Therapeutic Strategies Targeting Oncogenic Fusion Proteins in Sarcomas

Several drugs developed against cancer-specific molecular targets have been shown to offer survival benefits alone or in combination with standard treatments, especially for those cases where tumor pathogenesis is dominated by a single molecular abnormality. Such cases are also found in pediatric sarcomas which are characterized by specific chromosomal translocations generating oncogenic fusion proteins. In the majority of cases, these fusions are composed of transcription factors which can not be directly targeted by small-molecule compounds. However, the ability of transcription factors to regulate specific target genes is modulated by variety mechanisms such as post-translational modifications, protein stability, protein synthesis, and protein-protein interactions resulting in highly context-dependent regulatory networks. Here, I will discuss strategies to identify modulators of PAX/FKHR and EWS/FLI1 activity in rhabdomyosarcoma and Ewing's sarcoma, respectively. These include identification of small-molecule inhibitors of post-translational modifications in combination with histone deacetylase inhibitors, screening of chemical libraries for inhibition of fusion protein activity using specific read-out systems, as well as analysis of the fusion protein interactomes. The characterization of these transcriptional regulatory networks will provide novel opportunities for therapeutic interventions.