Milea Timbergen

30 Figure 1. A schematic presentation of the Wnt/β-catenin signalling pathway and the drugs that target this pathway in DTF. The graph shows that ipafricept (OMP-54F28), inhibits Wnt signalling by acting as a decoy receptor inhibiting Wnt signalling through the Frizzled 9 receptor. NSAIDs, like meloxicam, the angiogenesis inhibitor endostatin and MMP inhibitors act on target genes of the Wnt signalling pathway. The drug Nefo- pam, a non-opioid analgesic drug of the benzoxazocine class suppresses the effect of high levels of β-catenin. The blockage of Wnt/β-catenin signalling with the truncated Frizzled 9 receptor fused to the IgG1 Fc region (ipafricept, OMP-54F28), was recently tested in a Phase 1 study for solid tumours (Table 2). In this study, two patients with DTF were included that both exhibited stable disease, although it is unclear if this can be directly attributed to the treatment 76 . While the above-mentioned treatments, targeting Wnt/β-catenin targets constitute attractive therapeutic possibilities, no prospective clinical trials using these treatment strategies in sporadic DTF have been designed. Experimental inhibitors of Wnt/β-catenin signalling have been developed, however, systemic abolition of Wnt secretion is not preferable since this will result in defects in gut homeostasis, affects the immune system and affects both ß-catenin-dependent and independent Wnt signalling (reviewed by Zimmerli et al. 90 and Enzo et al. 91 ). Figure 1 displays the Wnt/β-catenin signalling pathway and putative drug targets in the context of DTF. 2