Jakob Wurth – Targeting transcriptional core regulatory circuit by epigenetic dependencies

Objectives

To assess the role of epigenetic regulatory complexes such as NuRD, SWI/SNF, and PRC as vulnerabilities in Ewing and Rhabdomyosarcoma. The project will involve CRISPR/Cas9 loss-of-function screens focused on the above-mentioned epigenetic complexes. These experiments will be complemented with a small molecule screen including known epigenetic drugs either already FDA approved or in pre-clinical development. Prioritized targets from these screens will be validated mechanistically and their role in maintaining the core regulatory circuit will be assessed using established cell line models. Identified targets will also be used in combination with each other, with known epigenetic drugs including HDACi and BRD4i or with standard chemotherapeutics. Further pre-clinical validation of targets/compounds will be extended to primary PDX models of the two diseases.

Expected Results

We expect to identify a small number of key molecules (3-7) as new therapeutic targets for paediatric sarcomas. About half of these are expected to be targetable by small molecule compounds.