Determining the role of ASCL1 in neuroendocrine prostate cancer
Determining the role of ASCL1 in neuroendocrine prostate cancer
批准号:
10452507
负责人:
Kathia E. Rodarte
金额:
$3.54万
依托单位国家:
美国
项目类别:
财政年份:
2021
资助国家:
美国
项目状态:
已结题
起止时间:
2021-07-09 至 2024-07-08
关键词:
ASCL1 geneATAC-seqAndrogen ReceptorAutomobile DrivingBasal CellBiologicalBiological AssayBiomedical ResearchCRISPR interferenceCancer BiologyCancer HistologyCancer PatientCell LineCell LineageCell SurvivalCellsChIP-seqChromatinComplexDevelopmentDevelopmental GeneDiagnosisDiseaseDisease modelDistalEngineeringEnterobacteria phage P1 Cre recombinaseEthicsExperimental ModelsExposure toFellowshipGene ExpressionGenesGeneticGenetic TranscriptionGenetically Engineered MouseGenomic SegmentGrowthHistologicHumanIn VitroKnock-outKnowledgeLoxP-flanked alleleMalignant NeoplasmsMalignant neoplasm of lungMalignant neoplasm of prostateModelingMusNeuroendocrine CellNeuroendocrine Prostate CancerNeurosecretory SystemsNucleic Acid Regulatory SequencesOrganoidsPatientsPlayPopulationPre-Clinical ModelProcessProstateProstate AdenocarcinomaProstate Cancer therapyRB1 geneRegulationRepressionResearchResistanceResistance developmentRoleSamplingTP53 geneTechniquesTestingTrainingTumor Suppressor GenesTumor Suppressor ProteinsXenograft procedureandrogen deprivation therapyantagonistcancer gene expressioncancer subtypescancer therapycastration resistant prostate cancercell growthcell typeenzalutamideexperienceinsightknock-downloss of functionlung small cell carcinomamouse modelneoplastic cellneuroendocrine cancerneuroendocrine phenotypenovel therapeutic interventionpatient derived xenograft modelpre-clinicalpressureprogramsprostate cancer cell lineprostate cancer modelsurvival outcometranscription factortumor
中文摘要
大多数前列腺癌患者,雄激素受体(AR)驱动的癌症,发展去势
耐药前列腺癌(CRPC)由于一线雄激素剥夺疗法的耐药性。因此,委员会认为,
作为二线疗法,患者用称为恩杂鲁胺(Enz)的有效AR拮抗剂治疗。然而,在这方面,
一部分接受Enz治疗的CRPC患者发生神经内分泌前列腺癌(NEPC),这是一种快速的
进展性癌症,治疗有限,生存结果差。了解CRPC的当前研究
向NEPC的转变提示了谱系可塑性模型,其中具有管腔细胞类型的AR依赖性肿瘤
特征通过多电位谱系状态转变。在治疗的选择压力下,细胞
向AR非依赖性神经内分泌谱系发展。几个研究小组已经发现了人类NEPC肿瘤
已经失去了RB 1和TP 53,在实验模型中,这两个基因的损失是需要这种过渡到
神经内分泌谱系值得注意的是,NEPC组织学和基因表达类似于另一种神经内分泌
癌症,小细胞肺癌(SCLC),一种也以RB 1和TP 53缺失为特征的癌症。在SCLC中,
转录因子ASCL 1是体外肿瘤细胞生长和小鼠模型中SCLC形成所必需的
这种疾病。ASCL 1存在于NEPC肿瘤和该疾病的一些细胞系模型中。当前
该提案旨在确定前列腺腺癌向NEPC的转变是否需要ASCL 1,
鉴定在此过程中由ASCL 1调控的基因程序。此外,导致
将探索升高的ASCL 1水平和RB 1/TP 53损失。ASCL 1的功能获得和丧失方法
在NEPC细胞系、NEPC患者来源的异种移植物和小鼠前列腺类器官模型中,
工程小鼠将进行,以确定如果任何ASCL 1在这种癌症中发挥什么作用。比较ASCL 1
NEPC与SCLC的功能和调节可能揭示了NEPC的共同机制和脆弱性,
这些和其他神经内分泌癌。该奖学金提供如何科学地执行
严格和道德的生物医学研究以及如何将科学发现传达给该领域,特别是
它涉及癌症的生物学机制。简约翰逊博士实验室的专业知识
发育转录因子和神经内分泌肺癌,以及平穆博士的前列腺癌实验室
治疗阻力将提供成功训练所需的必要知识和技术
项目的经验和完成情况。
英文摘要
Most patients with prostate adenocarcinoma, an androgen receptor (AR) driven cancer, develop castrate
resistant prostate cancer (CRPC) due to resistance to first-line androgen deprivation therapies. Consequently,
as a second-line therapy, patients are treated with a potent AR antagonist called enzalutamide (Enz). However,
a portion of CRPC patients treated with Enz develop neuroendocrine prostate cancer (NEPC), which is a rapidly
progressing cancer with limited therapies and poor survival outcomes. Current research to understand the CRPC
transition to NEPC suggests a model of lineage plasticity, where the AR-dependent tumors with luminal cell-type
features transition through a multi-potential lineage state. Under selection pressure of the therapy, the cells
progress towards an AR-independent neuroendocrine lineage. Several groups have found human NEPC tumors
have lost RB1 and TP53, and in experimental models, loss of both genes was required for this transition to a
neuroendocrine lineage. Notably, NEPC histology and gene expression resemble another neuroendocrine
cancer, small cell lung carcinoma (SCLC), a cancer also characterized by loss of RB1 and TP53. In SCLC, the
transcription factor ASCL1 is required for tumor cell growth in vitro, and for SCLC formation in a mouse model
of this disease. ASCL1 is present in NEPC tumors and in some cell line models of the disease. The current
proposal is aimed at determining if ASCL1 is required in the transition of prostate adenocarcinoma to NEPC, and
identifying the gene programs regulated by ASCL1 in this process. In addition, mechanisms leading to the
elevated levels of ASCL1 with RB1/TP53 loss will be explored. Gain- and loss-of-function approaches of ASCL1
in NEPC cell lines, NEPC patient-derived xenografts, and mouse prostate organoid models from genetically
engineered mice will be conducted to determine what role if any ASCL1 plays in this cancer. Comparing ASCL1
function and regulation in NEPC with those in SCLC may reveal common mechanisms and vulnerabilities in
these and other neuroendocrine cancers. This fellowship provides training in how to perform scientifically
rigorous and ethical biomedical research and how to communicate scientific findings to the field, particularly as
it relates to biological mechanisms underlying cancer. The expertise from Dr. Jane Johnson’s lab in
developmental transcription factors and neuroendocrine lung cancer, and Dr. Ping Mu’s lab in prostate cancer
therapy resistance will provide the necessary knowledge and techniques required for a successful training
experience and completion of the proposed project.
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Determining the role of ASCL1 in neuroendocrine prostate cancer
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批准号:10668442
-
项目类别:
-
资助金额:$3.63万
-
财政年份:2021
-
负责人:Kathia E. Rodarte
-
依托单位:
Determining the role of ASCL1 in neuroendocrine prostate cancer
-
批准号:10313551
-
项目类别:
-
资助金额:$3.47万
-
财政年份:2021
-
负责人:Kathia E. Rodarte
-
依托单位:
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