HSP90IES

Ewing sarcoma is a malignant bone and soft tissue tumour in children and young adults. Despite treatment advances, survival rates especially for patients with metastases or relapse are low. New therapeutic options are urgently needed. Most cancers show increased dependency on a class of proteins, called chaperones, which help to fold proteins into their functional form. Heat shock protein 90 (Hsp90) belongs to this class of chaperones and has approx. 400 client proteins, many of them involved in tumorigenesis. Inhibition of Hsp90 has already been shown to disrupt multiple signalling pathways, resulting in anticancer effects. Importantly, EWS::FLI1, the most common driver of Ewing sarcoma, is an Hsp90 client itself. We therefore speculate that targeting Hsp90 could be beneficial in Ewing sarcoma treatment . Our study will test this hypothesis. However, currently available Hsp90 inhibitors have shortcomings, which limit their potential for clinical applications. In this collaborative project, we set out to leverage synergies between experts in medicinal chemistry and experts in Ewing sarcoma modelling to improve current molecule designs for applications in Ewing sarcoma. We will synthesize completely novel small compounds targeting Hsp90 and we will test their antitumor effects on Ewing sarcoma cells in vitro and in vivo. This will provide new insights, if Hsp90-directed therapeutic strategies could constitute a novel path in the treatment of Ewing sarcoma.