Project 4: The BRCA Network in Medulloblastoma Responses to Replication Stress
项目 4:髓母细胞瘤中 BRCA 网络对复制压力的反应
基本信息
- 批准号:10396611
- 负责人:
- 金额:$ 42.25万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-05-01 至 2023-04-30
- 项目状态:已结题
- 来源:
- 关键词:AftercareBRCA mutationsBRCA1 geneBRCA2 geneBindingBrain NeoplasmsC-terminalCDKN1A geneCellsCessation of lifeCharacteristicsChromosomal BreaksChromosomesCodeComplexDNA Binding DomainDNA DamageDNA RepairDNA Repair GeneDNA biosynthesisDNA replication forkDNA strand breakDataDefectDevelopmentDown-RegulationEmbryoEpigenetic ProcessExhibitsFunctional disorderGenesGenomeGenomicsGerm-Line MutationGlial Fibrillary Acidic ProteinGoalsHealthHumanHypersensitivityIn VitroIndividualMalignant Childhood NeoplasmMalignant NeoplasmsMammary glandMediatingModelingMolecularMusMutationOrganOvaryPALB2 genePancreasPatientsPediatric NeoplasmPenetrationPharmaceutical PreparationsPlayProgression-Free SurvivalsProstateProteinsRadiationRecurrenceRiskRoleSignal TransductionSiteStructureTestingTimeTopoisomeraseTreatment ProtocolsUrsidae FamilyUstilagobasebrca genecancer predispositionchemotherapyconditional knockoutefficacy validationgene networkgenome-widegenomic biomarkergenomic signaturehigh riskhomologous recombinationinhibitoririnotecanknock-downmedulloblastomamedulloblastoma cell lineneoplastic cellnovel therapeutic interventionnovel therapeuticspreclinical studypromoterrecruitreplication stressresponsestem cellssuccesstargeted treatmenttherapeutic developmenttreatment responsetumortumorigenesis
项目摘要
The BRCA Network in Medulloblastoma Responses to Replication Stress (Project-4)
Abstract:
BRCA1 and BRCA2 are critical genes for the repair of DNA strand breaks (DSB) via homologous
recombination (HR). PALB2 functions to bridge BRCA1 with BRCA2. Due to the intimate relationship between
BRCA1, PALB2, and BRCA2, these genes and their coded proteins are considered the core of a “BRCA
network.” Cancers with BRCA mutations display unique molecular features of “BRCAness,” including
hypersensitivity to replication stress drugs. In addition to the core BRCA proteins, defects of other BRCA1/2-
associated genes often share the “BRCAness” characteristics.
Brain tumors are the leading cause of childhood cancer-related deaths, and medulloblastomas (MBs) account
for more than 60% of pediatric tumors. Current treatments of MBs mainly rely on local control by radiation in
combination with generic chemotherapy. Targeted therapy has not been vigorously considered for MBs.
Recently, it has been recognized that germline mutations in BRCA2 and PALB2, two of the core genes in the
“BRCA Network,” are among the top causes of MBs. Furthermore, widespread basal activation of DNA
damage signaling and excessive replication stress were common among different groups of MBs. Based on
genomic signatures, 20-30% of sporadic MBs, including those from MB groups 2, 3, and 4, likely bear HR
defects (HRD). These recent developments raise an important question of whether DNA damage repair
defects and replication stress represent common vulnerabilities of MBs to new therapeutic developments
targeting HRD. If so, how to efficiently identify the individual cases with HRD remains an issue.
In the preliminary studies, we established conditional knockouts of Brca1, Palb2, and Brca2 in embryonic
multi-potential stem and progenitor cells using the glial fibrillary acidic protein (GFAP) promoter-driven Cre
expression. For the first time, we demonstrated that conditional loss of Palb2 and Brca1 are effective inducers
of MBs, with a similar potency as that of Brca2 loss. An initial genomic characterization of these MBs exhibiting
“BRCAness” had identified several unique structural features that can be used to define the HRD status. By
treating the de novo MBs with a developing topoisomerase 1 inhibitor, we found it to be very effective to
extend the survival of mice with MBs. Thus, we hypothesize that MBs originated from BRCA defects have
unique genomic signatures to define the MBs with HRD, and targeted therapy of MBs with HRD will be more
effective than the current treatment regimens. In Project-4, we take advantage of our recent success in
establishing BRCA-related mouse MB models and strive to identify the genomic signatures associated with
HRD and to validate the MB “BRCAness” response to replication stress drugs. Aim 1 will identify the structural
and chromosome-context signatures that accurately reflect the HDR status in MBs exhibiting “BRCAness”.
Aim 2 will experimentally target the vulnerability of HRD in MBs and investigate the potential mechanism of
tumor recurrence after the treatment. The success of this study would effectively establish a new remedy for
MB treatment.
