Targeted therapies for advanced Ewing sarcoma family of tumors

Abstract

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.

Keywords: Ewing sarcoma; Targeted therapies.

Figure 1

Schematic figure of targeted molecules in ES-related pathways and drugs used in clinical and preclinical testing.

Figure 2

Indirect targeting of EWS-FLI1. A) Interaction between EWS-FLI1 and PARP. PARP inhibitors are used to directly target EWS-FLI1. B) EWS-FLI1 regulates gene expression by binding to RHA, a transcription modulator. YK-4-279, interrupts of the binding of RHA to EWS-FLI1. C) EWS-FLI1 regulates transcription of aurora kinase A, which is a cell cycle regulator. Aurora kinase inhibitors are being used to indirectly target EWS-FLI1.