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.
项目总结/文摘
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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定义组蛋白 H3K4 单甲基转移酶功能障碍在尿路上皮癌中的作用
- 批准号:
10522552 - 财政年份:2022
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Automatic Wide-Field Optical Coherence Tomography for Assessment of Transplant Kidney Viability
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10501992 - 财政年份:2022
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$ 102.6万 - 项目类别:
Evolution and inhibition of carbapenemase in beta-lactam resistance
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- 批准号:
10598501 - 财政年份:2021
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Evolution and inhibition of carbapenemase in beta-lactam resistance
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- 批准号:
10385772 - 财政年份:2021
- 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
用于个体化医疗的前列腺癌患者衍生模型
- 批准号:
10683753 - 财政年份:2019
- 资助金额:
$ 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
- 批准号:
10224110 - 财政年份:2017
- 资助金额:
$ 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
- 批准号:
9753189 - 财政年份:2017
- 资助金额:
$ 102.6万 - 项目类别:
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