Biophysical modelling across different radiation therapy modalities

Most cancer patients will receive ionizing radiation as a part of their treatment. Although current treatment modalities avail from technology that promote more conformal dose distributions, the inclusion of biophysical knowledge in treatment optimization remains as a largely unexplored frontier. Clinical dose-response models disregard the complexity of the underlying biology, particularly in modern techniques where radiosensitivity can be modulated by intrinsic characteristics, extrinsic factors and how radiation is delivered. There is a pressing need of an accurate description of the mechanisms involved in the interactions between ionizing radiation and biological tissues, and how this could be optimized to maximize therapeutic benefit. The development of more detailed mechanistic approaches is required to change the current clinical paradigm, unravel dose-response mechanisms and promote an optimized application of biophysical dose-response modelling.

DNA damage is the driving mechanism of biological response. Monte Carlo (MC) track-structure simulations characterize the interaction of radiation at the DNA scale and can be used for the first description of biological effects from radiation. A series of cellular repair mechanisms will then act on the initial damages. Here, the damage detection and response are critical to determine the radiosensitivity of the tissue. Different models for external beam radiotherapy consider cell-specific fitting parameters which can be of limited use in general radiosensitivity prediction. Moreover, the translation of such models to targeted radionuclide therapy (TRNT) comprehends additional challenges as models should consider the radiopharmaceutical biodistribution over time, variation in kinetics, the spatiotemporal distribution of particles and differences in how densely energy is deposited within the cells.

The aim of this PhD is to develop a framework for mechanistic dose-response modelling. The framework will be gradually built, increasing its level of complexity, considering morphology, physical interactions, initial distributions of DNA damage and following repair processes. The goal is to establish a workflow in which complex characteristics, e.g. intrinsic to radionuclides, such as heterogeneity or dose-rate effects, can be further explored, incremented and validated from experimental assays.

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