ATRX mutations, innate immune activation and therapeutic vulnerability in malignant gliomas

ATRX 突变、先天免疫激活和恶性胶质瘤的治疗脆弱性

基本信息

  • 批准号:
    10666347
  • 负责人:
  • 金额:
    $ 37.7万
  • 依托单位:
  • 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

项目摘要

ABSTRACT Gliomas, including oligodendroglioma and astrocytoma subtypes, are a diverse group of malignant primary brain tumors that respond to radiation, surgery and chemotherapy; however, relapse remains a major barrier affecting overall patient survival. Immunotherapy targeting the adaptive immune system such as checkpoint inhibitors has shown limited efficacy in gliomas. Thus, understanding the immunobiology of gliomas and mechanisms of resistance to immune therapies is crucial to therapeutically leverage the immune system for treating patients. Our long-term goal is to dissect the innate immune system in gliomas and identify vulnerabilities that can be exploited for designing therapies. Recent studies have implicated a link between mutations in ATRX, a SWI-SNF chromatin remodeler and immune cell infiltration in the tumor microenvironment of ATRX-mutant astrocytomas. Our preliminary data suggest that ATRX inactivation in gliomas leads to enriched inflammatory signatures and potentiation of type I interferon/pro-inflammatory signaling, and selective sensitization of tumors to double-stranded (dsRNA)-based immune agonists. Based on these preliminary findings, we hypothesize that ATRX inactivation induces innate inflammation and sensitizes tumors to immune surveillance and dsRNA agonist therapy; concurrent IDH mutations suppress innate inflammation to enable tumor immune evasion. We will test our hypothesis in the following specific aims. Aim 1: Define the role of ATRX inactivation in modulating glioma cell-intrinsic innate signaling; Aim 2: Elucidate the role of ATRX deficiency and concurrent IDH1R132H mutation in modulating anti- tumor immunity and the response to dsRNA agonist therapy in pre-clinical murine glioma models; Aim 3: Determine the extent to which dsRNA-based therapies induce inflammatory activation of lower-grade gliomas. Our proposal will: 1) delineate the novel role of ATRX loss in regulating innate immune signaling responses and their downstream effects in glioma, 2) examine the immunological interplay between ATRX mutations and its partner mutation, IDH1R132H and 3) lay preclinical groundwork for exploiting a potential therapeutic vulnerability in gliomas carrying ATRX mutations.
摘要 胶质瘤包括少突胶质细胞瘤和星形细胞瘤亚型,是一组多样化的恶性原发性胶质瘤, 脑肿瘤对放疗、手术和化疗有反应;然而,复发仍然是一个主要障碍 影响患者的总体存活率。针对适应性免疫系统的免疫治疗,如检查点 抑制剂在神经胶质瘤中显示出有限的功效。因此,了解神经胶质瘤的免疫生物学, 对免疫疗法的抗性机制对于治疗性地利用免疫系统以 治疗病人我们的长期目标是解剖神经胶质瘤中的先天免疫系统并找出其弱点 可以用来设计治疗方法。 最近的研究表明,ATRX(一种SWI-SNF染色质重塑剂)的突变与 ATRX突变型星形细胞瘤肿瘤微环境中的免疫细胞浸润。我们的初步数据 提示神经胶质瘤中ATRX失活导致丰富的炎性信号和I型胶原的增强, 干扰素/促炎信号传导,以及肿瘤对基于双链(dsRNA)的 免疫激动剂基于这些初步发现,我们假设ATRX失活诱导先天性 炎症并使肿瘤对免疫监视和dsRNA激动剂治疗敏感;并发IDH 突变抑制先天性炎症,使肿瘤免疫逃避。我们将测试我们的假设在 具体目标。目的1:确定ATRX失活在调节胶质瘤细胞内在先天性 目的2:阐明ATRX缺陷和并发IDH 1 R132 H突变在调节抗- 在临床前鼠神经胶质瘤模型中的肿瘤免疫和对dsRNA激动剂治疗的应答;目的3: 确定基于dsRNA的治疗诱导低级别胶质瘤炎症激活的程度。 我们的建议将:1)阐明ATRX损失在调节先天免疫信号反应中的新作用 以及它们在胶质瘤中的下游效应,2)检查ATRX突变和 其伴侣突变IDH 1 R132 H和3)为利用潜在的治疗弱点奠定了临床前基础 携带ATRX突变的神经胶质瘤。

