HIGH-THROUGHPUT MAPPING OF THE BIOLOGICAL EFFECTS OF PARTICLE THERAPY

Radiation therapy is an essential tool in the cure of many cancer patients. Charged particle based radiation therapies are gaining momentum as the physical dose distributions of ions are superior to standard photons due their limited range. Additionally, charged particle radiation has been shown to have linear energy transfer (LET) specific relative biological effectiveness (RBE) when compared to photons. It is essential to employ accurate biophysical models for particle beams in order to maximize the therapeutic potential of particle therapy through the introduction of biologically optimized treatment planning. The development of such models requires the support of large amounts of accurate physical and biological data for each pristine beam. Unfortunately, such data are limited and difficult to obtain. This work presents the development of a high-throughput irradiation methodology that utilizes automated high-throughput screening techniques to sample multiple locations along a therapeutic ion therapy beam in a single irradiation. Using a special irradiation apparatus designed and validated by our group, RBEs of adherent lung cancer cell lines at 12 positions along proton beams at the MD Anderson Proton Therapy Center (PTC) and the Heidelberg Ion Therapy (HIT) facility were measured. RBEs for helium and carbon ion beams were also measured at the HIT facility. This system was further employed to perform image-based, high-throughput mechanistic DNA damage response studies following exposure to particles at varying LETs. Furthermore, the biological response to particles was examined in additional model systems including glioma stem cell spheroids and normal rat brain organoids. For protons, all model systems demonstrated a rapid rise in RBE beyond the Bragg peak. These findings contrast with several current model predictions which assume the RBE trend linearly scales with proton LET. For the heavier particle measurements, we found absolute RBE values and relative trends comparable to literature values. However, overkill effects occurred for lower LETs than previously reported. DNA damage response assays correlated with RBE measurements. The discrepancy between model predictions and experimental data, especially in the high-LET regions, requires rigorous experimental validation to ensure the accuracy of existing models. The developed high-throughput irradiation system enables the rapid measurement of biological response data which will contribute to a more complete mapping of particle biological effects as well as biological susceptibilities of different cell types to charged particle radiation. Ultimately, this knowledge will contribute to more comprehensive biophysical models and the production of biologically optimized intensity-modulated particle therapy plans