Project Funding Details

Radiotherapy (RT) plays a pivotal role in the treatment of many types of cancer. Up to now, RT treatment schedules have been optimized according to the intrinsic radiosensitivity of tumour cells established in in-vitro experiments, without considering the complex biological interactions between the tumour and the so-called tumour microenvironment (TME). However, these effects play a crucial role when RT is combined with systemic treatment (e.g. chemotherapy, immunotherapy, radiosensitizers) in order to improve tumour control. We hypothesize that irradiation affects the TME characteristics, in particular the microvasculature, that sustain tumour growth and sensitivity to RT. To test this hypothesis, we will adopt a multi-modal approach: advanced in vitro experiments coupled to computational modelling and in-vivo clinical evaluation. (1) To measure damage to microvessels on microfluidic chips as a function of dose, using a clinical linear accelerator; (2) To adapt a pre-existing computational model of microcirculation to include the effects of radiation damage and to validate it upon experimental results; (3) To predict the effects of radiation on the tumour microenvironment and the surrounding normal tissue; (4) To validate the model predictions with the observed outcome on patients, by measuring the damage to microcirculation in a population of prostate/breast/head-and-neck cancer patients as a function of dose. (5) According to the conclusions on its predictive capability, to use the model to assess the hypothesis and to design guidelines to improve the efficacy of RT. Pre-clinical setting: Production of perfusable microvascular networks cultured on microfluidic devices, irradiation of chips at a clinical linear accelerator and measure of the damage to microvessels as a function of dose; In-silico setting: Computational modelling of the radiation induced microvascular damage and of its effect on tumour microenvironment and surrounding normal tissue, as a function of dose, dose/fractionation, radiation type, repair of sublethal damage. Tuning and validation using results from pre-clinical and clinical experiment; In-vivo setting: Clinical trial to measure damage to microcirculation in a population of prostate/breast/head-and-neck cancer patients as a function of dose (a) Development of a validated model with respect to the clinical need of describing the causal interactions among radiation, microcirculation damage and TME; (b) Quantitative evaluation of model adequacy in interpreting in-vivo results accrued through clinical trial; (c) Possibility of designing combined therapy schemes to improve RT effectiveness; (d) Increase of the power of in-vitro studies using microfluidic chips in the domain of radiobiology/radiotherapy. In future, the progress in technology coupled to radiation studies could aid development of new experiments, such as the study of the response to radiation of microfluidic devices seeded with both tumour and vasculature. The project will give a deeper understanding of the complex relationships between the tumour and its microenvironment and it is expected to have an important impact on the development of optimally combined therapy schemes, including immunotherapy, chemotherapy, use of radiosensitizers and radiotherapy at different doses, fractionations and with different radiation type. This will open the way to the design and optimization of effective trials combining different modalities, rationalizing the schemes to be proved.