . Grohar also holds an academic appointment at .
Osgood CL, Maloney N, Kidd CG, Kitchen-Goosen S, Segars L, Gebregiorgis M, Woldemichael GM, He M, Sankar S, Lessnick S, Kang M, Smith M, Turner L, Madaj ZM, Winn ME, N煤帽ez LE, Gonz谩lez-Sab铆n J, Helman LJ, Mor铆s F, Grohar PJ. In press. . Clin Cancer Res.
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