Milea Timbergen

22 Abstract Desmoid-type fibromatosis (DTF) is a rare, soft tissue tumour of mesenchymal origin, which is characterized by local infiltrative growth behaviour. Besides “wait and see”, surgery and radiotherapy, several systemic treatments are available for symptomatic patients. Recently, targeted therapies are being explored in DTF. Unfortunately, effective treatment is still hampered by the limited knowledge of the molecular mechanisms that prompt DTF tumorigenesis. Many studies focus on Wnt/β-catenin signalling, since the vast majority of DTF tumours harbour a mutation in the CTNNB1 gene or the APC gene. The established role of the Wnt/β- catenin pathway in DTF forms an attractive therapeutic target, however, drugs targeting this pathway are still in an experimental stage and not yet available in the clinic. Only few studies address other signalling pathways that can drive uncontrolled growth in DTF such as JAK/STAT, Notch, PI3 kinase/AKT, mTOR, Hedgehog, and the oestrogen growth regulatory pathways. Evidence for involvement of these pathways in DTF tumorigenesis is limited and predominantly based on the expression levels of key pathway genes or on observed clinical responses after targeted treatment. No clear driver role for these pathways in DTF has been identified, and a rationale for clinical studies is often lacking. In this review, we highlight common signalling pathways active in DTF and provide an up-to-date overview of their therapeutic potential. 2