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

以ATM为靶点提高脑干胶质瘤放射治疗的疗效 项目摘要/摘要 脑干胶质瘤是一种毁灭性的儿童脑肿瘤。脑干胶质瘤包括“弥漫性中线胶质瘤” H3K27M突变，在2016年世界卫生组织中枢神经系统肿瘤分类中，以及 包括以前被称为“弥漫性固有桥脑胶质瘤”或DIPG的肿瘤。脑干胶质瘤是 对病人都是致命的。放射治疗被认为是治疗这些疾病的唯一有效方法。 肿瘤，为症状和肿瘤进展提供暂时缓解。然而，脑干胶质瘤 放射治疗后不可避免的进展并导致患者死亡，从而导致中位生存期 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 生死存亡。一种有希望的研究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(ATM)。自动取款机是DNA损伤的主要传感器， 并在细胞受到电离辐射或其他DNA损伤后协调DNA损伤反应 破坏性因素。ATM灭活显著增加了基因工程小鼠模型的辐射敏感性 脑干胶质瘤。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，将小鼠的中位总生存期延长了约 与ATM完好的荷瘤小鼠相比，是三倍。然而，特定的细胞群体是 ATM失活辐射增敏及ATM失活辐射增敏脑干的机制 神经胶质瘤，是未知的。更深入地了解ATM失活的分子机制 需要放射增敏的脑干胶质瘤来实现合理的联合治疗设计， 结合ATM抑制、放射治疗和其他新的表观遗传和免疫疗法，以最大限度地 脑干胶质瘤患者的存活率。在这里，我将专门测试自动柜员机失活的假设 在我们的基因工程小鼠模型中对一组祖细胞样瘤细胞进行放射增敏 脑干胶质瘤。在这项工作的同时，我将剖析I型干扰素信号通路 自动取款机停用时会增加辐射敏感性。这些实验将绘制肿瘤的图谱 首次在单细胞分辨率下观察小鼠脑干胶质瘤模型的微环境。他们会 还证明了脑干胶质瘤的基因工程小鼠模型具有完整的免疫系统 免疫治疗方法的临床前研究。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拥有关键专业知识，这将有助于 我将转变为一名富有成效的独立调查员。

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.