Clinical transfer of Microbeam Radiation Therapy using a compact source

• Applicant: Dr. Laura Eling, Ph.D.
• Subject Area: Nuclear Medicine, Radiotherapy, Radiobiology ; Hematology, Oncology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 559727057

To date, brain cancers still have poor prognosis due to the normal brain tissue radiosensitivity limiting the efficacy of tumor control by radiation; very few therapeutic improvements have emerged in the last decades. Spatially fractionated radiotherapy (SFRT) has shown benefits in preserving normal brain tissues. Microbeam radiation therapy (MRT) has maximized the benefits of SFRT: X-rays, collimated into an array of quasi parallel, micron-wide beamlets, deliver hundreds to thousands of gray in the microbeam path (peak dose), while the dose diffusing between the beams amounts to only few gray (valley dose). This highly heterogeneous dose distribution results in an excellent normal brain tissue tolerance, while a preferential brain tumor-killing effect has been shown in preclinical studies. MRT has been established at large synchrotron facilities that allow the spatial fractionation of the beam without significant beam divergence due to the ultra-high dose rate. A compact X-ray source, able to produce microbeams, perfectly adapted for an installation in clinics, is currently in the final development phase at the Technical University of Munich, Germany. In this project, we plan to demonstrate that compact source-generated MRT is a relevant and realistic alternative for brain tumor treatment. Funding of this study will thus enable a continued development of MRT, creating a link with the large body of literature available for synchrotron-generated MRT. Using this new compact source, we wish to compare the differences between tumor responses induced by MRT to those induced by conventional radiotherapy (ConvRT). The proposed project aims at clarifying many yet unknown biologic, immunologic and radiation-induced changes in the brain tumor microenvironment. We assume that differential effects elicited by MRT on vascular networks in tumoral and normal tissues are also mediated by immunologic responses, namely the migration and polarization of macrophages in the brain tumor microenvironment. Indeed, we hypothesize that MRT is more efficient than ConvRT because of its induction of the pro-inflammatory, anti-tumoral M1 macrophage phenotype. In contrast, the polarization of macrophages into the anti-inflammatory, pro-tumoral M2 phenotype may explain the resistance of brain tumors to conventional radiation exposures. Using the novel MRT compact source, we will be able to optimize the current irradiation protocol. The proposed work allows the temporal fractionation of MRT, and grants us a unique opportunity that has never been presented before. It will allow the preparation of veterinary phase I MRT trials, and paves the way towards the first human patient treatments in the near future. This research will highlight new concepts for the treatment of brain tumors with compact X-ray sources. All of the information gathered from this project are highly relevant for the improvement of the still unsuccessful treatment approaches against human brain tumors.

• DFG Programme: WBP Position