Étude des mécanismes biologiques associés à la réponse à la radiothérapie par mini-faisceaux de protons (pMBRT)

Cancer remains one of the leading causes of death worldwide, affecting millions of people each year. Although many cancers can be treated with surgery, chemotherapy, and radiation therapy (RT), certain types of tumors, such as brain tumors, remain particularly challenging to treat due to their location, aggressive growth, and resistance to treatment. Improving cancer therapies is therefore a major challenge for medicine. RT works by using high-energy radiation (such as X-rays) to damage the DNA of cancer cells, preventing them from proliferating and dividing. However, radiation can also affect surrounding healthy tissue, causing side effects. Innovative and unconventional techniques have therefore emerged, such as spatially fractionated radiation therapy (SFRT). Among these, minibeam radiation therapy (MBRT) uses small, parallel beams arranged like the lines of a barcode. This creates alternating areas of high and low radiation doses in the treated region. The goal is to destroy the tumor while allowing healthy tissue in the low-dose areas to repair itself, which could reduce side effects. Another treatment method is the use of protons, which allows the majority of the dose to be delivered to the target volume, i.e. the tumor, while limiting the dose delivered to the surrounding tissue, thereby protecting the skin, for example. To this end, combining protons with MBRT means combining the spatial distribution of doses with the physical advantages of protons, which deposit most of their energy directly in the tumor while delivering a low dose at the entrance. This combination is called proton minibeam radiotherapy (pMBRT). During my doctoral thesis, I studied how this technique works in an experimental animal model of glioblastoma, one of the most aggressive brain tumors. I explored several key biological aspects of pMBRT, from its effect on tumor control to its impact on the tumor microenvironment and on the molecules that cells exchange after irradiation. This biological response was then compared to the well-known biological mechanisms of conventional proton therapy, using a uniform dose delivery pattern routinely employed in clinical practice. My work as shown that pMBRT is less dependent on oxygen than on homogenous dose distribution, a key factor in the effectiveness of RT, and that it can activate stronger and more durable immune responses against the tumor. I have also studied how tumor cells and normal brain cells react and communicate after treatment, particularly via tiny biological “messages” called extracellular vesicles. These results suggest that the specific dose distribution pattern not only directly destroys the tumor, but also alters how the tumor microenvironment, immune system, and vascular respond. Overall, my thesis shows that pMBRT has the potential to become a next-generation therapy for brain tumors, combining increased precision in tumor targeting with unique biological effects. Although further research is needed before it can be used in routine clinical practice, it is a promising step toward safer and more effective treatments.