Combined DNA Damage Repair Inhibition and Ion Beam Therapy: Development, Benchmark and Clinical Implications of a Mechanistic Biological Model.

Abstract

PURPOSE/OBJECTIVE(S)\nCellular radiosensitivity is tightly linked to DNA damage repair (DDR) capability. In a clinical context, inhibition of key DDR enzymes within tumor results in improved tumor control after radiotherapy and many preclinical and clinical trials of radiosensitizing drugs targeting DDR enzymes have been recently conducted or launched. Concurrently, interest in ion beam therapy continues to grow globally and its high precision may provide ideal treatment attributes in combination with tumor radiosensitizers. However, most studies of tumor radiosensitization based on DDR inhibition have been or are conducted using prevalent photon beams. Here, a mechanistic model of biological radiation response is presented to accurately translate findings in DDR inhibition studies to the case of charged particle radiation.\n\n\nMATERIALS/METHODS\nThe mechanistic UNIfied and VErsatile bio-response Engine (UNIVERSE) and its model of radiosensitization by DDR inhibition is extended to charged particles by implementing the heterogeneous dose distributions of protons and helium ions utilizing GPU computation. Predictions for monoenergetic and mixed fields over clinically relevant dose and LET range are compared to cell survival data from the literature and own dedicated experiments, including different cell lines and DDR inhibited variants. Our own experimental data represents the first comprehensive measurement of cell survival of repair competent and deficient cell lines in a helium spread-out bragg peak. Ultimately, the predictions of UNIVERSE are considered in a concrete clinical situation based on patient plan recalculations.\n\n\nRESULTS\nUNIVERSE is able to precisely predict cell survival of DDR competent and deficient cell lines in clinically relevant settings of ion beam therapy based only on up to 3 parameters derived solely from conventional photon data. With increasing LET the effect of DDR deficiency reduces. This results in a diminished RBE of ion beam radiation for DDR deficient cells in comparison to DDR proficient cells.\n\n\nCONCLUSION\nThe capabilities of UNIVERSE could lead towards more personalized and biological planning in charged particle therapy, that could be guided by bio-marker based imaging in the future. By increasing the coverage of a tumor with high-LET using modifications of the treatment planning optimizer or advanced irradiation techniques, one could exploit the reduced impact of DDR inhibition at high LET to reduce the adverse effects of heterogeneous tumor radiosensitivity. UNIVERSE could also aid the appraisal of clinical viability of combined administration of radiosensitizing drugs and charged particle therapy and the identification of patients with known DDR inhibition which might not benefit from ion beam therapy, facilitating the management of limited capacities at therapy centers.