Investigation of ecDNA as a driver of intratumoral heterogeneity and treatment resistance in high-risk medulloblastoma
EcDNA 作为高危髓母细胞瘤瘤内异质性和治疗耐药性驱动因素的研究
基本信息
- 批准号:10709196
- 负责人:
- 金额:$ 66.05万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-09-01 至 2028-08-31
- 项目状态:未结题
- 来源:
- 关键词:BiologicalBiopsyBromodomains and extra-terminal domain inhibitorCancer PatientCell NucleusCellsChemotherapy and/or radiationChildChildhood Malignant Brain TumorCircular DNAClinicalClustered Regularly Interspaced Short Palindromic RepeatsCodeCombined Modality TherapyComputing MethodologiesDNADNA RepairDNA-PKcsDataDependenceDevelopmentDiseaseDisease ProgressionEnhancersGene AmplificationGenesGenetic TranscriptionHumanImageIn VitroIndividualInstitutionInvestigationMYCN geneMalignant NeoplasmsMediatingMethodsMissionMolecularMolecular AnalysisMolecular EvolutionMonitorNeoplasm MetastasisNervous System TraumaNonhomologous DNA End JoiningOncogenesOncoproteinsOutcomePathogenesisPatientsPediatric HospitalsPoly(ADP-ribose) Polymerase InhibitorPredispositionPreventionPrimary NeoplasmProcessProliferatingPropertyPublic HealthRelapseResearchResistanceRoleSamplingSubgroupTestingTherapeuticTreatment EfficacyTreatment FailureTumor BiologyTumorigenicityUnited States National Institutes of HealthUntranslated RNAVariantWorkcancer genomicscohortcombinatorialdata repositorydetection methoddevelopmental diseaseexperimental studyextrachromosomal DNAgenome sequencinghigh riskhuman diseaseimprovedin vivoinhibitorinnovationmedulloblastomamultiple omicsneoplastic cellnovelnovel therapeutic interventionpatient derived xenograft modelpreclinical studyreconstructionstandard carestandard of caretargeted treatmenttherapeutic targettherapy resistanttumortumor growthtumor heterogeneitywhole genome
项目摘要
The overall objective of this proposal is to investigate circular extrachromosomal DNA (ecDNA) as a potential
driver of intratumoral heterogeneity and treatment resistance in medulloblastoma, the most common pediatric
malignant brain tumor. Intratumoral heterogeneity is one of the leading determinants of therapeutic resistance
and treatment failure and one of the main reasons for poor overall survival in cancer patients. However, the
functional relevance of ecDNA as a driver of tumor heterogeneity and treatment resistance in medulloblastoma
has hardly been studied. To analyze the clinical impact of ecDNA in the different molecular subgroups of
medulloblastoma, we assembled a multi-institutional cohort of Whole Genome Sequencing data from 468
medulloblastoma patient samples. Using novel computational methods for the detection and reconstruction of
ecDNA, we found ecDNA in 82 patients (18%) and observe that the presence of ecDNA is associated with
significantly poorer outcomes. In addition, we find that individual medulloblastoma tumors often harbor multiple
variants of ecDNA, each containing different amplified oncogenes along with co-amplified non-coding
regulatory DNA (‘enhancers’). Based on our preliminary results, we propose the central hypothesis that ecDNA
drives intratumoral heterogeneity and treatment resistance in high-risk medulloblastoma patients. The central
hypothesis will be tested through the following three specific aims: To investigate the molecular evolution of
ecDNA as a potential driver of treatment resistance (Aim 1); To evaluate combinatorial therapies targeted
against mechanisms of ecDNA formation and clustering to reduce treatment resistance (Aim 2); To probe
medulloblastoma tumor-dependencies by functional inhibition of coding and non-coding regulatory DNA co-
amplified on ecDNA (Aim 3). The research proposed in this application has technical, conceptual, and
biological innovations, including the analysis of ecDNA on the single-cell level using novel imaging and
multiome single-nucleus sequencing methods in medulloblastoma tumors and in patient-derived xenograft
(PDX) models. The proposed research is significant, because the current standard treatment for children with
medulloblastoma causes developmental disorders, neurological damage, and secondary metastases. Novel
therapeutic approaches are urgently needed. Our approach will test the impact of standard-of-care treatments
on the molecular evolution of ecDNA and functionally test novel combination treatments targeted against
ecDNA genesis and clustering. These preclinical studies have the potential to uncover novel mechanisms by
which ecDNA contributes to the pathogenesis of medulloblastoma and to identify new scientific leads for the
development of improved treatments. We expect that our studies will expose the contribution of ecDNA
variants to the emergence of therapy resistance, reveal their selection advantages, validate recently described
properties of ecDNA and their therapeutic susceptibilities, and identify novel tumor-dependency genes
amplified on ecDNA in some of the most aggressive medulloblastoma tumors.
