Determining the optimal ion and fractionation scheme for the treatment of GBM in a comprehensive human organoid model

项目概要/摘要 放射在最致命的中枢神经系统恶性肿瘤的治疗中起着核心作用， 胶质母细胞瘤（GBM），但局部控制率以及因此存活率对于这种疾病仍然令人沮丧。甚至小说 诸如免疫疗法的疗法在GBM的治疗中没有显示出有效性。同时，辐射 剂量递增研究已证明局部控制得到改善。然而，剂量递增治疗 受到周围组织中辐射诱导的脑坏死的发生率增加的阻碍。高let 粒子疗法具有既增加肿瘤细胞杀伤又降低正常组织毒性的潜力， 开发高LET生物学有效性临床治疗模型所需的数据 正常脑组织和GBM细胞上的光束很少。在考虑结果时，这一事实尤其正确 报道了利用GBM细胞起源和生长的适当环境-人 个脑袋我们已经实施了最近开发的高精度模型，这些模型真正开始 概括天然GBM生态位，以便将坏死诱导和进展与肿瘤 细胞反应与粒子束的物理参数。这些模型包括多细胞类型的人 脑类器官（脑类器官）以及免疫活性原位啮齿动物模型。使用这些 模型，我们将确定粒子束的物理因素，可能导致坏死。这是重要 因为这些数据将通过减少坏死和改善疾病控制来帮助设计更安全的治疗方法。 在我们研究的第二部分，我们将研究坏死的分子机制， 神经炎症而不是一个简单的意外，无组织的死亡，我们将确定是否辐射 诱导有序的程序性细胞死亡途径。总体而言，我们将实现以下目标：（1）确定 探讨治疗GBM的最佳颗粒和分级方法;（2）探讨GBM的细胞和分子生物学特性， 放射性脑损伤的机制;（3）建立临床应用的生物效应模型。 所获得的知识将迅速影响脑肿瘤患者的治疗，加快临床 胶质母细胞瘤重离子治疗简介

PROJECT SUMMARY/ABSTRACT Radiation plays a central role in the management of the most lethal central nervous system malignancy, glioblastoma (GBM), yet local control rates, and hence survival, remain dismal for this disease. Even novel therapies, such as immunotherapy, have not shown efficacy in the treatment of GBM. Meanwhile, radiation dose escalation studies have demonstrated improved local control. However, dose escalated treatments are hindered by the increased incidence of radiation induced brain necrosis in surrounding tissues. High LET particle therapy holds the potential to both increase tumor cell kill and decrease normal tissue toxicity, yet the data required to develop models for clinical treatments regarding the biological effectiveness of high LET beams on normal brain tissue and GBM cells is sparse. This fact is especially true when considering results reported utilizing the appropriate environment for the origination and growth of GBM cells – the human brain. We have implemented recently developed high accuracy models which are truly beginning to recapitulate the native GBM niche in order to correlate both necrosis induction and progression and tumor cell response with the physical parameters of particle beams. These models include multi-cell type human brain organoids (cerebral organoids) as well as immune-competent orthotopic rodent models. Using these models, we will identify the physical factors of particle beams which may lead to necrosis. This is significant in that this data will aid the design of safer treatments by reducing necrosis and improving disease control. In the second component of our study, we will examine the molecular mechanisms of necrosis and neuroinflammation. Rather than being a simple accidental, disorganized death, we will determine if radiation induces an orderly programmed cell death pathway. Overall, we will conduct the following aims; (1) identify the optimal particle and fractionation for treatment of GBM, (2) explore the cellular and molecular mechanisms of radiation induced brain damage, and (3) develop biological effect models for clinical use. The knowledge gained will quickly influence the treatment of brain tumor patients and expedite the clinical introduction heavy ion therapy for glioblastoma.