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The role of Frizzled-7 in gastric cancer

Austin, Chloe 2020. The role of Frizzled-7 in gastric cancer. PhD Thesis, Cardiff University.
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Abstract

Gastric cancer (GC) has an extremely low 5-year survival rate of only 30% and is the third-leading cause of cancer-related deaths worldwide. This is predominantly due to the highly metastatic nature of GC and the lack of available treatment strategies, highlighting the urgent and unmet need to identify novel therapeutic targets. The Wnt receptor Frizzled-7 (FZD7) regulates cell proliferation, epithelial-mesenchymal-transition (EMT), and invasiveness in many cancers. GC patients have mutations in genes that participate in or regulate Wnt signalling at the level of the Wnt receptor binding. Moreover, FZD7 is reported to be overexpressed in human gastric tumours suggesting that aberrant FZD7-mediated Wnt signalling drives GC growth and highlights FZD7 as a potential therapeutic target. However, the precise involvement of FZD7 in GC remains unclear and the specific Wnt receptor transmitting oncogenic Wnt signalling is unknown. Additionally, loss of function mutations to the negative regulator of the Wnt pathway, RNF43, has been implicated in the poor prognosis of GC. However, its functional significance in GC remains unknown. We have implicated FZD7 as the predominant Wnt receptor involved in the growth, EMT, migration and invasion of GC cells irrespective of APC mutation. Here we used inhibitors of Wnt/FZD (OMP-18R5/LGK-974) and shFZD7 to test the therapeutic potential of targeting Wnt signalling in GC. Pharmacological targeting of FZD inhibited the growth of GC in vitro and in vivo. Furthermore, we have confirmed the functional significance of RNF43 in GC. Conditional deletion of RNF43/ZNRF3 led to gastric tumours supporting the hypothesis of stratifying GC patients based on RNF43 mutations. OMP-18R5 and LGK-974 are currently in phase Ib clinical trials for multiple cancers. Our data expands the scope of patients that may benefit from these therapeutic approaches as we have demonstrated that these drugs are effective in treating GC patients regardless of APC mutation status.

Item Type: Thesis (PhD)
Date Type: Completion
Status: Unpublished
Schools: Biosciences
Subjects: Q Science > Q Science (General)
Date of First Compliant Deposit: 23 October 2020
Last Modified: 26 Oct 2020 11:19
URI: http://orca.cf.ac.uk/id/eprint/135885

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