Exploiting an understanding of the oncofetal protein 5T4 in the management of epithelial ovarian cancer

Abstract

5T4 is a tumour associated antigen whose expression correlates with tumour stage and progression free survival in ovarian cancer. In vitro, 5T4 expression has been associated with a more migratory phenotype that may be, in part, linked to its putative function in chemokine and Wnt pathways. This suggests a role for 5T4 as a marker of the activation of key pathways in metastasis and recurrence. Elimination of 5T4 expressing tumour cells may offer a promising therapeutic approach to limit tumour spread and prevent progression in women with epithelial ovarian cancer. This project aimed to explore the functional and molecular consequences of 5T4 expression using TALEN and CRISPR-mediated knockout in epithelial ovarian cancer cell lines and to demonstrate proof of principle that targeting 5T4 expressing tumour cells may delay cancer progression in an in vivo model. Functional and transcriptomic data provides further evidence for the role of 5T4 in cell morphology, movement and Wnt response, whilst highlighting the involvement of compensatory networks in determining the ultimate biological response which occurs in response to 5T4 expression. Molecular pathway prediction and network modelling identified epidermal growth receptor (EGFR), cyclin H (CCNH) and heat shock protein 90 (HSP90AA1) as key regulators of this functional response. These proteins play pivotal roles in the response to environmental and genotoxic shock. Their association with the 5T4 phenotype suggests that these factors may trigger tumour cells to express 5T4; promoting a migratory, tumour initiator cell-like phenotype. Concurrent treatment with the 5T4 antibody-drug conjugate A1mcMMAF and carboplatin reduces tumour growth, delays progression and prolongs survival in a SKOV3 xenograft model. These data support further work to determine the mechanism for the additive effect seen with carboplatin and A1mcMMAF and its efficacy in clinical trials.

Date of Award	1 Aug 2018
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Peter Stern (Supervisor), Henry Kitchener (Supervisor), David Gilham (Supervisor) & Lynne Hampson (Supervisor)