Improving pediatric brain tumor treatments using FLASH radiotherapy

使用 FLASH 放射治疗改善小儿脑肿瘤治疗

• 批准号: 10408856
• 负责人: Charles Limoli
• 金额: $ 50.27万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 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/10408856
• 关键词: Adolescent; Animals; Attention; Behavior; Behavioral; Blood Vessels; Brain; Brain Neoplasms; Cephalic; Child; Childhood; Childhood Brain Neoplasm; Childhood Medulloblastomas; Cisplatin; Clinic; Clinical; Clinical Data; Clinical Management; Clinical Treatment; Cognitive; Cognitive deficits; Cranial Irradiation; Data; Diagnosis; Disease; Dose-Rate; Exhibits; Exposure to; Female; Fractionation; Functional disorder; Goals; Hippocampus (Brain); 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; base; cerebral microbleeds; cerebrovascular; chemotherapy; clinical practice; clinical translation; clinically relevant; cognitive function; cohort; cone-beam computed tomography; contrast enhanced; 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

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.

项目概要 我们的 R01 申请题为“使用 FLASH 放射治疗改善儿科脑肿瘤治疗”是 专注于将新型照射方式转化为临床实践。下面我们来测试一下是否有辐射 超高剂量率（十分之一秒）输送，远远超过目前临床使用的剂量率 练习（分钟），可以显着减少与放射治疗相关的正常组织毒性 儿童髓母细胞瘤（MB）的治疗。总体目标是缓解长期 神经认知和脑血管并发症会影响MB幸存者的生活质量 维持肿瘤控制。为了实现这些目标，我们将使用临床相关的 FLASH 进行研究 和常规放射治疗方案。两种不同的人类MB肿瘤模型将被原位植入 在裸鼠大脑中同时研究肿瘤反应和神经认知功能 辐照。此外，为了进行长期随访，还将对无瘤小鼠进行颅脑照射 使用FLASH或常规剂量率照射。短期（1个月）和长期（4-6个月）研究 分别对荷瘤小鼠和无瘤小鼠进行，将严格评估肿瘤控制， 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、多种学习和记忆任务的行为表现、血管结构和 神经源性生态位的完整性和保留将明确阐明许多机制 FLASH 放射治疗的神经保护作用的基础。来自这些合作研究的数据 UCI 和 CHUV 之间的合作将促进 FLASH-RT 向儿科肿瘤学的临床转化，其中 尽管诊断为 MB 的儿童预后良好，但幸存者仍遭受终生并发症 这是由他们之前的放射治疗引起的，我们希望通过我们的创新 FLASH 技术来改善这种情况。