Targeting EWS-FLI1 Ewing Sarcoma through a rationale targeted therapy combination
The use of ALK inhibitors in ALK mutant familial and sporadic neuroblastoma has finally ushered in the era of targeted therapies in pediatric cancers, whereas in adult cancers, targeted therapies have been revolutionizing cancer care for more than a decade. Ewing’s Sarcoma, which is defined by a EWS-FLI1 translocation event in roughly 90% of cases, is an often fatal disease of children and adolescence. Importantly, these cancers are clearly driven by aberrant EWS-FLI1 expression, as evidenced directly by laboratory experiments and indirectly by its otherwise very low mutation burden. Unfortunately, targeted therapies that directly block transcriptional factors are not available, and implementation of effective targeted therapies will require exploiting specific vulnerabilities of these cancers. Using a comprehensive pharmacogenomic approach, we recently uncovered a novel targeted therapy combination in a genetically analogous cancer, neuroblastomas driven my amplification of the transcription factor, MYCN (Ham et al, Cancer Cell, in press). In this grant, we propose a similar system to identify an effective targeted therapy combination in EWS-FLI1 Ewing’s Sarcoma, and provide preliminary data that indeed this approach can yield a novel and effective targeted therapy combination for Ewing’s Sarcoma.