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

基本信息

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
项目类别：
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

项目摘要

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.

通过靶向 ATM 提高脑干胶质瘤放射治疗的疗效项目概要/摘要脑干胶质瘤是毁灭性的儿童脑肿瘤，包括“弥漫性中线胶质瘤”。 2016 年世界卫生组织中枢神经系统肿瘤分类中的“具有 H3K27M 突变”，以及包括以前称为“弥漫性脑桥胶质瘤”或 DIPG 的肿瘤。放射治疗被认为是对这些患者唯一有效的治疗方法。肿瘤，暂时缓解症状和肿瘤进展。放射治疗后不可避免地会出现进展并导致患者死亡，从而导致中位生存期需要新的策略来提高放射治疗的疗效以改善患者的状况。一种有前途的研究治疗策略是通过灭活肿瘤来提高放射敏感性。丝氨酸/苏氨酸激酶 Ataxia Telangiactasia Mutated (ATM) 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 ATM 失活可显着提高基因工程小鼠模型的放射敏感性。当我们的脑干胶质瘤小鼠模型的肿瘤细胞中 ATM 失活时，放射治疗特别有效，可将小鼠的中位总生存期延长约与具有完整 ATM 的肿瘤小鼠相比，其数量增加了三倍。 ATM 失活引起的放射增敏，以及 ATM 失活使脑干放射增敏的机制对于 ATM 失活的分子机制尚不清楚。需要对脑干胶质瘤进行放射增敏才能合理设计联合疗法，结合 ATM 抑制、放射治疗和其他新型表观遗传学和免疫疗法，以最大限度地提高在这里，我将检验 ATM 失活的假设。在我们的基因工程小鼠模型中，对一群类祖细胞肿瘤细胞进行放射增敏在这项工作的同时，我将剖析 I 型干扰素信号通路。当 ATM 失活时，这些实验将有助于绘制肿瘤图谱。他们将首次以单细胞分辨率研究小鼠脑干胶质瘤模型的微环境。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此外，拟议的工作将为我提供免疫治疗方法的临床前研究。拥有基因工程小鼠模型和免疫学研究方面的关键专业知识，这将有助于我转变为一名富有成效的独立调查员。