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

基本信息

批准号：
10154294
负责人：
Leigh Ellis
金额：
$ 19.52万
依托单位：
CEDARS-SINAI MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-25 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10154294
关键词：
Adopted Androgen Receptor Automobile Driving Basal Cell Binding Castration Cells Characteristics Chromatin Clinical Research Clinical Trials Clustered Regularly Interspaced Short Palindromic Repeats Complex DNA Binding DNA Modification Methylases Data Dependence Deposition Development Disease EZH2 gene Enhancers Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Epigenetic Process Event Gene Expression Gene Expression Profile Genes Genetic Genetic Predisposition to Disease Genetic Transcription Goals Heterochromatin Histone Deacetylase Histones Homologous Gene Human Immunoprecipitation Intercept Knock-out Lysine MDM2 gene MYCN gene Malignant neoplasm of prostate Mass Spectrum Analysis Mediating Metastatic Prostate Cancer Methyltransferase Molecular Multi-Institutional Clinical Trial Neuroendocrine Prostate Cancer Neurosecretory Systems Non-Small-Cell Lung Carcinoma Outcome PTEN gene Pathway interactions Patients Phenotype Phosphotransferases Physical condensation Polycomb Prostate Adenocarcinoma Proteins Proteomics Quality of life RB1 gene Receptor Signaling Repetitive Sequence Repression Research Personnel Resistance Retinoblastoma Retinoblastoma Protein Role Signal Transduction TP53 gene Testing Therapeutic Tumor Suppressor Genes Up-Regulation Work androgen deprivation therapy aurora kinase A base castration resistant prostate cancer chromatin remodeling cofactor combinatorial experimental study functional genomics gene repression histone methyltransferase inhibitor/antagonist loss of function loss of function mutation methylation pattern methylome mortality mouse genome neuroendocrine phenotype new therapeutic target novel pluripotency preclinical study prostate cancer cell line protein complex receptor expression resistance mechanism response scaffold stem cells targeted treatment therapeutic target therapy resistant transcription factor transcriptome sequencing treatment response treatment strategy tumor whole genome

项目摘要

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.

项目摘要转移性前列腺癌（MPCA）是无法治愈的，并且负责大多数PCA相关的死亡率。因此，迫切需要确定截然的治疗策略，以提供持久的反应患者。雄激素剥夺治疗（ADT）是MPCA的主要治疗方法。 ADT最初扩展生存期，但由于患者的肿瘤获得了cast割耐药性（MCRPC），因此无法治愈。大多数MCRPC 保持依赖于雄激素受体（AR）的功能。但是，增加对更有效的保留率 AR拮抗剂，例如enzalutamide，在一部分情况下（约20％）导致出现与AR活性无关的抗性机制（CRPC-AI）。通过谱系可塑性适应ADT的CRPC-AI，采用表型与AR表达和信号传导不再相关。这些肿瘤可能显示神经内分泌特征，茎或基本细胞样表型，激酶信号改变和特征表观遗传改变。最近，我们和其他人已经确定并验证了新的治疗目标和驱动因素 CRPC-AI，包括视网膜母细胞瘤-1（RB）和TP53的丢失以及特定的诱导表观遗传/重编程因素，例如（Zeste同源2的增强子）EZH2和SOX2。此外，我们的工作证实了RB1损失的重要性，这是转录更改的主要驱动力与谱系可塑性相关，神经内分泌特征的增加以及对ADT的敏感性提高。此外，我们证明了这种谱系重编程在很大程度上取决于EZH2，因为抑制了 EZH2使谱系逆转和重新敏感的RB缺乏的前列腺癌为ADT。重要的是，最近的数据来自MCRPC的患者发现RB遗传像差是预后不良的强有力预测指标。这些数据暗示RB是驱动致命前列腺癌的主要分子机制。现在没有治疗选择能够在RB功能丧失的患者中提供持久的反应（LOF）。因此，迫切需要描述RB LOF的下游效应，以便该治疗。可以在临床试验中识别和验证目标。我们假设RB损失显着改变EZH2 结合伴侣并实现了新型复合物的形成，从而改变EZH2的甲基化模式目标并有助于我们先前观察到的对EZH2功能的依赖。这些改变了复合物可以通过RB损失提供独家漏洞来抑制谱系可塑性驱动。具体的在此应用程序中，我们将表征含EZH2的复合物中发生的变化在不存在RB的情况下，甲基转移酶靶标并验证其在肿瘤发育中的功能相关性和线路可塑性（AIM 1）。我们将进一步执行功能性基因组筛选，该筛选将鉴定合成致死将与EZH2抑制在RB缺陷CRPC-AI方面合作的靶标，并将验证这些潜在目标（目标2）。最终，这些信息将使我们能够收集足够的初步证据提出一个令人信服的案例，以开始研究者引发的多中心临床试验。