Milea Timbergen

39 The PI3 kinase /AKT and mTOR signalling pathways and their role and thera- peutic potential in desmoid-type fibromatosis The relationship between DTF and the PI3 kinase/AKT and the mTOR signalling pathways has not been extensively studied. Immunohistochemical analysis of twenty-nine DTF tumour samples indicated the expression of ß-catenin and PDGFR-ß in all samples. No expression could be detected of PDGFR-α and phospho-Ser-473, suggesting inactive AKT signalling 123 . Meazza et al. showed that a substantial part of paediatric DTF cases had an E17K mutation in either AKT1 (eight out of twenty-eight 28; 31%), however no AKT1 mutations were observed in adult DTF cases (n = 33) 124 . Interestingly, DTF patients with an E17K AKT1 mutation had a longer recurrence free survival rate in agreement with the mutation-induced stimulation of downstream AKT signalling. Recently, Rosenberg et al. reported the anti-tumour effect of sorafenib, a multi-kinase inhibitor that targets multiple tyrosin kinases (e.g., VEGFR, c-Kit and PDGFR) expressed on patient derived DTF cell lines (Table 1). It was found that sorafenib decreased proliferation and invasion in a dose dependent manner and that the Ras/MEK/ERK and the PI3kinase/AKT/mTOR signalling pathways were affected. Additionally, they investigated the efficacy of everolimus, an mTOR inhibitor, as monotherapy and in combination with sorafenib, and found no synergistic or additive inhibitory effect on cellular proliferation (Table 1) 64 . Cates et al. compared the expression profiles of selected receptor- and non-receptor tyrosine kinases and downstream effectors of signalling activity in DTF (n = 27), reactive scars (n = 14) and fibrous tissue (n = 6) (Table 1). PDGFR-β, FAK 1 and MET were detected by IHC in almost all DTF and scar tissues and in at least half (PDGFR-β, FAK1) or none (MET) of the fibrous control tissue. Of note, AKT was phosphorylated in 56% of DTF samples, but significantly higher levels were observed in scar tissues and only low levels were observed in a subset of fibrous tissues 125 . Inhibition of various tyrosine kinases including PDGFR, with imatinib is a promising treatment strategy for DTF. Imatinib is effective in other solid tumours of mesenchymal origin like gastro-intestinal stromal tumours (GISTs) and dermatofibrosarcoma protuberans, in which it targets KIT or PDGFR-ɑ /PDGFR-ß (reviewed by Kosela-Paterczy et al. 126, 127 ). The efficacy of imatinib (either alone or combined with other treatment) was observed in several early phase clinical studies with DTF patients (Table 2) 79-84 . Chugh et al. and Penel et al. reported a 1-year progression free survival (PFS) of 66% and 67% respectively. However, the results of these studies should be interpreted with caution, since the majority of patients included in these trials received other treatments prior to treatment with imatinib (Table 2). Additionally, the relevant targets of imatinib in DTF remain unclear 81, 123 . Two phase 2 clinical trials including 2