Two-pronged therapeutic approach for glioblastoma: high dose radiation therapy then repair of radiation-induced brain injury

胶质母细胞瘤的双管齐下治疗方法：高剂量放射治疗然后修复放射引起的脑损伤

• 批准号: 9751998
• 负责人: Piotr Walczak
• 金额: $ 15.33万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2019-11-10
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9751998
• 关键词: Achievement; Acute; Astrocytes; Blood Vessels; Brain; Brain Injuries; Brain Neoplasms; Calcium; Cells; Cellular Structures; Cerebrovascular system; Complex; Data; Dependence; Development; Disease; Dose; Endothelium; Engraftment; Functional Imaging; Glioblastoma; Glioma; Hemorrhage; Image; Immunocompetent; Individual; Injury; Intra-Arterial Injections; Ischemia; Label; Literature; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of brain; Maximum Tolerated Dose; Mitotic; Modeling; Molecular; Molecular Biology; Mus; Nervous System Physiology; Neuroglia; Neurological Models; Neurons; Patients; Peripheral; Primary Brain Neoplasms; Radiation; Radiation Dose Unit; Radiation Injuries; Radiation induced damage; Radiation therapy; Regenerative Medicine; Reporter; Research; Resistance; Rodent; Rodent Model; Signal Transduction; Site; Testing; Therapeutic; Therapeutic Intervention; Time; Tissues; Transgenic Animals; Transgenic Organisms; Transplantation; Work; Xenograft procedure; anatomic imaging; base; bioluminescence imaging; dysmyelination; experimental study; fetal; imaging platform; improved; intravital imaging; multimodality; myelination; nervous system disorder; neuro-oncology; neurorestoration; oncology; preservation; prevent; progenitor; radiation effect; recruit; regenerative; repaired; restorative treatment; tool; treatment response; treatment strategy; tumor; two photon microscopy; white matter; white matter damage

Over the last few decades, we have witnessed exceptional progress in the fields of regenerative medicine and oncology in terms of defining molecular mechanisms of disease, developing research tools (molecular biology, imaging, transgenic animals) and identifying treatment strategies. While these two fields have overall divergent targets they are can be envisioned as being complementary. Further interfacing is needed: in particular, the field of neuro-oncology may greatly benefit from exploiting all the recent achievements in regenerative medicine. Glioblastoma multiforme (GBM) accounts for approximately 65% of all primary brain tumors and is characterized by low survival, with only 10% of patients surviving >5 years. Radiation therapy dose escalation has been explored but now abandoned due to radiation-induced brain injury, which is primarily manifested by damage to white matter and cerebral vasculature. We believe we can make significant advancements in developing a better cure for GBM. Our preliminary experiments indicate that tumors can be completely eradicated with radiation therapy provided that the dose is sufficiently high. We have shown complete elimination of tumors without reoccurrence with a single dose of 40 or 80 Gy. Importantly, the injury as manifested by white matter damage and the occurrence of hemorrhage as seen on magnetic resonance imaging (MRI) was detectable after 2-3 months, providing an ample time window for therapeutic intervention. We propose to perform a detailed characterization of radiation-induced brain injury following high dose radiation therapy and to test the feasibility of regenerative approaches aiming at reversing or preventing the injury to the most vulnerable components (white matter and vasculature). To this end, we will use a state-of-the art multimodal intravital imaging platform with MRI, bioluminescence imaging (BLI) and two-photon microscopy (2PM).

在过去的几十年里，我们见证了再生医学领域的非凡进步和 肿瘤学在定义疾病的分子机制、开发研究工具(分子生物学、 成像、转基因动物)和确定治疗策略。虽然这两个领域有总体上的分歧 可以想象，它们是相辅相成的目标。需要进一步对接：尤其是， 神经肿瘤学领域可能会从利用再生技术的所有最新成就中受益匪浅 医药。多形性胶质母细胞瘤(GBM)约占所有原发性脑肿瘤的65%。 以低存活率为特征，只有10%的患者存活5年。放射治疗剂量递增 曾被探索过，但现在由于辐射导致的脑损伤而被放弃，主要表现为 脑白质和脑血管受损。我们相信我们可以在以下方面取得重大进展 开发一种更好的治疗GBM的方法。我们的初步实验表明，肿瘤可以完全 只要剂量足够高，就可以用放射疗法根除。我们已经展示了完整的 单次照射40或80Gy可消除肿瘤，无复发。重要的是，受伤的原因 表现为脑白质损害和磁共振所见的出血 磁共振成像(MRI)在2-3个月后可检测到，为治疗干预提供了充足的时间窗口。 我们建议对高剂量辐射引起的脑损伤进行详细的描述。 并测试旨在逆转或预防癌症的再生方法的可行性 对最脆弱的部分(白质和血管)的损伤。为此，我们将使用 具有MRI、生物发光成像(BLI)和双光子显微镜的ART多模式活体成像平台 (下午2时)。

项目成果

Unlocking the potential of ultra-high dose fractionated radiation for effective treatment of glioblastoma.

释放超高剂量分割放射有效治疗胶质母细胞瘤的潜力。

• DOI: 10.21203/rs.3.rs-3500563/v1
• 发表时间: 2023
• 期刊: Research square
• 作者: Lan,Xiao-Yan;Kalkowski,Lukasz;Chu,Cheng-Yan;Jablonska,Anna;Li,Shen;Kai,Mihoko;Gao,Yue;Janowski,Miroslaw;Walczak,Piotr
• 通讯作者: Walczak,Piotr