Milea Timbergen

317 pazopanib) 14-18 . The evidence for most of these treatment regimens are based on small sized retrospective cohort studies with heterogeneous study populations. Drugs that form an attractive therapeutic option include gamma-secretase inhibitors. These drugs interfere with the Notch signalling pathway by inhibiting the final Notch processing step by which intra-cellular domain is released to act in the nucleus, consequently blocking Notch signalling 19 . The gamma-secretase inhibitor PF-03084014, later named Nirogacestat, was developed based on the positive results of decreased Notch target protein expression in in vitro studies. This led to the development of several clinical trials 21-23 . The results of the phase 3 trial (Nirogacestat vs. placebo) are currently awaited and will determine if Nirogacestat can be seen as a valid treatment option for DTF 24 . Other randomized data regarding systemic treatments for DTF that is currently available include two tyrosin kinase inhibitors: sorafenib and pazopanib. The first trial reported an advantage for sorafenib in the 2-year progression-free survival (PFS) over placebo (81% (95% confidence interval [CI], 69-96) versus 36% (95% CI, 22-57). The second trial reported an advantage for pazopanib over methotrexate-vinblastin in progression-free proportion of patients measured at 6 months (83.7% (95% CI 69.3–93.2) versus 45% (95% CI 23.1–68.5) 25, 26 . The result of these trials suggest that there seems to be a beneficial effect of tyrosin kinase inhibitors on DTF tumours. These drugs could therefore be seen as a valid treatment option, taking potential side effects and clinical benefits into account 27 . The increased level of β-catenin and consequent aberrant Wnt/β-catenin signalling are characteristics of DTF, but so far they have not yielded any therapeutic opportunities 28 . The cause of nuclear β-catenin accumulation are specific, non-synonymous mutations in the CTNNB1 gene. About 85% of DTF tumours contain a mutation located in exon 3 causing one of the following substitutions: a replacement of threonine to alanine at codon 41 (T41A), a replacement of serine for phenylalanine (S45F), or a replacement of serine for proline (S45P) at codon 45. The relevance for these mutations and their impact on prognosis and clinical growth behaviour remains uncertain. Clinical studies demonstrate clear differences in tumour behaviour between the most common mutation types. S45F-mutated DTF tumours exhibit a higher recurrence rate after primary resection than wild-type (WT) and T41A mutant tumours 29-32 . Several studies demonstrate that S45F tumours have an increased resistance to systemic treatments such as meloxicam 33 , sorafenib 34 , or doxorubicin 35 and that they are more resistant to apoptosis and exhibit deregulation of apoptotic-related genes 35 . 11