Innovative targeted therapy for Ewing sarcoma

• Applicant: Dr. Shunya Ohmura
• Subject Area: Pediatric and Adolescent Medicine
• Term: from 2017 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 391665916

Ewing sarcoma (EwS) is a highly aggressive bone tumor of childhood and adolescence. EwS often shows an unfavorable prognosis even with very intensive therapies. Especially the prognosis for patients with disseminated disease remains poor, which urges the development of innovative and in particular less toxic therapeutic options for EwS.In order to identify novel target structures for a more specific therapy we proceeded as follows: By means of comparative transcriptome analyses all genes were cataloged, which i) are highly overexpressed in EwS relative to normal tissues, ii) function as kinase or enzyme, iii) are overexpressed by the EwS-specific chimeric transcription factor EWSR1-FLI1, and iv) whose overexpression is associated with lower survival rates of patients with EwS. This led to the identification of the genes RRM2 (ribonucleotide reductase M2) and TTK (TTK protein kinase), of which possible oncogenic functions and therapeutic potentials for targeted therapy as well as biological relevance have not yet been thoroughly investigated in EwS.Our preliminary experiments indicated that these genes are indeed upregulated by EWSR1-FLI1 and that inhibition of their function by specific antagonists strongly inhibited proliferation and clonogenic growth of EwS cells at low doses. Furthermore, we validated the association between their overexpression and poor patient outcome in an independent retrospective cohort.This project specifically aims at i) investigating the biological relevance of RRM2 and TTK for tumorigenesis and progression of EwS in vitro and in vivo, ii) validating the antineoplastic effects of inhibitors specific for RRM2 and TTK in tumor growth in a preclinical xenograft model, iii) exploring a potential synergistic effect of these inhibitors with conventional chemotherapeutic drugs, iv) investigating the mechanisms of overexpression of both genes and their potential roles in genomic stability and chemo-resistance in EwS, and v) validating the value of RRM2 and TTK as prognostic markers on the protein level. Since the inhibitors targeting RRM2 and TTK are already commercially available, we anticipate that our preclinical results can be quickly translated into clinical trials.

• DFG Programme: Research Grants
• Co-Investigator: Professor Dr. Thomas Grünewald, Ph.D.