Patient-Derived Models of Prostate Cancer for Personalized Medicine
用于个体化医疗的前列腺癌患者衍生模型
基本信息
- 批准号:10219178
- 负责人:
- 金额:$ 102.6万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-08-01 至 2024-07-31
- 项目状态:已结题
- 来源:
- 关键词:1-Phosphatidylinositol 3-KinaseAddressAndrogen ReceptorAreaBiologicalBiological ModelsCancer ModelCellsClinicalClinical ResearchClinical TrialsComplementCritical PathwaysDNA DamageDNA Sequence AlterationDatabasesDevelopmentDistantEvolutionGene ExpressionGene-ModifiedGenesGeneticGenetic studyGenomicsGerm LinesGoalsGrowthHumanInvestigationKnowledgeLinkLongitudinal StudiesMalignant Bone NeoplasmMalignant NeoplasmsMalignant neoplasm of prostateMetastatic Prostate CancerModelingMolecularMorphologyMutationNeoplasm MetastasisOrganoidsPathologicPathologistPathway interactionsPatientsPharmaceutical PreparationsPhysiciansPoly(ADP-ribose) PolymerasesResearch PersonnelResistanceRoleSamplingScientistSeminalSignal TransductionSiteSpecimenStructureTestingTherapeuticTimeTissuesTumor-DerivedUrsidae FamilyVariantandrogen deprivation therapybasecancer genomicscastration resistant prostate cancerclinically relevantdesigndrug testingeffective therapyepigenomicsexome sequencinggenome sequencinghuman tissueimprovedinhibitor/antagonistinsightmenmigrationpatient derived xenograft modelpersonalized medicinepre-clinicalprostate cancer modelprostate cancer progressionresistance mechanismresponsesuccesstargeted treatmenttherapy developmenttherapy resistanttranscriptome sequencingtreatment responsetreatment strategytumorwhole genome
项目摘要
PROJECT SUMMARY/ABSTRACT
Metastatic prostate cancer (PCa) that progresses after androgen ablation therapy (i.e., castration-resistant
PCa [CRPC]) remains incurable. Gaining a mechanistic understanding of PCa progression has been
hampered by a lack of clinically relevant PCa models. Recently, patient-derived models of cancer (PDMCs;
e.g., patient-derived xenografts [PDXs] and organoids) have been used to develop therapeutically relevant
approaches. We hypothesize that longitudinal studies of tumor specimens (and corresponding PDMCs)
obtained over time from the same patient will lead to a better understanding of the diverse dominant pathways
that drive metastatic progression. We also hypothesize that organoids will complement PDXs as part of an
integrated analysis of human tissue and derived PDMCs (obtained at single time points) to understand the
mechanisms of response and resistance to target pathways commonly activated in CRPC. We will test these
hypotheses through the following specific aims: Aim 1. Analyze human donor tumors and corresponding
PDMCs to identify dominant molecular alterations that drive PCa progression and select models to study. We
will develop PDMCs from clinically annotated tumor specimens derived from men with potentially lethal PCa,
including PDMCs derived from tumor specimens obtained at different times during progression (longitudinal
studies) and from different areas of the same tumor. We will assess human PCa specimens and PDMCs’
morphology and expression of genes associated with PCa progression and subject them to whole-exome
sequencing and RNA sequencing. PCa specimens and PDMCs derived from the longitudinal studies will also
be subjected to whole-genome sequencing and epigenomic analysis. Finally, we will develop a publicly
available interactive database linking molecular and preclinical results of PDMC characterization with clinical
and molecular details of donor human PCa. These studies' findings will serve as the basis for the identification
and prioritization of aberrant molecular pathways for further study. This knowledge is also essential to
understanding how each PDMC provides information about the alterations in human donor tumor. Aim 2.
