Ewing sarcoma (ES) often has a dismal outcome, but increasing knowledge of its biology is bringing new hope for improved treatments. This rare malignancy occurs with an annual incidence of 3 in 1 million children under the age of 15 years, and it is the second most common malignant bone tumor in children and adolescents.1 The median age at diagnosis is 14 to 15 years.2 At diagnosis, 30% of patients present with metastases to the lungs, bone, or bone marrow. For patients with localized ES, the 5-year overall survival is 70%, but this rate has not changed in the past 10 years. For patients with disease that has metastasized at diagnosis, less than one-third are long-term survivors, and less than 10% with recurrent disease are long-term survivors.1

These dismal survival statistics and the current plateau that chemotherapy regimens have reached indicate the high need for improved treatment strategies, particularly for resistant, metastatic, and recurrent disease. Detailed insights into the biology of ES are yielding new targeted neoplastic agents.

The genetic marker of ES is rearrangements involving the EWS gene on chromosome 22q12 and fusion partners from the ETS oncogene family, most commonly FLI1.1 The chimeric fusion EWS-ETS proteins lack enzymatic activity but execute their oncogenic activity by acting as aberrant transcription factors.3 The EWS-FLI1 fusion protein partners with RNA Helicase A. This binding is blocked by the small molecule YK-4-279, which has activity against ES in preclinical studies.4

The EWS-FLI1 translocations dysregulate the insulin-like growth factor 1 receptor (IGF-1R) pathway.5 All ES cells express IGF-1R and, through autocrine loops, ES cells are stimulated by IGF-1R.6 Notably, ES incidence peaks around age 15 years, when the production of IGF-1R mediated by growth hormones is maximal. Several therapeutics and combinations have been directed against IGF-1R in ES. The growth factor ligands IGF-1 and IGF-2 activate IGF-1R, resulting in receptor autophosphorylation.7

Antibodies targeting IGF-1R

Clinical trials involving four antibodies against IGF-1R have recently been reported. In the phase 2 trial of ganitumab, a fully human monoclonal antibody against IGF-1R that blocks the binding of both IGF-1R and IGF-2, two ES patients out of 35 (6%) enrolled achieved partial responses (PR), and 17 (49%) had stable disease (SD).5 However, only six patients (17%) had a clinical benefit, which was defined as PR or SD lasting more than 24 weeks. The median progression-free survival (PFS) was 7.9 months for ES patients.5