Milea Timbergen

43 accelerated tumour growth by using oral contraceptives and tumour regression in menopause are reported 10, 141 . Although DTF does not express ER-α, Deyrup et al. discovered that DTF tumours express ER-ß 142 . The involvement of oestrogens in DTF offers a variety of interesting hormone-related drugs which can be a potential treatment for DTF. Tamoxifen is most extensively studied in the setting of DTF and is often used in various dosages in combination with other drugs, frequently NSAIDs, like sulindac (reviewed by Bocale et al. 143 ). A meta-analysis by Bocale and Rotelli et al. verified that tamoxifen, administered as a single agent, gave an overall response rate (partial or complete response) of 58% (22 out of 38 patients). In combination with NSAIDs, this response rate decreased to 35% 143 . Likewise, toremifene has been shown to have an anti-tumour effect in DTF 71, 144 . Although it does not influence cell proliferation, toremifene decreased the total amount of glycosaminoglycan’s (GAG), TGFß1, collagen and fibronectin levels and it diminished the affinity of type I and II TGFβ1 receptors for 125 I-TGF-ß1 (Table 1) 65, 70 . Toremifene in retrospective clinical studies, administered alone or in combination with other drugs like melatonin, sulindac or IFN-ɑ, yielded an overall complete and partial response rate of 56%. When comparing tamoxifen and toremifene, used as a single agent, no differences in overall response rate were found (reviewed by Bocale et al. 143 ). Raloxifene, a drug initially developed for treating chronic osteoporosis, was administered to thirteen patients with FAP-related DTF which were refractory to other treatments. Eight patients displayed a complete remission and a partial response was seen in five cases 145 . Despite a clear involvement of oestrogens in DTF, response rates to anti-oestrogen agents vary and the number of prospective clinical studies is still limited. One phase 2 trial combined sulindac (NSAID) with tamoxifen in pediatric DTF patients and showed a 1-year PFS of 36% (Table 2) 89 . Future directions and conclusion This review aims to provide a summary of the current knowledge of important, cancer- related signalling pathways in the setting of DTF. The role of Wnt/β-catenin signalling in DTF has been firmly established in numerous studies, showing the presence of β-catenin signalling enhancing mutations in the vast majority of tumours. Therapeutic options targeting the Wnt/β-catenin signalling pathway remain scarce and are not yet widely tested in the clinical setting for DTF. Several clinical trials, targeting other signalling pathways, like Notch and Hedgehog, are currently ongoing, but few study the contribution of these pathways to DTF tumorigenesis. 2