BRCA网络在髓母细胞瘤复制应激反应中的作用(项目-4)
摘要:
BRCA 1和BRCA 2是通过同源性DNA修复DNA链断裂(DSB)的关键基因。
重组(HR)。PALB 2用于桥接BRCA 1和BRCA 2。由于他们之间的亲密关系,
BRCA 1、PALB 2和BRCA 2基因及其编码蛋白被认为是“BRCA”的核心
网络”。具有BRCA突变的癌症显示出独特的“BRCA阴性”分子特征,包括
对复制应激药物过敏。除了核心BRCA蛋白,其他BRCA 1/2-
相关基因通常具有“BRCAness”特征。
脑肿瘤是儿童癌症相关死亡的主要原因,髓母细胞瘤(MB)占
超过60%的儿科肿瘤。目前MB的治疗主要依赖于局部控制,
与一般化疗联合。尚未积极考虑MB的靶向治疗。
最近,人们已经认识到,BRCA 2和PALB 2的生殖系突变,这两个核心基因在肿瘤的发生和发展中起着重要作用。
“BRCA网络”是MB的主要原因之一。此外,DNA的广泛基础激活
损伤信号和过度复制应激在不同MB组中很常见。基于
基因组特征,20-30%的散发性MB,包括来自MB组2、3和4的MB,可能携带HR
缺陷(HRD)。这些最新的进展提出了一个重要的问题,即DNA损伤修复是否
缺陷和复制压力代表了MB对新治疗发展的共同脆弱性
目标是人权捍卫者如果是这样,如何有效地查明与人力资源开发有关的个案仍然是一个问题。
在前期研究中,我们建立了Brca 1、Palb 2和Brca 2的条件性敲除,
使用胶质细胞酸性蛋白(GFAP)启动子驱动的Cre的多潜能干细胞和祖细胞
表情我们首次证明了Palb 2和Brca 1的条件性缺失是有效的诱导剂,
MBs,具有与Brca 2缺失相似的效力。这些MB的初始基因组表征表现出
“BRCAness”确定了可用于界定人力资源开发状况的若干独特结构特征。通过
用一种正在发展的拓扑异构酶1抑制剂治疗新生MB,我们发现,
延长了患有心肌梗塞的小鼠的存活时间。因此,我们假设起源于BRCA缺陷的MB
独特的基因组特征来定义HRD MB,HRD MB的靶向治疗将更加重要。
比目前的治疗方法更有效。在项目-4中,我们利用我们最近的成功,
建立BRCA相关的小鼠MB模型,并努力识别与BRCA相关的基因组特征,
HRD和验证MB“BRCAness”对复制应激药物的反应。目标1将确定结构
以及准确反映表现出“BRCAness”的MB中的HDR状态的染色体背景特征。
目标2将实验性地针对MBs中HRD的脆弱性,并研究其潜在机制。
治疗后肿瘤复发。这项研究的成功将有效地建立一种新的补救办法,
MB处理。
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)
专利数量(0)
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Zhiyuan Shen其他文献
Zhiyuan Shen的其他文献
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{{ truncateString('Zhiyuan Shen', 18)}}的其他基金
Regulation of Ku70 methylation and functions by SETD4
SETD4 对 Ku70 甲基化和功能的调节
- 批准号:
10330477 - 财政年份:2021
- 资助金额:
$ 42.25万 - 项目类别:
Mechanisms of the BRCA-network in tumorigenesis and therapeutic response
BRCA 网络在肿瘤发生和治疗反应中的机制
- 批准号:
10599895 - 财政年份:2021
- 资助金额:
$ 42.25万 - 项目类别:
Project 4: The BRCA Network in Medulloblastoma Responses to Replication Stress
项目 4:髓母细胞瘤中 BRCA 网络对复制压力的反应
- 批准号:
10599907 - 财政年份:2021
- 资助金额:
$ 42.25万 - 项目类别:
Regulation of Ku70 methylation and functions by SETD4
SETD4 对 Ku70 甲基化和功能的调节
- 批准号:
10546482 - 财政年份:2021
- 资助金额:
$ 42.25万 - 项目类别:
Regulation of Ku70 methylation and functions by SETD4
SETD4 对 Ku70 甲基化和功能的调节
- 批准号:
10228239 - 财政年份:2021
- 资助金额:
$ 42.25万 - 项目类别:
Mechanisms of the BRCA-network in tumorigenesis and therapeutic response
BRCA 网络在肿瘤发生和治疗反应中的机制
- 批准号:
10396606 - 财政年份:2021
- 资助金额:
$ 42.25万 - 项目类别:
Molecular modulators of radiation-induced chromosome instability and hematopoietic damage
辐射引起的染色体不稳定和造血损伤的分子调节剂
- 批准号:
10438851 - 财政年份:2015
- 资助金额:
$ 42.25万 - 项目类别:
Molecular modulators of radiation-induced chromosome instability and hematopoietic damage
辐射引起的染色体不稳定和造血损伤的分子调节剂
- 批准号:
10626749 - 财政年份:2015
- 资助金额:
$ 42.25万 - 项目类别:
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