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

在综合人体类器官模型中确定治疗 GBM 的最佳离子和分级方案

基本信息

批准号：
10360627
负责人：
DAVID R GROSSHANS
金额：
$ 46.13万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-01 至 2026-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10360627
关键词：
3-Dimensional Animal Model Apoptosis Area Biological Biological Models Brain Brain Diseases Brain Glioblastoma Brain Injuries Brain Neoplasms Carbon Carbon ion Cell Death Cell Survival Cells Cerebrum Cessation of life Clinical Clinical Treatment Clinical Trials Coculture Techniques Data Deposition Disease Dose Dose Fractionation Effectiveness Environment Fractionation Glioblastoma Glioma Growth Heavy Ions Heterogeneity High-LET Radiation Human Immunocompetent Immunotherapy In Vitro Incidence Ions Knowledge Lead Malignant Neoplasms Maps Mission Mitotic Modeling Molecular Mus National Cancer Institute Necrosis Necrosis Induction Neuraxis Neurons Normal tissue morphology Organoids Pathway interactions Patients Pharmacology Photons Play Protons Public Health Radiation Radiation Dose Unit Radiation necrosis Radiation therapy Relative Biological Effectiveness Reporting Research Research Support Rodent Model Roentgen Rays Role Scheme Signal Pathway Survival Rate System Tissues Toxic effect Transgenic Animals Treatment Efficacy Variant base brain tissue cancer cell cancer rehabilitation cancer therapy carbon ion therapy cell killing cell type clinical practice clinically relevant combinatorial density design disorder control improved in vitro Model in vivo in vivo Model induced pluripotent stem cell interest ionization irradiation neoplastic cell neuroinflammation novel novel therapeutics particle particle beam particle therapy patient response phenomenological models physical property process optimization programs proton therapy radiation resistance radiation response radioresistant response stem cells success therapy development treatment planning treatment response tumor

项目摘要

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.

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发挥着核心作用，胶质母细胞瘤（GBM），但这种疾病的局部控制率和生存率仍然很低，甚至是一种新疾病。免疫疗法等疗法尚未显示出治疗 GBM 的功效。剂量递增研究已证明局部控制得到改善，但剂量递增治疗仍存在局限性。高 LET 导致周围组织中辐射引起的脑坏死发生率增加，从而阻碍了这一进程。粒子疗法具有增加肿瘤细胞杀伤和降低正常组织毒性的潜力，但开发有关高 LET 生物学有效性的临床治疗模型所需的数据考虑到结果时，正常脑组织和 GBM 细胞上的光束是稀疏的。据报道，利用适当的环境来促进GBM细胞的起源和生长——人类我们已经实施了最近开发的高精度模型，这些模型真正开始了。概括天然 GBM 生态位，以便将坏死诱导和进展与肿瘤相关联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。脑类器官（大脑类器官）以及具有免疫能力的原位啮齿动物模型。模型中，我们将识别出可能导致坏死的粒子束物理因素，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中，我们将研究坏死和坏死的分子机制。我们将确定是否是辐射引起的，而不是简单的意外、无组织的死亡。总体而言，我们将实现以下目标：（1）确定。治疗 GBM 的最佳颗粒分级，（2）探索细胞和分子辐射引起的脑损伤的机制，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并加快临床进展介绍胶质母细胞瘤的重离子治疗。