Optimizing Carbon Ion Therapy for Pediatric CNS Tumors

优化小儿中枢神经系统肿瘤的碳离子治疗

• 批准号: 10735860
• 负责人: John G. Eley
• 金额: $ 60.31万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-18 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10735860
• 关键词: Acute; Address; Adult; Anatomy; Biological; Biological Assay; Biology; Blood Vessels; Brain; Brain Neoplasms; Cancer Patient; Carbon ion; Central Nervous System; Central Nervous System Neoplasms; Cessation of life; Charge; Childhood; Childhood Brain Neoplasm; Childhood Central Nervous System Neoplasm; Childhood Glioma; Chronic; Clinical; Cognitive; Complex; Control Groups; Cranial Irradiation; DNA Damage; Data; Development; Dose; Electrons; Exposure to; Foundations; Fright; Genetic Diseases; Glioma; Heterozygote; High-LET Radiation; Immune response; Immunocompetent; Immunohistochemistry; Impaired cognition; In Vitro; Induced Mutation; Knowledge; Laboratories; Late Effects; Linear Energy Transfer; Link; Longevity; Low Dose Radiation; Malignant - descriptor; Malignant Childhood Neoplasm; Malignant Neoplasms; Malignant neoplasm of brain; Malignant neoplasm of central nervous system; Mediating; Methods; Modality; Modeling; Monitor; Mus; Neurologic; Neurosciences; Normal tissue morphology; Outcome; Outcome Assessment; PDGFRA gene; Pathologic; Patients; Pediatric Neoplasm; Physics; Pre-Clinical Model; Property; Protons; Radiation; Radiation Dose Unit; Radiation Oncology; Radiation therapy; Relative Biological Effectiveness; Research; Risk; Rodent Model; Roentgen Rays; Second Primary Cancers; Solid Neoplasm; TP53 gene; Testing; Therapeutic; Tissues; Toxic effect; Treatment outcome; Tumor Tissue; Uncertainty; United States National Aeronautics and Space Administration; Variant; Work; X-Ray Therapy; behavior test; biophysical properties; cancer risk; carbon ion therapy; clinical practice; clinically relevant; density; disorder control; efficacy evaluation; experience; high-LET heavy ion therapy; human disease; improved; in vivo; in vivo imaging; insight; interdisciplinary approach; ionization; millimeter; mosaic analysis; neurogenesis; neuroinflammation; neurotoxic; novel therapeutics; particle; particle therapy; pediatric patients; physical property; pre-clinical; radiation carcinogenesis; radiation risk; radioresistant; recombinase-mediated cassette exchange; response; side effect; sound; treatment risk; tumor; tumor growth; white matter damage

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 𝑑𝐸∆/𝑑𝑙 by a charged particle per unit distance 𝑑𝑙 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 cancers, can be expected to improve the therapeutic window for pediatric high-grade glioma patients. Furthermore, we will contribute fundamental new knowledge regarding treatment risks and neurotoxic side effects relevant for all pediatric CNS tumors treated with radiation.

概括 原发性中枢神经系统（CNS）肿瘤是儿童中最常见的实体瘤 与儿童相关死亡的原因。这是迫切需要确定新型治疗疗法的。 这样的进步是碳离子放射疗法（CIRT）。然而，目的地治疗20,000名患者2 几十年来，由于担心 正常的组织将受到无法弥补的损害。这种恐惧是许多问题的结果 关于量化CIRT相对生物学有效性（RBE）的能力的未解决的能力。一个重要的 带电颗粒传递的物理剂量的属性是电离密度，它随粒子电荷而变化 和速度。电离密度经常用线性能传递（LET）描述，定义为 平均能量损失𝑑𝐸∆/𝑑𝑙通过单位距离的带电粒子𝑑𝑙由于与电子的相互作用而越过 在物质上。对于带电的颗粒，剂量和让末端急剧增加 原始的bragg峰值停止。一个主要的不确定性是从剂量和生物学作用的缩放， 以复杂的方式在肿瘤和正常组织中范围。计算剂量和RBE模型 在毫米级上模拟剂量，能量和LET光谱和粒子片段的变化 患者解剖结构并将这些物理特性与生物数据联系起来，通常由体外克隆性确定 生存测定。知识的关键差距是临床上对高LET辐射的真实体内组织反应 相关的生物测定。不确定性是巨大的，并且不正确分配RBE值的影响 在临床实践中，给定的素可能是灾难性的。因此，需要用 最大的准确性。我们的中心假设是优化碳离子辐射疗法将 允许改善儿科脑肿瘤的治愈结局，具有等效或较低的神经系统 与X射线治疗相比，毒性。将使用两个具体目标来检验假设。目标1意志 在小儿大脑的啮齿动物模型中系统地量化CIRT正常组织毒性的RBE 与X射线治疗相比，可变剂量和LET的功能和病理终点。 AIM 2将测试 工作假设，高量碳离子在控制小儿高级神经胶质瘤方面比 常规辐射。这项工作的总体目的是研究正常的脑毒性，认知 与小儿患者相关的临床前模型中的副作用，第二种癌症风险和抗肿瘤效率， 为将这种方式推进临床实践提供了合理的基础。我们将回答有关的问题 碳 - 离子疗法是否显示出历史上放射性癌的巨大潜力，可以是 预计将改善儿科高级神经胶质瘤患者的治疗窗口。此外，我们会的 关于治疗风险和与所有人相关的神经毒性副作用的基本知识 用辐射治疗的小儿中枢神经系统肿瘤。