Unravelling the role of PSMA in prostate cancer while assessing the value of PSMA as a novel nano-therapy target

Abstract

Prostate cancer (PCa) is the most common cancer among men in the UK, and while the disease remains localised, radiotherapy represents a major curative treatment modality. In recent years a spotlight has focused on the potential of prostate specific membrane antigen (PSMA) as a disease specific target due to high expression in tumour tissue relative to surrounding normal tissue. As such several valuable diagnostic and therapeutic agents have been developed to exploit this biology, but despite this little is known about the contribution of PSMA to prostate cancer development. The work presented within this thesis aims to develop the wider knowledge base relating to PSMA biology, while also developing a novel PSMA targeting gold nanoparticle to act as a sensitiser to radiotherapy.

Previous studies have showed that PSMA expression positively correlates with Gleason Score and progression to more aggressive disease. Using various cell models with differential androgen receptor activity (LNCaP and C4-2B) along with genetically manipulated PSMA, a series of phenotypic studies were conducted. While the androgen receptor and PSMA have established distinct roles, there is increasingly evidence pointing to an inter-connected relationship. Since AR signaling is the driving force for prostate cancer progression, we conducted various studies co-targeting PSMA and AR. Finally, we observed uptake of PSMA617-PEG2k-AuNP, a novel PSMA targeting gold nanoparticle formulated as part of this PhD study. This targeted nanoparticle resulted in enhanced radiosensitisation in both LNCaP and C4-2B tumour models.

Thesis is embargoed until 31 December 2028.

Date of Award	Dec 2023
Original language	English
Awarding Institution	Queen's University Belfast
Supervisor	Jonathan Coulter (Supervisor) & Niamh Buckley (Supervisor)