Investigation of luminal stem cells and castration resistance in prostate cancer
前列腺癌管腔干细胞和去势抵抗的研究
基本信息
- 批准号:9039555
- 负责人:
- 金额:$ 11.28万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2015
- 资助国家:美国
- 起止时间:2015-04-01 至 2018-03-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAdultAffectAndrogen ReceptorAndrogensArchitectureBiological AssayBiological MarkersCancer BiologyCastrationCell modelCellsClinicalCollaborationsDataDevelopmentEnvironmentEpithelialEpithelial CellsFDA approvedFutureGenesGeneticGoalsGrowthHealthHormonesHumanIndolentInstitutionInvestigationLaboratoriesLeadMalignant neoplasm of prostateMentorsMolecularMusOrganogenesisOrganoidsPathway interactionsPatient-Focused OutcomesPatientsPharmaceutical PreparationsPhasePlayPopulationPropertyProstateProstate Cancer therapyProstatic NeoplasmsReceptor SignalingRecurrenceRegulator GenesResearchResearch DesignResearch PersonnelResistanceSamplingSignal TransductionStem cellsSystemSystems BiologyTissue MicroarrayTissuesTranslatingTranslational ResearchTumor Stem CellsValidationabirateroneanticancer researchbasecancer biomarkerscancer initiationcancer recurrencecancer stem cellcancer therapycareercastration resistant prostate cancerdeprivationexperiencegenome-widein vivoinhibitor/antagonistinsightmouse modelneonateneoplastic cellnovelnovel therapeuticsprogenitorprogramsprostate cancer cellresistance mechanismresponseself-renewalskillsstemstem cell populationtumortumor progressionvalidation studies
项目摘要
DESCRIPTION (provided by applicant): The mainstay of treatment for advanced prostate cancer is androgen deprivation therapy, but most prostate cancers that initially respond to treatment ultimately become castration resistant and recur. The focus of this K99/R00 proposal is on understanding how prostate stem/progenitor cells and tumor propagating cells are affected by androgen deprivation. Previous studies from the Shen lab have identified a Nkx3.1 expressing luminal stem cell population (CARNs) in the normal regressed adult mouse prostate that can act as a cell of origin for prostate cancer. New preliminary data suggests that CARNs can also be found in the developing prostate, which is an environment with limited circulating androgens, and thus an ideal system to study castration resistance and the differentiation potential and plasticity of prostate cells. This application is based on the central hypothesis tht luminal stem cells in normal developing prostates have a predetermined ability to survive androgen deprivation, and that prostate cancers also contain tumor propagating cells with preexisting resistance to androgen deprivation. I propose to investigate the properties of stem cells and tumor propagating cells using genetic lineage tracing and ex vivo culture approaches with the following specific aims: (1) Analysis of prostate progenitor cells in the absence of androgen signaling (K99 phase), (2) Analysis of tumor propagating cells in prostate tumors and their response to androgen deprivation (K99 and R00 phases), and (3) Investigation of molecular drivers of tumor propagation in castration resistant prostate cancer (R00 phase). These studies are designed to expand our understanding of the differences and similarities between castration resistant stem cells in normal prostates and in tumors, and provide insights into the molecular mechanisms controlling intrinsic resistance to androgen deprivation. Such information will be important for understanding why hormone deprivation therapies fail, and for developing better treatments for castration resistant prostate cancers. If successful, these studies could lead to the identification of new mechanisms for castration resistance that could be translated to biomarkers for distinguishing indolent and aggressive prostate cancers and prostate cancer treatments. My long-term career goal is to establish an independent laboratory at an academic institution and conduct basic scientific research to address fundamental questions related to stem cells and cellular differentiation in cancer initiation and recurrence. M immediate goal is to develop a competitive independent research program and gain additional cancer research and translational research experience. My proposed studies of novel genes and pathways involved in tumor propagation in castration resistant prostate cancer should allow me to distinguish myself from my mentor.
描述(由申请人提供):晚期前列腺癌的主要治疗方法是雄激素剥夺治疗,但大多数前列腺癌最初对治疗有反应,最终变得去势抵抗并复发。K99/R 00提案的重点是了解前列腺干/祖细胞和肿瘤增殖细胞如何受到雄激素剥夺的影响。Shen实验室先前的研究已经在正常退化的成年小鼠前列腺中鉴定出表达Nkx3.1的管腔干细胞群(CARN),其可以作为前列腺癌的起源细胞。新的初步数据表明,CARN也可以在发育中的前列腺中发现,这是一个循环雄激素有限的环境,因此是研究去势抵抗和前列腺细胞分化潜力和可塑性的理想系统。 该申请基于中心假设,即正常发育的前列腺中的管腔干细胞具有在雄激素剥夺中存活的预定能力,并且前列腺癌还含有对雄激素剥夺具有预先存在的抗性的肿瘤增殖细胞。我建议使用遗传谱系追踪和离体培养方法研究干细胞和肿瘤增殖细胞的特性,具体目标如下:(1)在雄激素信号传导不存在下的前列腺祖细胞的分析(2)前列腺肿瘤中肿瘤增殖细胞的分析及其对雄激素剥夺的反应(K99和R 00期),和(3)去势抵抗性前列腺癌(R 00期)中肿瘤增殖的分子驱动因素的研究。这些研究旨在扩大我们对正常前列腺和肿瘤中去势抵抗干细胞之间差异和相似性的理解,并提供对控制雄激素剥夺内在抵抗的分子机制的见解。这些信息对于理解激素剥夺疗法失败的原因以及开发更好的去势抵抗性前列腺癌治疗方法非常重要。如果成功的话,这些研究可能会导致鉴定去势抵抗的新机制,这些机制可以转化为区分惰性和侵袭性前列腺癌以及前列腺癌治疗的生物标志物。我的长期职业目标是在学术机构建立一个独立的实验室,并进行基础科研,以解决与干细胞和细胞分化在癌症发生和复发中的基本问题。M的近期目标是发展一个有竞争力的独立研究项目,并获得额外的癌症研究和转化研究经验。我提出的研究新的基因和途径参与肿瘤传播的去势抵抗性前列腺癌应该让我区别于我的导师。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Stem cells in genetically-engineered mouse models of prostate cancer.
- DOI:10.1530/erc-15-0367
- 发表时间:2015-12
- 期刊:
- 影响因子:3.9
- 作者:Shibata M;Shen MM
- 通讯作者:Shen MM
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Maho Shibata其他文献
Maho Shibata的其他文献
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{{ truncateString('Maho Shibata', 18)}}的其他基金
Regulation of prostate organogenesis by tissue-resident macrophages
组织驻留巨噬细胞对前列腺器官发生的调节
- 批准号:
10555589 - 财政年份:2023
- 资助金额:
$ 11.28万 - 项目类别:
Investigation of luminal stem cells and castration resistance in prostate cancer
前列腺癌管腔干细胞和去势抵抗的研究
- 批准号:
9914223 - 财政年份:2018
- 资助金额:
$ 11.28万 - 项目类别:
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