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

项目摘要/摘要 放射在最致命的中枢神经系统恶性肿瘤的治疗中发挥着核心作用， 胶质母细胞瘤(GBM)，然而，局部控制率，因此，生存，仍然是令人沮丧的疾病。甚至是小说 免疫疗法等治疗方法在治疗GBM方面并未显示出疗效。与此同时，辐射 剂量递增研究表明，局部控制有所改善。然而，剂量递增的治疗是 由于辐射导致周围组织脑坏死的发生率增加，这一点受到了阻碍。高字母 粒子疗法既有可能增加肿瘤细胞的杀伤力，又有可能降低正常组织的毒性 开发有关高LET生物有效性的临床治疗模型所需的数据 正常脑组织和基底膜细胞上的射束稀疏。在考虑结果时，这一事实尤其正确 报告利用适当的环境来产生和生长GBM细胞--人 大脑。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 概述天然的GBM生态位，以便将坏死的发生和进展与肿瘤联系起来 细胞响应与粒子束的物理参数。这些模型包括多细胞类型的人类 脑器官(脑器官)以及具有免疫能力的原位啮齿动物模型。使用这些 模型中，我们将确定可能导致坏死的粒子束的物理因素。这一点意义重大 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和 神经炎。与其说是一起简单的意外、无组织死亡，我们将确定辐射是否 诱导一条有序的程序性细胞死亡途径。总的来说，我们将实现以下目标：(1)确定 治疗基底膜的最佳粒度和分级方法，(2)细胞和分子水平的探讨 辐射致脑损伤的机制，以及(3)开发临床使用的生物效应模型。 所获得的知识将迅速影响脑肿瘤患者的治疗，加快临床进程 介绍胶质母细胞瘤的重离子治疗。

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.