Enhancing the efficacy of Radiation Therapy for brainstem glioma by targeting ATM

通过靶向 ATM 提高脑干胶质瘤放射治疗的疗效

• 批准号: 10448205
• 负责人: Zachary Reitman
• 金额: $ 21.35万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10448205
• 关键词: Address; Adult; Ataxia; Brain; Brain Neoplasms; Brain Stem; Brain Stem Glioma; Cells; Central Nervous System Neoplasms; Cessation of life; Child; Childhood Brain Neoplasm; Classification; Clinical Trials; Clinical Trials Design; Combined Modality Therapy; DNA Damage; Data; Diffuse intrinsic pontine glioma; Enterobacteria phage P1 Cre recombinase; Etiology; Future; Genetic; Genetically Engineered Mouse; Genomics; Glioma; Goals; H3 K27M mutation; Histones; Immune; Immune response; Immune system; Immunocompetent; Immunologics; Immunotherapeutic agent; Immunotherapy; Innate Immune Response; Interferon Type I; Interferons; Investigation; Ionizing radiation; Lead; LoxP-flanked allele; Maps; Mediating; Modeling; Molecular; Mus; Mutate; Mutation; Neurologic Symptoms; Oncogenes; Pathway interactions; Patients; Pharmacology; Phenotype; Population; Process; Protein-Serine-Threonine Kinases; Radiation Tolerance; Radiation therapy; Radiosensitization; Research Personnel; Resolution; Retroviridae; Signal Pathway; Signal Transduction; System; Testing; Therapeutic; Time; Tissues; Treatment-related toxicity; Work; World Health Organization; cell injury; clinical investigation; design; diffuse midline glioma; driver mutation; ds-DNA; effective therapy; epigenetic therapy; experimental study; improved; in vivo; inhibitor; mouse model; neoplastic cell; nerve stem cell; novel; novel therapeutic intervention; pre-clinical; progenitor; radiation resistance; rational design; recruit; reduce symptoms; response; sensor; treatment strategy; tumor; tumor immunology; tumor microenvironment; tumor progression

Enhancing the efficacy of radiation therapy for brainstem glioma by targeting ATM Project Summary/Abstract Brainstem gliomas are devastating pediatric brain tumors. Brainstem gliomas include “diffuse midline gliomas with H3K27M mutation” in the 2016 World Health Organization Classification of Tumors of the CNS, and includie tumors previously referred to as “diffuse intrinsic pontine gliomas” or DIPG. Brainstem gliomas are uniformly lethal to the patients. Radiation therapy is thought to be the only effective treatment for these tumors, providing temporary relief from symptoms and from tumor progression. However, brainstem gliomas inevitably progress after radiation therapy and result in death of the patient resulting in a median survival of less than one year. New strategies are needed to improve the efficacy of radiation therapy to improve patient survival. One promising investigational therapeutic strategy is to radiosensitize tumors by inactivating the serine/threonine kinase Ataxia Telangiactasia Mutated (ATM). ATM is the master sensor for DNA damage, and orchestrates the DNA damage response after cells are damaged by ionizing radiation or other DNA damaging agents. ATM inactivation dramatically radiosensitizes a genetically engineered mouse model of brainstem glioma. When ATM is inactivated in the tumor cells of our mouse model of brainstem glioma, radiation therapy is particularly effective and extends median overall survival of the mice by approximately threefold compared to mice bearing tumors with intact ATM. However, the specific cell populations that are radiosensitized by ATM inactivation, and the mechanisms by which ATM inactivation radiosensitizes brainstem gliomas, is unknown. A deeper understanding of the molecular mechansisms by which ATM inactivation can radiosensitize brainstem gliomas is needed to enable the rational design of combination therapies that combine ATM inhibition, radiation therapy, and other novel epigenetic and immunologic therapies to maximize survival of patients with brainstem gliomas. Here, I will test the hypothesis that ATM inactivation specifically radiosensitizes a population of progenitor-like tumor cells in our genetically engineered mouse model of brainstem glioma. In parallel with this work, I will dissect type I interferon signaling pathways that are contribute to radiosensitivity when ATM is inactivated. These experiments will map the tumor microenvironment of a mouse model of brainstem glioma at single cell resolution for the first time. They will also credential a genetically-engineered mouse model of brainstem glioma with an intact immune system for preclinical investigations of immunotherapeutic approaches. Additionally, the proposed work will provide me with critical expertise in genetically engineered mouse models and in immunologic investigations that will help me transition to a productive independent investigator.

靶向ATM提高脑干胶质瘤放射治疗的疗效 项目总结/摘要 脑干神经胶质瘤是一种毁灭性的小儿脑肿瘤。脑干胶质瘤包括“弥漫性中线胶质瘤 2016年世界卫生组织CNS肿瘤分类中的“H3 K27 M突变”， 包括以前称为“弥漫性内在脑桥胶质瘤”或DIPG的肿瘤。脑干神经胶质瘤是 对病人都是致命的放射治疗被认为是唯一有效的治疗这些 肿瘤，提供症状和肿瘤进展的暂时缓解。然而，脑干神经胶质瘤 放射治疗后不可避免地进展，并导致患者死亡，导致中位生存期为 不到一年需要新的策略来提高放射治疗的疗效，以改善患者的预后。 生存一种有希望的研究性治疗策略是通过灭活肿瘤细胞来使肿瘤放射增敏。 丝氨酸/苏氨酸激酶共济失调毛细血管扩张突变（ATM）。ATM是DNA损伤的主要传感器， 并在细胞被电离辐射或其他DNA损伤后协调DNA损伤反应 破坏剂。ATM失活显著地使一种遗传工程小鼠模型放射增敏， 脑干神经胶质瘤当ATM在我们的脑干胶质瘤小鼠模型的肿瘤细胞中失活时， 放射治疗特别有效， 是携带完整ATM肿瘤的小鼠的三倍。然而，特定的细胞群， ATM失活的放射增敏作用，以及ATM失活使脑干放射增敏的机制 神经胶质瘤，未知。更深入地了解ATM失活的分子机制， 需要放射增敏脑干神经胶质瘤以使得能够合理设计联合治疗， 联合收割机ATM抑制、放射治疗和其他新的表观遗传和免疫治疗， 脑干胶质瘤患者的生存率。在这里，我将测试ATM失活的假设， 在我们的遗传工程小鼠模型中， 脑干神经胶质瘤在这项工作的同时，我将剖析I型干扰素信号通路， 当ATM失活时，会增加辐射敏感性。这些实验将绘制出肿瘤 这是第一次在单细胞分辨率下观察脑干胶质瘤小鼠模型的微环境。他们将 还证明了具有完整免疫系统的脑干胶质瘤基因工程小鼠模型， 免疫学方法的临床前研究。此外，拟议的工作将为我提供 在基因工程小鼠模型和免疫学研究方面具有重要的专业知识， 让我成为一名卓有成效的独立调查员