Towards the Development of Double Strand Break Repair Simulation in the Biological Stage of Geant4-DNA

Abstract

Radiotherapy is used to deliver a lethal dose of radiation to a target tumour volume whilst sparing healthy tissue as much as possible. The physical characteristics of protons make them advantageous in this regards as they come to a full stop within the patient at a depth determined by their initial energy. However, it is known that there exists a difference between the biological effect of the same dose delivered through photons compared to that of protons. To understand this difference it is not only important to investigate the differences between the radiations but also how the cell responds to these different challenges presented to it. These challenges are viewed by the cell in terms of damage to its DNA, of which double strand breaks are the most significant. Various mechanisms exist within the cell nucleus to repair these double strand breaks, ranging in complexity from direct ligation through to use of homologous sections of DNA to accurately reconstitute the damaged segment. These processes are not fully characterised, with many challenges posed to both in vitro or in vivo experimentation; not least of which is the overwhelming complexity and interdependencies of the various circuits in the nucleus. In this thesis an in silico approach is presented to investigate these systems. Initially a model of the non-homologous end joining repair pathway is developed. Through this model the compatibility of three experimentally supported mechanisms is demonstrated by fitting the behaviour of the resultant system to literature reported data. This work highlights the importance of motion for correct determination of the overall repair response. The model was then used in combination with track structure damage simulations to investigate which parameters of the physical beam are most impactful on the biological response of the implemented pathway. This work reveals that, for the model detailed in this thesis, the primary determinant of repair fidelity is the number of nearby interactive partners. Whilst the systems implemented in these models are inherently simplified versions of the processes in biological systems, they are still complex enough that intrinsic assumptions and dependencies may go unnoticed. To this end the damage model (developed separately) and the repair model (this work) were tested in combination with models developed at other institutes. From this work we demonstrate that the importance of motion and number of nearby neighbours are conserved between these models despite large differences in their workings and overall complexity. This demonstrates the utility of such inter-comparative work, and to facilitate future collaborations between other researchers in the field, the development of a standard format for reporting DNA damage was initiated. The University of Manchester John-William Warmenhoven Doctor of Philosophy "Towards the Development of Double Strand Break Repair Simulation in the Biological Stage of Geant4-DNA" 30th March 2018

Date of Award	31 Dec 2018
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Ranald Mackay (Supervisor), Karen Kirkby (Supervisor) & Mike Merchant (Supervisor)