Genomics and epigenomics approaches to characterize novel therapy targets in Ewing sarcoma

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Ewing sarcoma (ES) is a highly malignant bone and soft tissue neoplasm that arises predominantly in the pelvis and long bones in children and young adults with early metastasis to lung and bone. Survival expectancy increased for pediatric malignancies in recent years. However, only two thirds of ES patients without metastases currently achieve long lasting remissions by multimodal therapy approaches. Moreover, advanced ES has an even worse prognosis. Genetically, ES is defined by balanced chromosomal EWS/ETS translocations, which give rise to oncogenic chimeric transcription factors (EWS-ETS) that are currently not targetable. Other contributing somatic mutations involved in disease development have only been observed at low frequency. Recently, we identified EZH2 as an important driver for metastasis development in ES. Also, we have performed whole exome and genome sequencing in primary ES. We identified several recurrently mutated genes at low frequency. Of interest, activating point mutations of FGFR1, frequent amplification of this locus (31.7%) in primary tumors and widespread increased expression suggested significant FGFR1 activity as an important attribute of this disease. The various mechanisms of FGFR1 activation and the epigenetic mechanisms associated with EZH2 point towards a combination of epigenetic and genetic driver alterations in ES. The main aim of this proposal is therefore to characterize the therapeutic opportunities of relevant driver mechanisms in ES. We will combine specific gene knock outs generated via gene editing with a CRISP/Cas9-based system in a lethality screen together with different sublethal doses of Ponatinib in ES cell lines. Furthermore, we will combine gene knock-outs of previously identified key players of ES metastasis in such a screen for synthetic lethality gene defects. Promising candidate combinations will be evaluated together with genomic, epigenetic and clinical data and their potential druggability will be tested in preclinical model systems. We anticipate a better comprehension of key malignant mechanisms that help to improve therapy for ES, and to develop new therapeutic treatment modalities for cancer in general.