这项建议的总体目标是研究环状染色体外dna(Ecdna)作为一种潜在的
儿童最常见的髓母细胞瘤的瘤内异质性和治疗耐药性的驱动因素
恶性脑瘤。肿瘤内的异质性是治疗耐药性的主要决定因素之一。
治疗失败也是癌症患者总体存活率较低的主要原因之一。然而,
髓母细胞瘤中ecDNA作为肿瘤异质性和治疗耐药的驱动因素的功能相关性
几乎没有人研究过。分析ecDNA在不同分子亚群中的临床影响
髓母细胞瘤,我们收集了468个全基因组测序数据的多机构队列
髓母细胞瘤患者样本。使用新的计算方法来检测和重建
我们在82名患者(18%)中发现了ecDNA,并观察到ecDNA的存在与
结果要糟糕得多。此外,我们还发现,单个髓母细胞瘤常伴有多发性
EcDNA的变种,每个变种包含不同的扩增癌基因以及共扩增的非编码基因
监管DNA(“增强剂”)。基于我们的初步结果,我们提出了ecDNA的中心假设
导致高危髓母细胞瘤患者肿瘤内的异质性和治疗耐药性。中环
假说将通过以下三个具体目标进行检验:研究
EcDNA作为治疗耐药的潜在驱动因素(目标1);评估有针对性的联合治疗
针对ecDNA的形成和聚集机制以减少对药物的耐药性(目标2);探索
髓母细胞瘤编码和非编码调节性DNA协同功能抑制与肿瘤的相关性
在ecDNA上扩增(目标3)。本申请中提出的研究具有技术、概念和
生物创新,包括使用新的成像技术在单细胞水平上分析ecDNA
髓母细胞瘤和患者来源的异种移植中的多组单核测序方法
(PDX)型号。这项拟议的研究意义重大,因为目前对儿童的标准治疗
髓母细胞瘤会导致发育障碍、神经损伤和继发性转移。小说
迫切需要治疗方法。我们的方法将测试标准护理治疗的影响
论ecDNA的分子进化及靶向靶向的新型联合治疗
EcDNA的起源和聚集性。这些临床前研究有可能通过以下方式揭示新的机制
哪种ecDNA在髓母细胞瘤的发病机制中起作用并为
开发改进的治疗方法。我们期望我们的研究将揭示ecDNA的作用。
出现治疗耐药的变异,揭示其选择优势,验证最近描述的
EcDNA的性质及其治疗敏感性,并鉴定新的肿瘤依赖基因
在一些最具侵袭性的髓母细胞瘤的ecDNA上扩增。
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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Lukas Chavez其他文献
Lukas Chavez的其他文献
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{{ truncateString('Lukas Chavez', 18)}}的其他基金
Transcriptional activation of RCOR2 as a novel oncogenic mechanism in supratentorial ependymoma
RCOR2的转录激活作为幕上室管膜瘤的新型致癌机制
- 批准号:
10762312 - 财政年份:2023
- 资助金额:
$ 66.05万 - 项目类别:
Disruption of a DNA loop as a complementary mechanism of H3.3K27M mutations
DNA 环的破坏作为 H3.3K27M 突变的补充机制
- 批准号:
10762308 - 财政年份:2023
- 资助金额:
$ 66.05万 - 项目类别:
Transcriptional activation of LAMC1 as a resistance mechanism in recurrent PFA Ependymoma
LAMC1 的转录激活作为复发性 PFA 室管膜瘤的耐药机制
- 批准号:
10762310 - 财政年份:2023
- 资助金额:
$ 66.05万 - 项目类别:
Transcriptional activation of LAMC1 as a resistance mechanism in recurrent PFA Ependymoma
LAMC1 的转录激活作为复发性 PFA 室管膜瘤的耐药机制
- 批准号:
10308691 - 财政年份:2020
- 资助金额:
$ 66.05万 - 项目类别:
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