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

基本信息

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
项目类别：
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

项目摘要

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，也是主要的实体瘤。因此，迫切需要确定新的治疗方法。其中一项进步是碳离子放射治疗 (CIRT)，尽管在 2 年间治疗了 20,000 名患者。几十年来，由于恐惧，人们非常不愿意使用这种方式来治疗儿童脑肿瘤这种恐惧是许多问题的结果。关于量化 CIRT 的相对生物有效性 (RBE) 的能力尚未得到解答。带电粒子传递的物理剂量的属性是电离密度，它随粒子电荷的变化而变化电离密度通常用线性能量传递 (LET) 来描述，定义为带电粒子因与电子相互作用而经过每单位距离 𝑑𝑙 时损失的平均能量 𝑑𝐸Δ/𝑑𝑙 对于带电粒子，剂量和 LET 在粒子末端几毫米处急剧增加。粒子停止时的原始布拉格峰主要的不确定性是从剂量和 LET 到生物效应的比例，计算剂量和 RBE 模型在肿瘤和正常组织中以复杂的方式变化。在毫米尺度上模拟剂量、能量和 LET 光谱以及粒子碎片光谱的变化患者的解剖结构并将这些物理特性与生物数据联系起来，这些数据通常是通过体外克隆形成确定的生存测定中的一个关键知识空白是临床上对高 LET 辐射的真实体内组织反应。相关的生物学测定的不确定性是巨大的，并且 RBE 值的错误分配会产生影响。对给定体素的影响在临床实践中可能是灾难性的，因此，RBE 值需要根据我们的中心假设是碳离子放射治疗的优化将可以改善小儿脑肿瘤的疗效，并具有同等或更低的神经功能与 X 射线治疗相比的毒性将使用两个具体目标来检验该假设。必须量化儿童大脑啮齿动物模型中 CIRT 正常组织毒性的 RBE，对于各种与 X 射线治疗相比，目标 2 将测试不同剂量和 LET 的功能和病理终点。工作假设：高 LET 碳离子在控制儿童高级神经胶质瘤方面比因此，这项工作的总体目标是研究正常的脑毒性、认知能力。与儿科患者相关的临床前模型中的副作用、第二癌症风险和抗肿瘤功效，我们将回答以下问题：碳离子疗法对历史上具有抗辐射性的癌症显示出巨大的潜力，是否可以预计将改善儿童高级别神经胶质瘤患者的治疗窗口此外，我们将。贡献有关与所有人相关的治疗风险和神经毒性副作用的基本新知识儿童中枢神经系统肿瘤接受放射治疗。