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.

项目概要转移性前列腺癌 (mPCa) 无法治愈，并且是导致大多数 PCa 相关死亡的原因。因此，迫切需要确定拦截性治疗策略，以提供持久的反应雄激素剥夺疗法 (ADT) 是 mPCa 的主要治疗方法。生存，但由于患者的肿瘤出现去势抵抗 (mCRPC)，因此无法治愈。大多数 mCRPC。仍然依赖于雄激素受体 (AR) 的功能，但是，人们越来越依赖更有效的雄激素受体。 AR 拮抗剂，例如恩杂鲁胺，在部分病例（约 20%）中导致出现独立于 AR 活性的耐药机制（CRPC-AI）通过谱系可塑性适应 ADT，这些肿瘤可能会表现出不再依赖 AR 表达和信号传导的表型。神经内分泌特征、干细胞或基底细胞样表型、激酶信号传导和特征最近，我们和其他人已经确定并验证了新的治疗靶点和驱动因素。 CRPC-AI 的影响，包括 Retinoblastoma-1 (RB) 和 TP53 的丢失，以及特异性的诱导表观遗传/重编程因子，例如（Zeste 同源物增强子 2）EZH2 和 SOX2。此外，我们的工作验证了 RB1 丢失作为转录变化主要驱动因素的重要性与谱系可塑性、神经内分泌特征增加和 ADT 敏感性降低相关。此外，我们证明这种谱系重编程很大程度上依赖于 EZH2，因为抑制 EZH2 使谱系逆转并使 RB 缺陷的前列腺癌对 ADT 重新敏感。来自 mCRPC 患者的研究发现 RB 基因畸变是预后不良的最强预测因子。这些数据表明 RB 是目前驱动致死性前列腺癌的主要分子机制。没有治疗方案能够为 RB 功能丧失患者提供持久的缓解 (LOF) 因此，迫切需要描述 RB LOF 的下游效应器，以便进行治疗。我们发现 RB 丢失会显着改变 EZH2。结合伴侣并能够形成新型复合物，从而改变 EZH2 的甲基化模式目标并导致我们之前观察到的对 EZH2 功能的依赖。复合物可能提供独特的弱点来抑制由 RB 特定损失驱动的谱系可塑性。在此应用中，我们将描述包含 EZH2 的复合物中发生的变化，甲基转移酶在缺乏 RB 的情况下靶向并验证其在肿瘤发展和中的功能相关性我们将进一步进行功能基因组筛选，以鉴定合成致死性。将与 EZH2 抑制配合治疗 RB 缺陷的 CRPC-AI 的目标，并将验证这些目标最终，这些信息将使我们能够收集足够的初步证据来确定潜在的目标（目标 2）。提出令人信服的理由来启动研究者发起的多中心临床试验。