ESTRO 2024 - Abstract Book

S5408

Radiobiology - Tumour biology

ESTRO 2024

Medras performed well in predicting the LET-RBE dependence across a broad range of experimental data from the PIDE (R2=0.77 comparing modelled and observed Mean Inactivation Doses (MID) ). In CRISPR-knockout lines, Medras accurately reproduced the impact of these DNA repair defects on survival following X-ray irradiation (R2>0.85), validating its predictions for low-LET exposures. For higher LET exposures in these systems, Medras once again effectively reproduces overall trends in sensitivity (R2>0.8 comparing modelled and observed MIDs across all lines and LETs). Notably, this model suggests that there is no additional dependence on HR due to individual break complexity at higher LETs, and that instead sensitivity to higher-LET irradiation is highly correlated with that to X-rays.

Modelled and observed DNA repair kinetics were qualitatively similar across the different systems, but precise comparison was complicated by limited resolution in foci immunofluorescence studies.

Conclusion:

This analysis suggests that break complexity and DNA repair pathway choice do not significantly differ in determining response at high LETs compared to low LETs. Consequently, there are no significantly elevated RBEs in HR defective cell lines. Indeed, this analysis suggests that RBEs are generally higher in more resistant cells, suggesting that DNA repair defective cancers may not be the best choice for biological prioritisation for particle therapy.

Keywords: RBE, DNA repair, Predictive modelling

References:

[1] McMahon SJ, Prise KM. A Mechanistic DNA Repair and Survival Model ( Medras ): Applications to Intrinsic Radiosensitivity , Relative Biological Effectiveness and Dose-Rate. Frontiers in Oncology. 2021 Jun 29;11:1–18.

[2] Friedrich T, Pfuhl T, Scholz M. Update ofthe particle irradiation data ensemble (PIDE) for cell survival. Journal of Radiation Research. 2021;62(4):645–55.

[3] Liberal FDCG, McMahon SJ. Characterization of Intrinsic Radiation Sensitivity in a Diverse Panel of Normal, Cancerous and CRISPR-Modified Cell Lines. IJMS. 2023 Apr 26;24(9):7861.

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