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: 10269365
• 负责人: Charles Limoli
• 金额: $ 52.79万
• 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/10269365
• 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.

项目摘要 我们的R 01申请题为“使用FLASH放射疗法改善儿科脑肿瘤治疗”， 专注于将一种新的放射疗法转化为临床实践。在这里，我们将测试辐射是否 以超高剂量率（十分之一秒）输送，远远超过目前临床上使用的剂量率。 实践（分钟），可以显着减少与放射性相关的正常组织毒性 儿童髓母细胞瘤（MB）的管理。首要目标是缓解长期 神经认知和脑血管并发症损害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 和常规的放射疗法。将原位植入两种不同的人MB肿瘤模型 在裸鼠脑中同时研究肿瘤反应和神经认知功能， 辐照此外，为了长期随访，无肿瘤小鼠也将接受颅脑照射 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 分别在荷瘤和无瘤小鼠中进行，将严格评价肿瘤控制， 这些队列的神经认知、脑血管和分子结果。临床前研究 MB肿瘤的反应，多个学习和记忆任务的行为表现，血管结构和 完整性和保留神经原性小生境将明确阐明许多机制 这是FLASH放疗的神经保护作用的基础。从这些合作研究中获得的数据 UCI和CHUV之间的合作将有助于将FLASH-RT临床转化为儿科肿瘤学， 尽管确诊患有MB的儿童预后良好，但幸存者仍会遭受终生的并发症 我们希望通过我们的创新FLASH技术来改善这种情况。