Improving pediatric brain tumor treatments using FLASH radiotherapy

使用 FLASH 放射治疗改善小儿脑肿瘤治疗

基本信息

批准号：
10653165
负责人：
Charles Limoli
金额：
$ 51.35万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
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：
2021-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10653165
关键词：
Adolescent Animals Attention Behavior Behavioral Blood Vessels Brain Brain Neoplasms Cephalic Child Childhood Childhood Brain Neoplasm Childhood Medulloblastomas Cisplatin Classification Clinic Clinical Clinical Management Clinical Treatment Cognitive Cognitive deficits Cranial Irradiation Data Diagnosis Disease Dose Rate Exhibits Exposure to Female Fractionation Functional disorder Gliosis Goals Hippocampus Human Image Immunocompromised Host Impaired cognition Impairment Implant Injections Ionizing radiation Lead Learning Light Link Longterm Follow-up Magnetic Resonance Imaging Malignant Childhood Neoplasm Malignant neoplasm of brain Memory Methods Modality Modeling Molecular Monitor Mood Disorders Morbidity - disease rate Mus Necrosis Neurocognitive Neurologic Normal tissue morphology Nude Mice Outcome Pathology Patients Pediatric Oncology Performance Physiologic pulse Posterior Fossa Precision therapeutics Prevalence Prognosis Protocols documentation Quality of life Radiation Radiation Tolerance Radiation Toxicity Radiation therapy Regimen Series Spinal Structure Survival Rate Survivors Technology Testing Time Toxic effect Translating Tumor Tissue Vertebral column X-Ray Computed Tomography arm astrogliosis cerebral microbleeds cerebrovascular chemotherapy clinical practice clinical translation clinically relevant cognitive function cohort comparison control cone-beam computed tomography contrast enhanced conventional dosing density executive function improved innovation insight irradiation male medulloblastoma medulloblastoma cell line myelination neoplastic cell nerve stem cell neurogenesis neuroinflammation neuroprotection neurotoxic novel pediatric patients pre-clinical preclinical study preservation radiation effect radiation-induced cognitive dysfunction response side effect stem cells stroke risk therapy outcome tumor tumor growth vascular abnormality white matter

项目摘要

PROJECT SUMMARY Our R01 application entitled, “Improving pediatric brain tumor treatments using FLASH radiotherapy” is focused on translating a novel irradiation modality into clinical practice. Here we will test whether radiation delivered in ultra-high dose rate (one-tenth of second), which far exceed the dose rate used in current clinical practice (minutes), can significantly reduce normal tissue toxicities associated with the radiotherapeutic management of childhood medulloblastoma (MB). The overarching goal is to alleviate the long term neurocognitive and cerebrovascular complications that compromise the quality of life of MB survivors while maintaining tumor control. To achieve these goals, we will undertake studies using clinically relevant FLASH and conventional radiation regimens. Two distinct human MB tumor models will be orthotopically implanted in the brain of nude mice to investigate simultaneously tumor response and neurocognitive function after irradiation. In addition, for long-term follow up, tumor-free mice will also be subjected to cranial irradiation using FLASH or conventional dose rate irradiation. Short-term (1-month) and longer term (4-6 months) studies conducted on tumor bearing and tumor free mice respectively, will critically evaluate tumor control, neurocognitive, cerebrovascular and molecular outcomes in these cohorts. Preclinical studies investigating the response of MB tumors, behavioral performance on multiple learning and memory tasks, vascular structure and integrity and the sparing of the neurogenic niche will unambiguously elucidate many of the mechanisms underlying the neuroprotective effects of FLASH radiotherapy. Data derived from these collaborative studies between UCI and the CHUV will facilitate the clinical translation of FLASH-RT to pediatric oncology, where despite the favorable prognosis of children diagnosed with MB, survivors still suffer a lifetime of complications caused by their prior radiotherapy, a scenario we hope to ameliorate with our innovative FLASH technology.

项目摘要我们的R01应用标题为“使用Flash放射疗法改善小儿脑肿瘤治疗”是专注于将新颖的辐照方式转化为临床实践。在这里，我们将测试是否辐射以超高剂量率（十分之一）递送，远远超过当前临床中使用的剂量率练习（分钟），可以显着降低与放射性治疗相关的正常组织毒性儿童髓母细胞瘤（MB）的管理。总体目标是减轻长期的神经认知和脑血管并发症，损害MB表面的生活质量，而保持肿瘤控制。为了实现这些目标，我们将使用临床相关的闪光进行研究和常规辐射方案。两个不同的人类MB肿瘤模型将是原始植入的在裸鼠的大脑中，在研究之后简单地研究肿瘤反应和神经认知功能辐照。此外，对于长期随访，无肿瘤的小鼠也将受到颅辐照使用闪光或常规剂量辐射。短期（1个月）和长期（4-6个月）研究分别在肿瘤轴承和无肿瘤小鼠上进行，将严重评估肿瘤控制这些队列中的神经认知，脑血管和分子结果。临床前研究调查 MB肿瘤的反应，对多个学习和记忆任务的行为表现，血管结构和完整性和神经源性小众的保留将明确阐明许多机制闪光放射疗法的神经保护作用的基础。这些协作研究得出的数据在UCI和CHUV之间，将促进闪存 - RT向小儿肿瘤学的临床翻译，其中尽管被诊断出患有MB的儿童的预后有利，但生存仍然遭受一生的并发症由他们先前的放射疗法引起的，我们希望通过创新的闪存技术来改善这种情况。