Targeted therapies for advanced Ewing sarcoma family of tumors

•The prognosis of patients with metastatic Ewing sarcoma remains dismal and 5-year survival usually does not exceed 30%.•Targeting IGF-1R was found effective in preclinical models and small subsets of patients with advanced Ewing sarcoma.•Other targeted therapies such as therapies against EWS-FLI1-related targets are in clinical development.•Biomarkers predicting efficacy of novel targeted therapies remain to be identified.

The prognosis of adolescent and young adult patients battling metastatic Ewing sarcoma family of tumors (ESFT) remains less than 30% despite the development of systemic therapies. In the era of personalized medicine, novel molecular targets have been tested in preclinical or clinical settings in ESFT. In this review, we focus on early clinical and translational research that identified multiple molecular targets, including IGF-1R; mTOR; tyrosine kinase inhibitors; EWS-FLI1-related targets, and others. Overall, novel targeted therapies demonstrated modest efficacy; however pronounced and durable antineoplastic responses have been observed in small subsets of treated patients, for example with IGF-1R antibodies. Identifying outcome-predicting biomarkers and overcoming treatment resistance remain major challenges. Due to the rarity of ESFT, multi-institutional collaboration efforts of clinicians, basic and translational scientists are needed in order to understand biology of therapeutic response or resistance, which can lead to development of novel therapeutic methods and improved patient outcomes.