Investigational therapies for Ewing sarcoma: a search without a clear finding

ABSTRACT

Introduction: Ewing sarcoma family tumors (ESFT) are a group of aggressive diseases, characterized histologically by small, round, blue cells and genetically by translocation involving EWS and ETS partner genes. The current treatment of localized Ewing sarcoma (ES) requires a multi-disciplinary approach, including multidrug chemotherapy, administrated before and after local treatment, surgery and radiation therapy. Unfortunately, the cure rate of metastatic or refractory/recurrent disease is still very poor.

Areas covered: In this review, the authors summarize the new types of therapy and strategies aimed to improve the prognosis or cure ES. Herein, the authors discuss several preclinical and phase I-II studies with new-targeted therapies. The most studied therapies are insulin-like growth factor receptor (IGF1R) inhibitors but have limited efficacy. Other strategies include Mammalian Target of Rapamycin (mTOR) Inhibition, poly ADP ribose polymerase (PARP) inhibition, vascular endothelial growth factor (VEGF) inhibition, tyrosine kinase inhibitors and telomerase inhibitors, all with limited effectiveness.

Expert opinion: Future treatment strategies should combine one or more targeted therapies with conventional chemotherapy. Some combined modality treatments are under clinical study. However, treatment breakthroughs are still needed to improve the relatively poor prognosis of recurrent/metastatic ESFT.

KEYWORDS:

• Ewing sarcoma family tumors
• IGF1R
• mTOR
• PARP
• review
• target therapy

Article highlights

• Refractory or recurrent ES is a challenging disease, with low long-term survival rates irrespective of the type and intensity of second-line chemotherapy.

• Second line chemotherapy is still palliative; however, the highest response rates have been achieved so far with a combination of irinotecan with temozolamide or trabectedine.

• In ESFT, the EWSR1-FLI1 translocations induce dysregulation of the type-1 insulin-like growth factor receptor (IGF1R) pathway. Despite promising preclinical results, data from phase II studies of monotherapy with IGF1R antibodies were disappointing.

• Other directions include targeting of different pathways and mechanisms leading to tumor development, included EWSR1-FLI1, mTOR, PARP, VEGF, lysine-specific demethylase, telomerase, bone lysis. Most of these directions showed promising results in preclinical studies but failed clinically as single agents.

Combination of new types of therapy with chemotherapy agents or one another seems to be the future direction in the treatment of refractory ES, and should be the focus of early clinical trials.

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Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.