This project aims to provide a fast, semi-high throughput and cheap animal model for identifying and/or characterizing promising drug targets for treating desmoid tumors. We have obtained proof of principle that, in an approach of mosaic multiplexed gene knockout using CRISPR/Cas9, we can identify genes that are critical for desmoid tumor formation. Using a streamlined experimental pipeline, we will be able to further assess whether additional genes that are highly expressed in human desmoid tumors play an essential role in tumor proliferation and could serve as anchor points for novel therapeutic drug development. In addition we will further evaluate and optimize the EZH2 inhibitors GSK126 and Tazemetostat (EPZ-6438) on desmoid tumor formation in our experimental Xenopus model. We will also test inhibitors for membrane cleavage – hence activation – of the transcription factor CREB3L1. Such inhibitors – AEBSF and PF429242 – have recently been described to block CREB3L1 activation and AEBSF has been used in an in vivo context (Feng et al. , Nat. Comm. 2017). We will copy the treatment protocol (intraperitoneal injection) to our Xenopus model. Evidently more specific inhibitors will have to be developed since AEBSF also interferes with the proteolytic activation of SREBP, a master transcription factor for lipogenesis. We believe that our model offers a unique experimental platform that can foster the research lines of several groups active in the field.
LAY VERSION OF ABSTRACT- “Identifying targets for therapy in a novel genetic Xenopus model for desmoid tumor formation.”