SUMMARY Primary central nervous system (CNS) tumors are the most common solid tumors in children and the leading cause of childhood-cancer-related deaths. Thus, there is an urgent need to identify novel therapeutic treatments. One such advancement is carbon-ion radiation therapy (CIRT). Yet, despite treating 20,000 patients over 2 decades, there is a significant reluctance to use this modality to treat pediatric brain tumors because of a fear that normal tissue would be irreparably harmed. This fear is a consequence of the many questions that are unanswered regarding the ability to quantify the relative biologic effectiveness (RBE) of CIRT. An important attribute of the physical dose delivered by charged particles is ionization density, which varies with particle charge and velocity. Ionization density is frequently described in terms of linear energy transfer (LET), defined as the mean energy lost ππΈβ/ππ by a charged particle per unit distance ππ traversed due to interactions with electrons in matter. For charged particles, the dose and LET increase dramatically over the terminal few millimeters of the pristine Bragg peak as the particle halts. A major uncertainty is the scaling from dose and LET to biological effect, which varies within tumors and normal tissues in a complex manner. The computational dose and RBE models simulate on a millimeter-scale the variation of dose, energy and LET spectra, and particle fragment spectra within the patient anatomy and link these physical properties to biologic data, often determined from in vitro clonogenic survival assays. A critical gap in knowledge is the true in vivo tissue response to high-LET radiation in clinically relevant biological assays. The uncertainty is enormous and the impact of incorrect assignment of an RBE value to a given voxel can be catastrophic in clinical practice. Therefore, RBE values need to be determined with the greatest possible accuracy. Our central hypothesis is that optimization of carbon-ion radiation therapy will allow for improved curative outcomes for pediatric brain tumors, with equivalent or lower neurologic toxicity compared to x-ray therapy. Two specific aims will be used to test the hypothesis. Aim 1 will systematically quantify the RBE of CIRT normal-tissue toxicity in a rodent model of pediatric brain, for various functional and pathologic endpoints, at variable dose and LET, compared to x-ray therapy. Aim 2 will test the working hypothesis that high-LET carbon ions are more effective in controlling pediatric high-grade glioma than conventional radiation. Thus, the overall objective of this work is to investigate the normal brain toxicity, cognitive side effects, second cancer risks, and anti-tumor efficacy in preclinical models relevant for pediatric patients, providing a sound foundation for advancing this modality into clinical practice. We will answer the question as to whether carbon-ion therapy, which shows immense potential for historically radioresistant ...