The Role of human DNA-binding Proteins during FLASH radiotherapy with ultra-high dose-rates

• Applicants: Dr. Marc Benjamin Hahn; Privatdozent Dr. Harald Seitz
• Subject Area: Physical Chemistry of Molecules, Liquids and Interfaces, Biophysical Chemistry ; Biophysics ; Medical Physics, Biomedical Technology
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 442240902

One of the main challenges during radiotherapy to treat cancer is to spare healthy tissue while delivering a sufficient radiation dose to the tumour. Here, the problem is, that under conventional treatment conditions with low dose-rates the mutated cancer cells are often more radiation resistant than the healthy cells. In contrast, recent experiments in animal models have shown that the relative radio-sensitivity of various cancer cell lines increases in comparison to their healthy counterparts, when ultra-high dose-rates are applied. This behaviour is known as the “FLASH effect”, and is envisioned to provide new ways of overcoming the limitations of current therapies, by allowing for a more efficient delivery of the therapeutic dose. This improved selectivity would directly lead to better tumour control and thus more successful therapies. Despite it’s high potential, little is known about the underlying, molecular mechanisms of the FLASH effect. In particular, the question needs to be answered "which intrinsic differences between healthy and cancerous tissues lead to their different dose-rate dependent radiosensitivity", in order to fully exploit the potential of FLASH based therapies. In addition to DNA, proteins are essential for all cellular functions and play an important role in the radiation response of cells. Moreover, protein expression varies considerably between different cells, so they are thought to play a key role in understanding differences in radiation sensitivity. In order to understand the radiation response of proteins under FLASH conditions, the dose-rate dependence, the influence of the oxygen content in the cells and the radical chemistry involved, are of great interest. Therefore, we investigate the influence of these parameters in model systems of selected DNA binding proteins. The first type are single-strand binding proteins, which are involved in DNA replication and repair. The second type binds to double-stranded DNA and are DNA transcription factors involved in gene regulation. This project will quantify the radiation response of the above systems at different dose-rates, ranging from settings used in conventional radiotherapy to the ultra-high dose rates where the FLASH effect is observed. Therefore, irradiation of proteins at ultra-high dose rates and subsequent analytics are combined with computational Monte Carlo simulations, to understand the associated damage mechanisms at the molecular level. Considering the current controversy in the literature about the mechanisms underlying the FLASH effect, the results obtained during this project will provide valuable information to gain a deeper understanding, and bring FLASH radiotherapy closer to clinical application.

• DFG Programme: Research Grants