Proton beam therapy is increasingly applied in cancer treatment, as it promises to reduce normal tissue damage at critical radiosensitive structures. However, some recent reports point to a potential biological effect of the increased LET of protons at the distal edge of the spread-out Bragg peak (SOBP) in tumor models and normal tissue damage models in vitro and in vivo. So far, potential differences in the biology of induced DNA damage and the resulting cellular responses between irradiation with photons or protons are not well understood. We propose to use state-of-the-art radiobiology endpoints as well as innovative molecular (CRISP/cas9) and cell biology methods (e.g. 2D, 3D culture) and high-resolution microscopy to compare the consequences of irradiation with photons and protons at the molecular (DNA damage and repair) and cellular level (survival, signaling) in tumor cells and normal tissue cells and to explore the consequences of genetic or pharmacologic inhibition of molecular factors involved in the regulation or execution of DNA repair.
The proposed project will define similarities and differences in DNA damage induction and repair, cell survival and cell signaling of tumor and normal tissue cells in response to irradiation with photons and protons (plateau, spread out Bragg peak, distal Bragg peak) and elucidate if cells with specific defects in the DNA damage response might be more sensitive or resistant to proton irradiation. These results are of clinical relevance as they may help to select patients that could particularly benefit from proton or photon therapy and to define rational approaches for combining proton therapy with drugs targeting components of the DNA repair machinery.