Radiobiological mechanisms and novel imaging biomarkers in metastatic prostate cancer treated with radium-223

Abstract

Prostate cancer is the most commonly diagnosed form of disease and the most frequent cancer among men in the UK. The vast majority of metastatic prostate cancer patients who initially respond to Androgen deprivation therapy (ADT), will eventually progress to castration-resistant prostate cancer (CRPC). Bone metastases are an extremely common disease state, present in 90% of patients with metastatic CRPC (mCRPC). The use of alpha (α)-particle radionuclide emitters for the treatment of metastatic bone disease is an active area of research in targeted radionuclide therapies, in particular radium-223.

Radium-223 is a targeted α-therapy, which several clinical trials have shown not only to have a palliative benefit but also to improve overall survival of mCRPC patients with bone metastases. The clinical utility of radium-223 has encouraged the combination of current systemic therapies with radium-223 for treatment of patients with mCRPC. Even though the clinical utility of radium-223 has been established, there is a lack of data regarding the underlying mechanisms of radium-223 in the metastatic setting. There is an urgent, unmet need to provide further insight into understanding the radiobiological mechanisms of action of radium-223 in tumour cells so that the use of radium-223 in next generation clinical trials can be designed optimally. The research work presented in this thesis focused on studying the impact of radium-223 exposure in both in vitro and clinical studies of prostate cancer.

The in vitro studies presented in this thesis focused on a better understanding of the radiobiological mechanisms of action of radium-223 in tumour cells. This was possible by evaluating the biological effects of exposure to external (X-rays and α-particle source) and systemic (radium-223) radiation in vitro on a panel of cancer cell lines through various radiobiological endpoints such as cell survival, DNA damage, changes in the cell cycle distribution and the mechanism of cell death. The obtained results indicate that high-LET radiation (radium-223) has a significant impact on prostate and osteoblastic bone models compared to low-LET radiation. Radium-223 was shown to be biologically more effective in inducing cell death compared to external X-ray and α-particle source. This provided new understanding of the impact of radium-223 exposure on cellular response and improved approaches for assessing metastatic bone damage.

In addition, investigation of radiological data of patients in a clinical trial was carried out. In the ADRRAD trial, metastatic castration-sensitive prostate cancer (mCSPC) received radium-223 treatment in combination with EBRT. The clinical studies presented in this thesis focused on studying whether bone tumour metastases in regions receiving both radium-223 and EBRT (in-field) may exhibit differential responses to metastases out-of-field (i.e. those receiving radium-223 only). A novel custom software tool, metastatic bone scan tool (MetsBST) was designed and implemented to offer the ability to delineate different anatomical areas of disease in isotope bone scan (IBS) and investigate differential response in areas of disease receiving multi-modal radiation therapies. This tool was validated by comparing its performance with the automated bone scan index (aBSI). MetsBST can accurately identify and quantify bone metastases on IBS, offering quantitative evaluation of the extent of tumour burden in bone. In addition, the clinical utility of MetsBST for assessment of bone metastases was illustrated by applying it to two different cohorts of patients: castration-resistant and castration-sensitive prostate cancer patients treated with radium-223. MetsBST facilitates the elucidation of changes in targeted anatomical areas, e.g. areas that received the combined treatment of radium-223 and EBRT compared to areas that received a single treatment.

This thesis has provided new understanding of the impact of radium-223 exposure on cellular response and improved approaches for assessing metastatic bone damage. Further work is required to understand mechanisms of action of radium-223 and to fully quantify the impact on bone metastasis in patients.

Date of Award	Jul 2021
Original language	English
Awarding Institution	Queen's University Belfast
Sponsors	Ministry of Education, Saudi Arabia
Supervisor	Joe O'Sullivan (Supervisor), Kevin Prise (Supervisor) & Aidan Cole (Supervisor)