项目成果

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David M. Ashley其他文献

Phase II study of carboplatin (CBDCA) in progressive low-grade gliomas.
卡铂 (CBDCA) 在进行性低级别胶质瘤中的 II 期研究。
  • DOI:
  • 发表时间:
    1998
  • 期刊:
  • 影响因子:
    4.1
  • 作者:
    Albert Moghrabi;Henry S Friedman;David M. Ashley;K. Bottom;T. Kerby;Elizabeth A. Stewart;Carol S. Bruggers;James M. Provenzale;Martin A. Champagne;Linda Hershon;M. Watral;Janis Ryan;Karima Rasheed;Shelley Lovell;David N. Korones;Herbert E. Fuchs;Timothy M George;R. McLendon;A. Friedman;Edward G. Buckley;D. Longee
  • 通讯作者:
    D. Longee
Brain immunology and immunotherapy in brain tumours
脑肿瘤中的脑免疫学与免疫疗法
  • DOI:
    10.1038/s41568-019-0224-7
  • 发表时间:
    2019-12-05
  • 期刊:
  • 影响因子:
    66.800
  • 作者:
    John H. Sampson;Michael D. Gunn;Peter E. Fecci;David M. Ashley
  • 通讯作者:
    David M. Ashley
A peptide vaccine targeting the CMV antigen pp65 in children and young adults with recurrent high-grade glioma and medulloblastoma: a phase 1 trial
针对患有复发性高级别胶质瘤和髓母细胞瘤的儿童和青少年的针对巨细胞病毒抗原 pp65 的肽疫苗:一项 1 期试验
  • DOI:
    10.1038/s43018-025-00998-z
  • 发表时间:
    2025-06-12
  • 期刊:
  • 影响因子:
    28.500
  • 作者:
    Eric M. Thompson;David M. Ashley;Katayoun Ayasoufi;Pamela Norberg;Gerald Archer;Evan D. Buckley;James E. Herndon;Ashley Walter;Bridget Archambault;Charlene Flahiff;Denise Jaggers;Laura Gorski;Luis A. Sanchez;Kendra Congdon;Kelly Hotchkiss;Sarah L. Cook;Eliese Moelker;Gordana Vlahovic;Elizabeth Reap;Kristin Schroeder;Dina Randazzo;Annick Desjardins;Margaret O. Johnson;Katherine Peters;Mustafa Khasraw;Henry Friedman;Duane A. Mitchell;John H. Sampson;Daniel Landi
  • 通讯作者:
    Daniel Landi
The evolution of the histology in pleomorphic xanthoastrocytomas in children: a study of 15 cases
儿童多形性黄色星形细胞瘤15例组织学演变
  • DOI:
    10.1097/pat.0b013e328340bb98
  • 发表时间:
    2011
  • 期刊:
  • 影响因子:
    4.5
  • 作者:
    Xiangru Wu;P. Bandopadhayay;J. Ng;David M. Ashley;C. Chow
  • 通讯作者:
    C. Chow
The Role of Social Support in Families Coping with Childhood Brain Tumor
社会支持在家庭应对儿童脑肿瘤中的作用
  • DOI:
    10.1080/07347330802614634
  • 发表时间:
    2009
  • 期刊:
  • 影响因子:
    2.1
  • 作者:
    A. Jackson;Kate Enderby;M. O'Toole;Shane. Thomas;David M. Ashley;J. Rosenfeld;E. Simos;Nicole Tokatlian;R. Gedye
  • 通讯作者:
    R. Gedye

David M. Ashley的其他文献

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{{ truncateString('David M. Ashley', 18)}}的其他基金

ATRX mutations, innate immune activation and therapeutic vulnerability in malignant gliomas
ATRX 突变、先天免疫激活和恶性胶质瘤的治疗脆弱性
  • 批准号:
    10375084
  • 财政年份:
    2022
  • 资助金额:
    $ 37.7万
  • 项目类别:
Administrative Core
行政核心
  • 批准号:
    10488238
  • 财政年份:
    2021
  • 资助金额:
    $ 37.7万
  • 项目类别:
6-thio-2'-deoxyguanosine: A Novel Immunogenic Telomerase-Mediated Therapy in Glioblastoma - A Duke and UTSW Collaboration
6-硫代-2-脱氧鸟苷:一种新型免疫原性端粒酶介导的胶质母细胞瘤疗法 - 杜克大学和 UTSW 合作
  • 批准号:
    10305565
  • 财政年份:
    2021
  • 资助金额:
    $ 37.7万
  • 项目类别:
6-thio-2'-deoxyguanosine in GBM: Pre-clinical Evaluation of Mechanism of action, Efficacy and Biomarker identification
GBM 中的 6-硫代-2-脱氧鸟苷:作用机制、功效和生物标志物鉴定的临床前评估
  • 批准号:
    10488242
  • 财政年份:
    2021
  • 资助金额:
    $ 37.7万
  • 项目类别:
6-thio-2'-deoxyguanosine: A Novel Immunogenic Telomerase-Mediated Therapy in Glioblastoma - A Duke and UTSW Collaboration
6-硫代-2-脱氧鸟苷:一种新型免疫原性端粒酶介导的胶质母细胞瘤疗法 - 杜克大学和 UTSW 合作
  • 批准号:
    10488237
  • 财政年份:
    2021
  • 资助金额:
    $ 37.7万
  • 项目类别:
Administrative Core
行政核心
  • 批准号:
    10305566
  • 财政年份:
    2021
  • 资助金额:
    $ 37.7万
  • 项目类别:
6-thio-2'-deoxyguanosine in GBM: Pre-clinical Evaluation of Mechanism of action, Efficacy and Biomarker identification
GBM 中的 6-硫代-2-脱氧鸟苷:作用机制、功效和生物标志物鉴定的临床前评估
  • 批准号:
    10305568
  • 财政年份:
    2021
  • 资助金额:
    $ 37.7万
  • 项目类别:
Is Low Tumor Mutational Burden Predictive of Response to Oncolytic Polio Virus Therapy in Recurrent Glioblastoma?
低肿瘤突变负荷是否可以预测复发性胶质母细胞瘤对溶瘤脊髓灰质炎病毒治疗的反应?
  • 批准号:
    9807277
  • 财政年份:
    2019
  • 资助金额:
    $ 37.7万
  • 项目类别:
Experimental Therapy for Brain Tumors
脑肿瘤的实验治疗
  • 批准号:
    10005980
  • 财政年份:
    2018
  • 资助金额:
    $ 37.7万
  • 项目类别:
Career Development Program
职业发展计划
  • 批准号:
    9546619
  • 财政年份:
    2018
  • 资助金额:
    $ 37.7万
  • 项目类别:

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