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Identifying EZH2-dependent vulnerabilities in RB deficient prostate cancer

Identifying EZH2-dependent vulnerabilities in RB deficient prostate cancer
鉴定 RB 缺陷型前列腺癌中 EZH2 依赖性脆弱性
批准号:
10154294
负责人:
Leigh Ellis
金额:
$19.52万
依托单位:
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:
2021-05-25 至 2023-08-31
关键词:
AdoptedAndrogen ReceptorAutomobile DrivingBasal CellBindingCastrationCellsCharacteristicsChromatinClinical ResearchClinical TrialsClustered Regularly Interspaced Short Palindromic RepeatsComplexDNA BindingDNA Modification MethylasesDataDependenceDepositionDevelopmentDiseaseEZH2 geneEnhancersEpidermal Growth Factor Receptor Tyrosine Kinase InhibitorEpigenetic ProcessEventGene ExpressionGene Expression ProfileGenesGeneticGenetic Predisposition to DiseaseGenetic TranscriptionGoalsHeterochromatinHistone DeacetylaseHistonesHomologous GeneHumanImmunoprecipitationInterceptKnock-outLysineMDM2 geneMYCN geneMalignant neoplasm of prostateMass Spectrum AnalysisMediatingMetastatic Prostate CancerMethyltransferaseMolecularMulti-Institutional Clinical TrialNeuroendocrine Prostate CancerNeurosecretory SystemsNon-Small-Cell Lung CarcinomaOutcomePTEN genePathway interactionsPatientsPhenotypePhosphotransferasesPhysical condensationPolycombProstate AdenocarcinomaProteinsProteomicsQuality of lifeRB1 geneReceptor SignalingRepetitive SequenceRepressionResearch PersonnelResistanceRetinoblastomaRetinoblastoma ProteinRoleSignal TransductionTP53 geneTestingTherapeuticTumor Suppressor GenesUp-RegulationWorkandrogen deprivation therapyaurora kinase Abasecastration resistant prostate cancerchromatin remodelingcofactorcombinatorialexperimental studyfunctional genomicsgene repressionhistone methyltransferaseinhibitor/antagonistloss of functionloss of function mutationmethylation patternmethylomemortalitymouse genomeneuroendocrine phenotypenew therapeutic targetnovelpluripotencypreclinical studyprostate cancer cell lineprotein complexreceptor expressionresistance mechanismresponsescaffoldstem cellstargeted treatmenttherapeutic targettherapy resistanttranscription factortranscriptome sequencingtreatment responsetreatment strategytumorwhole genome

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英文摘要
PROJECT SUMMARY Metastatic prostate cancer (mPCa) is incurable and responsible for the majority of PCa associated mortality. Therefore, there is a critical need to identify interceptive therapeutic strategies to provide durable responses in patients. Androgen deprivation therapy (ADT) is the primary line of treatment for mPCa. ADT initially extends survival but is not curative as the patient’s tumor acquires castration resistance (mCRPC). A majority of mCRPC remain dependent on the function of the androgen receptor (AR). However, increasing reliance on more potent AR antagonists, such as enzalutamide, has led to the emergence, in a subset of cases (approximately 20%), of resistance mechanisms independent of AR activity (CRPC-AI). CRPC-AI adapt to ADT via lineage plasticity, adopting a phenotype no longer reliant on AR expression and signaling. These tumors may display neuroendocrine features, a stem or basal cell-like phenotype, altered kinase signaling, and characteristic epigenetic alterations. Recently, we and others have identified and validated new therapeutic targets and drivers of CRPC-AI, including loss of Retinoblastoma-1 (RB) and TP53, and induction of specific epigenetic/reprogramming factors such as (Enhancer of Zeste Homolog 2) EZH2 and SOX2. Additionally, our work validated the importance of loss of RB1 as the primary driver of transcriptional changes correlating with lineage plasticity, increased neuroendocrine features, and decreased sensitivity to ADT. Moreover, we demonstrated that this lineage reprogramming was largely dependent upon EZH2, as inhibition of EZH2 enabled lineage reversal and re-sensitized RB-deficient prostate cancer to ADT. Importantly, recent data from patients with mCRPC identified RB genetic aberrations as the strongest predictor of poor outcome. These data implicate RB as a dominant molecular mechanism driving lethal prostate cancer. Currently there is no therapeutic option able to provide durable response in patients with RB loss-of-function (LOF). Therefore, there is a critical need to delineate downstream effectors of RB LOF so that therapeutic targets can be identified and validated in clinical trials. We hypothesize that RB loss significantly alters EZH2 binding partners and enables formation of novel complexes, resulting in altered methylation patterns of EZH2 targets and contributing to the dependence on EZH2 function that we have previously observed. These altered complexes may provide exclusive vulnerabilities towards inhibiting lineage plasticity driven by RB loss. Specific to this application, we will characterize the changes which occur in EZH2-containing complexes and methyltransferase targets in the absence of RB and validate their functional relevance in tumor development and linage plasticity (Aim 1). We will further perform a functional genomic screen which will identify synthetic lethal targets which will cooperate with EZH2 inhibition in treatment of RB-deficient CRPC-AI and will validate these potential targets (Aim 2). Ultimately, this information will enable us to gather sufficient preliminary evidence to make a compelling case to commence investigator-initiated multi-center clinical trials.
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Identifying EZH2-dependent vulnerabilities in RB deficient prostate cancer
  • 批准号:
    10410374
  • 项目类别:
  • 资助金额:
    $19.61万
  • 财政年份:
    2021
  • 负责人:
    Leigh Ellis
  • 依托单位:
ATR Dependency as a Novel Therapeutic Target in Lethal RB Deficient Prostate Cancer.
  • 批准号:
    10034539
  • 项目类别:
  • 资助金额:
    $13.03万
  • 财政年份:
    2020
  • 负责人:
    Leigh Ellis
  • 依托单位:
ATR Dependency as a Novel Therapeutic Target in Lethal RB Deficient ProstateCancer
  • 批准号:
    10304098
  • 项目类别:
  • 资助金额:
    $27.12万
  • 财政年份:
    2020
  • 负责人:
    Leigh Ellis
  • 依托单位:
ATR Dependency as a Novel Therapeutic Target in Lethal RB Deficient ProstateCancer
  • 批准号:
    10186723
  • 项目类别:
  • 资助金额:
    $36.75万
  • 财政年份:
    2020
  • 负责人:
    Leigh Ellis
  • 依托单位:
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