Milea Timbergen

35 binding, the receptor undergoes two processing steps. The first cleavage is mediated by a member of the disintegrin and metalloproteinase family (ADAM10 or ADAM17) and releases the NECD which remains bound to its ligand and is internalized by endocytosis in the cell that sends the signal. Subsequently in the receiving cell, a presenilin-dependent ɣ-secretase complex, removes the NICD from the NTMD. This NICD is translocated into the nucleus where it interacts with the CSL (CBF1/Suppressor of hairless/Lag-1) repressor complex, converting it into an activation complex that interacts with a co-activator protein mastermind-like 1 (MAML1). These interactions results in the transcriptional activation of several Notch target genes such as MYC , p21 , HRT , Notch receptors, Notch ligands, cyclin D1 , and HES -family members (reviewed by Takebe et al. 100 . and Ranganathan et al. 101 ). The Notch signalling pathway in cancer Deregulation of the Notch signalling pathway is described in hematologic malignancies, notably T-cell acute lymphoblastic leukaemia which harbours an activating mutation in NOTCH 1 that result in a constitutive Notch signalling pathway activity 102 . Although activating mutations in members of the Notch family are uncommon in solid tumours, Notch signalling may play a role in tumorigenesis (reviewed by Egloff and Grandis 103 ). For example, NOTCH3 transcript and protein levels are upregulated in a subset of colorectal cancers promoting tumour growth 104 . The Notch signalling pathway and its role and therapeutic potential in des- moid-type fibromatosis Inhibition of Notch signalling forms an appealing therapeutic approach. Small molecular inhibitors, including ɣ-secretase inhibitors (GSI), siRNAs and monoclonal antibodies against Notch receptors and ligands have been developed (reviewed by Yuan et al. 105 ). Particularly GSI’s are of interest as these drugs inhibit the final Notch processing step by which NICD is released to act in the nucleus, consequently blocking Notch signalling. A number of GSI’s (e.g., MK-0752 and RO4929097) have already been studied in solid cancers other than DTF in early phase clinical trials 106, 107 . Few studies investigated the role of the Notch signalling in DTF, however, DTF tumours have been shown to express NOTCH1 and its downstream target HES1 108 . Preliminary evidence, from a phase 1 clinical trial indicated a partial response in five out of seven DTF patients to the oral GSI PF-03084014 (Table 2) 109 . This prompted an in vitro study performed by Shang et al., which demonstrated a significant higher expression of nuclear HES1 in DTF tissues compared to scar tissue by IHC and reported expression of NOTCH1, JAGGED1 2