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:10375084
- 负责人:
- 金额:$ 42.23万
- 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
- 来源:
- 关键词:19qATRX geneAdaptive Immune SystemAffectAftercareAgonistAstrocytomaBrainCartoonsCell LineCellsChemosensitizationChromosomesDataDependenceDouble-Stranded RNAGene ExpressionGliomaGoalsHumanImmuneImmune Response GenesImmune checkpoint inhibitorImmune signalingImmune systemImmunobiologyImmunologic SurveillanceImmunologicsImmunotherapeutic agentImmunotherapyInfiltrationInflammationInflammatoryInnate Immune ResponseInnate Immune SystemInterferon Type IKnock-outKnockout MiceLinkMalignant - descriptorMalignant GliomaMalignant NeoplasmsMeasuresMediatingMental RetardationModelingMolecular ProfilingMusMutateMutationNatural ImmunityOligodendroglioma-AstrocytomaOperative Surgical ProceduresPatientsPoly ICLCPrimary Brain NeoplasmsProductionProteinsRNARadiationRelapseRoleSWI/SNF Family ComplexSignal TransductionSpecimenTP53 geneTestingThe Cancer Genome AtlasTherapeuticTimeTissuesTumor EscapeTumor ImmunityWorkalpha-Thalassemiabasechemotherapychromatin remodelingcohortcytokineeffective therapyimmune activationin vivoinhibitorinnovationinsightlink proteinmembermutantneoplastic cellnoveloligodendrogliomapre-clinicalresistance mechanismresponsetherapeutic evaluationtherapy designtumortumor growthtumor microenvironmenttumor progressiontumor-immune system interactions
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)描述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
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
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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
Evolocumab as an immunomodulator in glioma: A window of opportunity trial evaluating PCSK9 inhibition to enhance surface MHC-I on tumor
Evolocumab 作为神经胶质瘤的免疫调节剂:评估 PCSK9 抑制以增强肿瘤表面 MHC-I 的机会之窗试验
- DOI:
- 发表时间:
2024 - 期刊:
- 影响因子:0
- 作者:
Kirit Singh;Matthew W. Foster;Marlene J. Violette;K. Hotchkiss;C. Railton;E. Blandford;Kathryn E. Blethen;Elizabeth L. Thomas;David M. Ashley;A. Desjardins;Henry Friedman;Margaret O. Johnson;Allan Friedman;Stephen T Keir;E. Buckley;James Herndon;R. McLendon;John H. Sampson;Evan Calabrese;Giselle Y. Lopez;Gerald A. Grant;Anoop P. Patel;Chuan;P. Fecci;M. Khasraw;The Preston - 通讯作者:
The Preston
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:
10666347 - 财政年份:2022
- 资助金额:
$ 42.23万 - 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:
$ 42.23万 - 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:
$ 42.23万 - 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:
$ 42.23万 - 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:
$ 42.23万 - 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:
$ 42.23万 - 项目类别:
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A Y CHROMOSOME MODEL FOR THE SEX DETERMINING FUNCTION OF THE HUMAN ATRX GENE
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- 批准号:
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- 批准号:
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