Analysis of AR/AR-V7signalling pathways in circulating tumour cells of prostate cancer patients

Abstract

Biomarkers detected in liquid biopsy (such as circulating tumour cells, CTCs) demonstrate high concordance with biomarkers detected in conventional tissue biopsy. Prostate cancer, when metastatic, is treated with androgen deprivation therapy (ADT). However, resistance to ADT evolves into a clinical state referred to as castrate resistant prostate cancer (CRPC), in which increased, abnormal, androgen receptor (AR) signalling through changed AR structures (amplification, point mutations or variant expression) occurs. Although CRPC also facilitates development of other, complex signalling pathways that promote cell survival, our hypothesis is that the abnormal AR signalling is tightly linked to PTEN/AKT and Hippo/YAP pathways that contribute to the oncogenic driver role that confers ADT resistance. This PhD project aims to evaluate the role of AR, PTEN, and Hippo driver pathways in CRPC through analysis of CTCs, which have become important biological correlates and sources to study tumour biology in prostate cancer. The main focus was on the AR splice variant 7 (ARV7), a promising predictive and prognostic CRPC biomarker. The overall outcomes of this PhD project were to (i) investigate the role of AR, PTEN, and Hippo pathways implicated in CRPC, (ii) validate liquid-biopsy-detected AR-V7 as a CRPC biomarker, (iii) define the best antibody to detect AR-V7 CTCs in CRPC patient blood, and (iv) optimise methods that enable multiplex immunocytostaining of prostate cancer cells, including CTCs with a view to conduct 'proteomic microscopy' in the future. This work in this PhD puts in place basic procedures and methods that will enable CTC multiplex "proteomic microscopy" a method that could change the current paradigm of CTC analysis by allowing analysis of these rare cells for multiple markers targeting multiple biological pathways at the same time.

Date of Award	2022
Original language	English