Study genomic alterations acquired in metastasis specimens in the longitudinal studies for their potential to
confer metastatic ability to cells. We will genetically modify organoids to create the genomic alterations found in
the metastases. We will subsequently study how the genetic modification of these genes influences specific
steps involved in metastasis, namely invasion, migration, and ability to grow at distant sites. Aim 3. Utilize
PDMCs to study mechanisms of PCa response/resistance to targeted therapies on pathways implicated in PCa
progression. We will seek a mechanistic understanding of PCa response and/or resistance to therapies in
clinical trials targeting the AR, DNA damage response, Wnt-canonical, and PI3K pathways. These studies will
inform the discovery and elucidation of resistance mechanisms, the development of effective therapies and will
provide insights into the roles of PDMCs as model systems for studying signaling and therapeutic response.
项目概要/摘要
雄激素消融治疗后进展的转移性前列腺癌 (PCa)(即去势抵抗性癌症)
PCa [CRPC])仍然无法治愈。对 PCa 进展的机制了解已经
由于缺乏临床相关的 PCa 模型而受到阻碍。最近,源自患者的癌症模型(PDMC;
例如,患者来源的异种移植物 [PDX] 和类器官)已被用于开发治疗相关的
接近。我们假设肿瘤标本(和相应的 PDMC)的纵向研究
随着时间的推移从同一患者获得的数据将有助于更好地理解不同的主要途径
驱动转移进展。我们还假设类器官将作为 PDX 的补充
对人体组织和衍生的 PDMC(在单个时间点获得)进行综合分析,以了解
对 CRPC 中常见激活的靶途径的反应和抵抗机制。我们将测试这些
通过以下具体目标提出假设: 目标 1. 分析人类供体肿瘤和相应的
PDMC 可识别驱动 PCa 进展的主要分子改变并选择要研究的模型。我们
将利用来自患有潜在致命 PCa 的男性的临床注释肿瘤标本开发 PDMC,
包括源自进展过程中不同时间获得的肿瘤标本的 PDMC(纵向
研究)和来自同一肿瘤的不同区域。我们将评估人类 PCa 样本和 PDMC
与 PCa 进展相关的基因的形态和表达,并将其置于全外显子组中
测序和RNA测序。来自纵向研究的 PCa 标本和 PDMC 也将
进行全基因组测序和表观基因组分析。最后,我们将开发一个公开的
可用的交互式数据库将 PDMC 表征的分子和临床前结果与临床联系起来
以及供体人类 PCa 的分子细节。这些研究结果将作为鉴定的基础
以及异常分子途径的优先顺序以供进一步研究。这些知识对于
了解每个 PDMC 如何提供有关人类供体肿瘤变化的信息。目标2。
研究纵向研究中转移标本中获得的基因组改变,以了解其潜在的
赋予细胞转移能力。我们将对类器官进行基因改造,以产生在
转移。我们随后将研究这些基因的遗传修饰如何影响特定的
涉及转移的步骤,即侵袭、迁移和在远处生长的能力。目标 3. 利用
PDMC 将研究 PCa 对 PCa 相关通路靶向治疗的反应/耐药机制
进展。我们将寻求对 PCa 反应和/或治疗耐药的机制理解
针对 AR、DNA 损伤反应、Wnt 经典和 PI3K 通路的临床试验。这些研究将
为耐药机制的发现和阐明、有效疗法的开发和意志提供信息
深入了解 PDMC 作为研究信号传导和治疗反应的模型系统的作用。
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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{{ truncateString('Yu Chen', 18)}}的其他基金
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- 批准号:
10522552 - 财政年份:2022
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- 批准号:
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- 资助金额:
$ 102.6万 - 项目类别:
Patient-Derived Models of Prostate Cancer for Personalized Medicine
用于个体化医疗的前列腺癌患者衍生模型
- 批准号:
10472536 - 财政年份:2019
- 资助金额:
$ 102.6万 - 项目类别:
Patient-Derived Models of Prostate Cancer for Personalized Medicine
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- 批准号:
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$ 102.6万 - 项目类别:
Understanding the role of an aberrant hepatic nuclear transcription circuit in prostate cancer tumorigenesis and castration resistance
了解异常肝核转录回路在前列腺癌肿瘤发生和去势抵抗中的作用
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- 批准号:
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