Investigating combinations of radium-223 and androgen deprivation therapies in advanced prostate cancer

Abstract

Abiraterone and Enzalutamide are anti-androgens shown to be among the treatments to improve overall and progression-free survival in mCRPC. However, although commonly used in clinical settings, many questions exist regarding drug selection, scheduling with radiation, potential synergy with radiation and the underlying mechanisms governing any potential synergy. Another key unexplored area of interest is if the combination of AR inhibitors with the α-emitter radium-223, which targets bone metastases, can be utilised to improve patient response over radium223 alone.

This thesis addressed these issues by conducting the first detailed analysis of the effects of Abiraterone and Enzalutamide alone or in combination with X-rays, radium-223 or Olaparib across a range of biological endpoints, including, survival, DNA damage, cell cycle, DNA repair and cell death across a panel of AR-insensitive (PC3) and AR-sensitive (LNCaP) prostate models and osteosarcoma bone (SJSA-1) models. The results of this study report that in AR-sensitive settings, Abiraterone and Enzalutamide radiosensitise in both low and high LET settings through the downregulation of essential DNA repair proteins involved in homologous recombination (HR) and nonhomologous end joining (NHEJ), with reductions in HR at least in part due to cell cycle distribution changes, resulting in increased levels of DNA damage and cell death. Furthermore, synthetic lethality approaches using Olaparib in combination with Abiraterone or Enzalutamide showed combinations resulted in increased radiosensitisation, DNA damage and cell death over single agent use.

In conclusion, this thesis provides the first in vitro comparison of Abiraterone and Enzalutamide with and without radium-223, demonstrating that while both Abiraterone and Enzalutamide could be used to enhance tumour response, Abiraterone proved superior across all endpoints measured and synthetic lethality approaches could be used to enhance this efficacy even further. Overall this thesis supports that combinations of Abiraterone and Enzalutamide can be utilised with radium-223 to improve tumour response.

Date of Award	Jul 2023
Original language	English
Awarding Institution	Queen's University Belfast
Sponsors	Northern Ireland Department for the Economy
Supervisor	Aidan Cole (Supervisor) & Kevin Prise (Supervisor)