A multi-disciplinary in silico strategy to address the radiobiological effects in non-conventional irradiation conditions

The advanced radiotherapeutic strategies aim at reducing toxicity relying on non-conventional administration of therapeutic doses. In particular, the FLASH effect, consists in a relative sparing of non-cancerous tissues obtained by administering irradiation at very high dose rates in short pulses, while a similar effect has been observed using shaped in spatial combs (minibeam effect). In spite of the increasingly accumulating data, the mechanistic determinants of these effects are not completely clarified. In silico studies are particularly challenging, because the radiobiological cascade of events started by irradiation spans 12–15 orders of magnitude in the size/time domains, from the local ionization, to creation and diffusion of radicals damaging DNA, and finally to the cell signaling biochemistry determining its different possible fates. At each different stage, computer modelling requires different techniques which must be matched. Here we report the general workflow of the modelling strategy we developed under the Tuscany Health Ecosystem Spoke-1 PNRR, and within the MIRO-INFN project. The different stages include the use of Monte-Carlo reaction diffusion, atomistic reactive and coarse grained molecular dynamics, development and optimization of low resolution and stochastic empirical models. We exploited a continuous exchange of data between experiment and simulations, used to both validate models, and to support measurement interpretation. AI algorithms are integrated, both in the simulation data analysis and in the models optimization. We illustrate in more detail, a low resolution model of chromatin aimed at unravelling the clustering of damage on DNA, observed in super-resolution fluorescence microscopy images, which displays some differences between conventional and unconventional irradiation modalities By combining different modelling approaches and experimental data in a coherent view we aim at giving global picture of the sub-cell molecular determinants of the sparing effects in non conventional irradiation modality. We acknowledge PNRR-M4C2-I1.5-ECS00000017-Tuscany Health Ecosystem and INFN-CSN5 Minibeam Radiotherapy (MIRO) project.