ESTRO 2024 - Abstract Book

S5407

Radiobiology - Tumour biology

ESTRO 2024

2305

Digital Poster

Mechanistic modelling of the interaction between DNA repair defects and radiation quality

Francisco Liberal, Stephen J McMahon

Queen's University Belfast, Patrick G Johnston Centre for Cancer Research, Belfast, United Kingdom

Purpose/Objective:

While particle therapy (utilizing protons or carbon ions) has undergone rapid expansion in recent years, its availability remains limited. Consequently, there is considerable interest optimizing both the use of these therapies and their allocation across diverse patient populations. While dosimetric concerns dominate decision-making, radiation quality effects and individual patient biology are areas of interest to further refinements. Radiation quality is significant due to the connection between the Linear Energy Transfer (LET) of radiation and its Relative Biological Effectiveness (RBE). Higher LETs delivered by particle therapies being associated with greater RBEs. However, the robust optimisation of these parameters remains complex, and is further complicated by a potential relationship with patient genetics. Notably, DNA repair defects in the Homologous Recombination (HR) pathway have been suggested to preferentially sensitise cells to high-LET radiation. This may indicate these patients should be prioritised for particle therapy, but the relationship remains incompletely understood.

In this work, we apply integrated models of radiation quality and DNA repair capacity to explore the interplay of these effects in relevant in vitro model systems.

Material/Methods:

This study applies the Medras (Mechanistic DNA Repair and Survival) model to simulate cellular radiation responses [1]. Medras describes the repair and misrepair of DNA damage, considering its yield and spatial distribution as a function of LET, as well as the fidelity of repair based on the availability and activity of relevant DNA repair pathways. Notably, however, Medras does not consider individual break complexity as a factor in misrepair probability. For a given radiation exposure and DNA repair capacity, Medras predicts endpoints such as survival, DNA damage yield and repair, and yields of chromosome aberrations and mutations. We benchmarked Medras’ predictions against various datasets, including a systematic review of the Particle Irradiation Data Ensemble (PIDE) database [2]. Additionally, using CRISPR-Cas9, we generated RPE-1 normal human cells with defined deletions in key DNA repair genes (including ATM, BRCA1, DCLRE1C, LIG4, PRKDC, TP53 and FANCD2). These cells were exposed to X-rays, low and high LET protons (1 and 12 keV/µm) and alpha particles (129 keV/µm), after which survival and DNA repair kinetics (via 53BP1 immunofluorescence) were evaluated [3]. These experiments were used to verify Medras’ predictions of the impact of both DNA repair defects and high-LET exposures.

Results: