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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：
10570305
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/10570305
关键词：
3-Dimensional Accidents Animal Model Apoptosis Area Biological Biological Models Brain Brain Diseases Brain Glioblastoma Brain Injuries Brain Neoplasms Carbon Cell Death Cell Survival Cells Central Nervous System 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 Malignant Neoplasms Maps Mission Modeling Molecular Mus National Cancer Institute Necrosis Necrosis Induction Neurons Normal tissue morphology Organoids Pathway interactions Patients 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 brain tissue cancer cell cancer rehabilitation cancer 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 pharmacologic phenomenological models physical property postmitotic process optimization 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.

项目总结/文摘