Targeted Therapy of Ewing's Sarcoma

Abstract

Refractory and/or recurrent Ewing's sarcoma (EWS) remains a clinical challenge because the disease's resistance to therapy makes it difficult to achieve durable results with standard treatments that include chemotherapy, radiation, and surgery. Recently, insulin-like-growth-factor-1-receptor (IGF1R) antibodies have been shown to have a modest single-agent activity in EWS. Patient selection using biomarkers and understanding response and resistance mechanisms in relation to IGF1R and mammalian target of rapamycin pathways are areas of active research. Since EWS has a unique tumor-specific EWS-FLI1 t(11;22) translocation and oncogenic fusion protein, inhibition of EWS-FLI1 transcription, translation, and/or protein function may be key to eradicating EWS at the stem-cell level. Recently, a small molecule that blocks the protein-protein interaction of EWS-FLI1 with RNA helicase A has been shown in preclinical models to inhibit EWS growth. The successful application of this first-in-class protein-protein inhibitor in the clinic could become a model system for translocation-associated cancers such as EWS.

Figure 1

Current and future EWS treatment options. Current treatment of EWS typically employs VAC+IE or VIDE regimens. Local control includes surgery and/or radiation therapy. With this regimen, patients with only local disease have about 70% disease-free survival (EFS). However, patients with EWS who have metastatic disease or who have recurrence have <20% EFS. Second-line relapse regimens as shown below often provide temporary benefit. New agents against IGF1R and /or mTOR are currently available. Future options include innovative targeted therapies. V: vincristine; D: doxorubicin; C: cyclophosphamide; I: ifosphamide/mesna; E: etoposide; IGF1R insulin-like growth factor 1 receptor inhibitor; mTOR: mammalian target of rapamycin inhibitor.

Figure 2

Five-year survival rates for Ewing's sarcoma (EWS), 1975–2006. The 5-year survival rates for EWS among children and adolescents is shown by age group and time period of diagnosis from 1975 through 2002, with follow-up of survival through 2006; data are from the Surveillance, Epidemiology, and End Results 9 (SEER 9) registries (Reprinted with permission from Smith et al. J Clinical Onc 2010; 28:2625-2634).

Figure 3

Insulin-like growth factor 1 receptor (IGF1R) system. Ligands (IGF-I, IGF-II, and insulin) bind to the receptors (IGF1R, IGF-2R, and insulin receptor [IR]) with different affinity. The IGF1R and IR possess tyrosine kinase activity. Binding of the IGF-1 ligand to IGF1R leads to a conformational modification of the receptor and activation of the tyrosine kinase subunit. Each receptor triggers complex and different intracellular signaling cascades.

Figure 4

A simplified view of fusion protein: RNA helicase protein disruption, the mechanism of action of a new EWS-FL1 targeted molecule, YK-4-279. Because EWS-FLI1 is a disordered protein that precludes standard structure-based small-molecule inhibitor design, a divergent strategy was designed. EWS-FLI1 interaction with RNA helicase A is critical for oncogenesis. YK-4-279 blocks RHA interaction with EWS-FLI1. This protein–protein inhibition induces apoptosis in EWS cells and reduces the growth of EWS orthotopic xenografts.