A molecular informed therapy for Diffuse Intrinsic Pontine Gliomas (DIPG)
弥漫性内源性脑桥胶质瘤 (DIPG) 的分子信息疗法
基本信息
- 批准号:10708134
- 负责人:
- 金额:$ 24.9万
- 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:2022-09-20 至 2025-08-31
- 项目状态:未结题
- 来源:
- 关键词:6 year oldAcetylationAcuteAddressAffectAffinityAmino AcidsAnimalsAutomobile DrivingBindingBiochemicalBiochemistryBiological AssayBrain NeoplasmsBrain StemBromodomainBromodomains and extra-terminal domain inhibitorCRISPR screenCell ProliferationCell SeparationCellsCharacteristicsChemosensitizationChildChildhoodChildhood Brain Stem NeoplasmChildhood Central Nervous System NeoplasmChildhood Solid NeoplasmChromatinClinicalCombined Modality TherapyComplexDataDepositionDiagnosisDiffuseDiffuse intrinsic pontine gliomaDiseaseDisease ProgressionEpigenetic ProcessEventExclusionGene ExpressionGene Expression ProfileGene SilencingGenerationsGenesGeneticGenetic EngineeringGenetic TranscriptionGliomaGoalsH3 K27M mutationHeterozygoteHistone H3HistonesIn VitroIncidenceKnowledgeLysineMaintenanceMeasuresMediatingMentorsMethionineMethylationModelingMolecularMolecular BiologyMusMutationNucleosomesOncogenicOutcomePathogenicityPathway interactionsPatientsPhasePhase I Clinical TrialsPoint MutationPolycombPontine structurePositioning AttributePropertyProtein IsoformsProteinsRadiation therapyReactionRecurrenceRegulationResistanceRoleSamplingSiteSystemTherapeuticTissuesTreatment ProtocolsUniversitiesWorkXenograft procedureclinically relevantefficacious treatmentepigenomeexperimental studygenome-wideimprovedin vivoinhibitor therapyinsightmortalitymouse modelmutantneoplastic cellpharmacologicpre-clinicalrecruitresistance mechanismsmall molecule inhibitorstandard of caretumortumor growthtumorigenesis
项目摘要
Diffuse
characterized
histone
substitution
levels
and By profilying the epigenome
of H3K27M mutant DIPG patient cells I found that H3K27M co-localizes with H3K27
acetylation (H3K27ac). In accordance with previous biochemical data, heterotypic H3K27M-
K27ac nucleosomes co-localize with bromodomain proteins at actively transcribed genes,
whereas PRC2 is excluded from these regions, suggesting that PRC2 is not sequestered at sites of
incorporation of H3K27M. I also showed that the heterotypic nucleosomes H3K27M-K27ac co-
localize with bromodomain proteins in DIPG, importantly treatment with BET bromodomain
inhibitors in DIPG xenograft mouse models potently reduces tumor growth and extend animal
survival. During my mentored phase (K99) I'm planning to study the molecular details of the
formation of the heterotypic nucleosomes using in vitro biochemistry and molecular biology
assays and gather further insights in the pathogenic mechanisms of aberrant acetylation and
H3K27M deposition in DIPG. While transitioning toward the independent phase (R00) I'm
planning to improve the BET inhibitors therapeutic strategy by identifying mechanisms of
resistance and cooperative factors that can lead to an improved and durable therapy for children
affected by DIPG. Altogether my plan is to perform experiments that push forward our
knowledge of this incurable disease with the goal of finally having a standard-of-care option that
can offer a reliable and efficacious treatment for DIPG patients.
Intrinsic Glioma (DIP G) a highly aggressive pediatric brainstem tumor
by rapid and nearly uniform patient demise. A heterozygous point mutation of
H3 occurs in more than 80% of these tumors, and results in a lysine-to-methionine
(H3K27M). Expression of this histone mutant is accompanied by a reduction in the
of Polycomb Repressive Complex 2 (PRC2) mediated H3K27 trimethylation (H3K27me3)
this is hypothesized to be a driving event of DIPG oncogenesis.
Pontine is
扩散
特征化的
组蛋白
替代
级别
通过分析表观基因组
H3K27M 突变 DIPG 患者细胞 我发现 H3K27M 与 H3K27 共定位
乙酰化(H3K27ac)。根据之前的生化数据,异型H3K27M-
K27ac 核小体与溴结构域蛋白共定位于活跃转录的基因处,
而 PRC2 被排除在这些区域之外,这表明 PRC2 并未被隔离在
H3K27M 的合并。我还表明异型核小体 H3K27M-K27ac 共同
用 DIPG 中的溴结构域蛋白进行定位,重要的是用 BET 溴结构域进行处理
DIPG 异种移植小鼠模型中的抑制剂可有效减少肿瘤生长并延长动物寿命
生存。在我的指导阶段(K99),我计划研究分子细节
利用体外生物化学和分子生物学形成异型核小体
分析并收集有关异常乙酰化和的致病机制的进一步见解
H3K27M 在 DIPG 中沉积。在向独立阶段(R00)过渡时,我
计划通过确定 BET 抑制剂的机制来改进治疗策略
抵抗和合作因素可以为儿童带来改进和持久的治疗
受 DIPG 影响。总而言之,我的计划是进行实验来推动我们的
对这种不治之症的了解,目的是最终拥有一种标准护理选择
可为DIPG患者提供可靠、有效的治疗。
内在神经胶质瘤(DIP G)是一种高度侵袭性的儿童脑干肿瘤
患者迅速且几乎一致的死亡。杂合点突变
H3 出现在超过 80% 的此类肿瘤中,并导致赖氨酸转化为蛋氨酸
(H3K27M)。该组蛋白突变体的表达伴随着
Polycomb 抑制复合物 2 (PRC2) 介导的 H3K27 三甲基化 (H3K27me3)
这被假设为 DIPG 肿瘤发生的驱动事件。
桥桥是
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Andrea Piunti的其他文献
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{{ truncateString('Andrea Piunti', 18)}}的其他基金
A molecular informed therapy for Diffuse Intrinsic Pontine Gliomas (DIPG)
弥漫性内源性脑桥胶质瘤 (DIPG) 的分子信息疗法
- 批准号:
10654155 - 财政年份:2022
- 资助金额:
$ 24.9万 - 项目类别:
A molecular informed therapy for Diffuse Intrinsic Pontine Gliomas (DIPG)
弥漫性内源性脑桥胶质瘤 (DIPG) 的分子信息疗法
- 批准号:
10015227 - 财政年份:2019
- 资助金额:
$ 24.9万 - 项目类别:
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