Milea Timbergen

29 Pharmacological options targeting the Wnt/ß-catenin signalling pathway Although many studies implicated aberrant Wnt/β-catenin signalling in DTF tumorigenesis, therapeutic targeting of this pathway remains challenging. Wnt/β-catenin target-genes that do form attractive therapeutic targets in DTF are cyclooxygenase (COX), a member of the COX enzyme family (COX1 and COX2) and the vascular endothelial growth factor (VEGF), a protein that regulates angiogenesis. A role of COX in DTF has been indicated by the expression of COX2 and by the expression of phosphorylated, and thus activated, associated growth factors receptors such as the platelet derived growth factor receptor ɑ and ß (PDGF-ɑ and PDGF-ß) 56, 73 . Activation of their receptors (PDGFR-ɑ /PDGFR-ß) takes place by an autocrine/paracrine loop and is initiated by COX2 overexpression due to Wnt/ß- catenin deregulation 56, 73 . Inhibition of COX with sulindac decreased cell proliferation in DTF cell culture and therefore forms an attractive therapeutic target in DTF, especially because COX inhibitors are already widely used in the clinic 56, 57 . Halberg et al. reported decreased DTF tumour numbers in Apc Min/+ p53 -/- mice treated with piroxicam, a drug which is a non-steroidal anti-inflammatory drug (NSAID) which works by inhibiting both prostaglandins and the COX enzyme (Table 1) 58 . A preclinical study by Poon et al. used the non-opioid analgesic drug nefopam (benzoxazocine class), and reported a decrease in ß-catenin levels and cellular proliferation rate, as well as a reduction in tumour number and volume in Apc + / Apc 1638N mice (Table 1) 60 . The working mechanism of this drug in DTF has not been entirely clarified yet, but is presumably due to an inhibition of serine-9-phosphorylation of GSK3-β (Figure 1) 60 . Overexpression of VEGF has been correlated with ß-catenin nuclear staining in DTF 74 . Additionally, microvessel density, a phenomenon correlated to angiogenesis, was shown to be higher in samples with VEGF overexpression. This high vascularity potentially increases the growth potential of DTF tumours 74 . These findings reveal a possible new treatment strategy for DTF by interfering with angiogenesis. Endostatin, an anti-angiogenic protein with the ability to inhibit the Wnt/β-catenin signalling pathway in colorectal cancer cells, directed the induction of cell death in primary FAP-associated DTF-cells in culture 59 . Endostatin has been proven to be well tolerated in a Phase 1 study, with minimal toxicities in patients with solid tumours other than DTF; however, no studies report the use of endostatin for DTF in the clinic 75 . 2