Understanding Resistance to Next Generation Antiandrogens

了解下一代抗雄激素的耐药性

• 批准号: 10083715
• 负责人: CHARLES L. SAWYERS
• 金额: $ 40.41万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10083715
• 关键词: ATAC-seq; Address; Androgen Antagonists; Androgen Receptor; Androgens; Antiandrogen Therapy; Appearance; Attention; Automobile Driving; Breast Melanoma; Bypass; CRISPR library; CRISPR screen; Cancer Patient; Castration; Cell Separation; Cell surface; Cells; ChIP-seq; Characteristics; Chromatin; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Combined Modality Therapy; Complex; DNA Sequence Alteration; DNA sequencing; Data; Dependence; Development; Disease; Drug Targeting; Drug resistance; EZH2 gene; Enhancers; Ensure; Enzymes; Epithelial; Epithelial Cells; Event; Evolution; Funding; Gene Amplification; Gene Expression; Genes; Genetic Transcription; Genomics; Glucocorticoid Receptor; Goals; Human; In Vitro; Investigation; Kinetics; Laboratories; Libraries; Maintenance; Malignant neoplasm of lung; Malignant neoplasm of prostate; Maps; Mediating; Mesenchymal; Metastatic Prostate Cancer; Modeling; Molecular; Mus; Mutation; Neuroendocrine Cell; Neurosecretory Systems; Organoids; Paper; Patients; Pharmacology; Phenotype; Play; Pre-Clinical Model; Process; Progress Reports; Prostate; Prostate Cancer therapy; Publications; RB1 gene; Receptor Signaling; Regimen; Reporting; Reproducibility; Research; Resistance; Resistance development; Role; Sampling; Series; Signal Transduction; TACSTD1 gene; TP53 gene; Technology; Therapeutic Intervention; Tumor Suppressor Genes; Up-Regulation; Validation; Work; Xenograft procedure; base; castration resistant prostate cancer; clinical phenotype; clinically relevant; comparative; drug candidate; experimental study; hormone therapy; implantation; in vivo; inducible gene expression; insight; malignant breast neoplasm; men; neoplastic cell; next generation; novel; novel strategies; patient subsets; prevent; programs; promoter; prostate cancer cell; prostate cancer model; resistance mechanism; resistance mutation; single-cell RNA sequencing; transcription factor; transcriptional reprogramming; transcriptome sequencing; transcriptomics; tumor

PROJECT SUMMARY/ABSTRACT This R01 competitive renewal application focuses on a novel mechanism of acquired resistance to hormone therapy in castration resistant prostate cancer (CRPC) called lineage plasticity. During the initial 5 year funding cycle, we focused primarily on two other mechanisms of resistance: mutation or amplification of the androgen receptor (AR) and bypass of AR signaling through upregulation of the closely related glucocorticoid receptor. This work is described briefly in the Progress Report section of the Research Strategy and in the papers cited in the Progress Report Publication List. Here we shift our attention to a third mechanism of acquired resistance that we recently reported called lineage plasticity, in which prostate cancers escape hormone therapy by changing their identity from an AR dependent luminal lineage phenotype to an AR independent non-luminal lineage. This resistance mechanism occurs primarily in tumors deficient in the tumor suppressor genes TP53 and RB1 (which account for ~15% of CRPC) and is explained, in part, by upregulation of the reprogramming factor SOX2 which enables luminal epithelial cells to acquire characteristics of basal epithelial, mesenchymal and neuroendocrine cells that are no longer dependent on AR signaling for survival. We have developed genetically-defined mouse and human prostate cancer models (using organoid technology, xenografts and orthotopic tumor models) that recapitulate all the phenotypes of lineage plasticity observed in CRPC patients with reproducible, defined kinetics that make these models suitable for detailed mechanistic investigation. In Aim 1, we will identify the regulators of these lineage transitions, starting with a series of timecourse experiments using RNA-seq, ATAC-seq, chromatin ChIP-seq and single cell RNA-seq to define the transcriptomic and chromatin landscape changes associated with these changing phenotypes. Aim 2 will address the mechanism by which antiandrogen therapy can accelerate the development of lineage plasticity, which we postulate is through disruption of an AR-driven transcriptional program that helps maintain luminal identity. The results could have implications for the timing and context in which hormone therapy is used clinically. In Aim 3, we will identify candidate drug targets that block the development of lineage plasticity by conducting a pooled CRISPR screen of a library focused exclusively on chromatin modifying enzymes (selected based on our recent data implicating EZH2 as one such target). We will characterize the hits from this screen with the long range goal of developing combination therapy regimens (with antiandrogen therapy) that prevent resistance. In summary, this application will generate novel mechanistic insight into lineage plasticity in prostate cancer, with obvious implications for the clinical challenge of drug resistance. The findings are also likely to have relevance for other epithelial tumor types such as lung cancer, breast cancer and melanoma where evidence implicating lineage plasticity as a cause of drug resistance has also emerged.

项目总结/摘要 该R 01竞争性更新应用关注获得性激素抗性的新机制 去势抵抗性前列腺癌（CRPC）的治疗称为谱系可塑性。在最初的5年里， 在资助周期中，我们主要关注其他两种耐药机制： 雄激素受体（AR）和通过上调密切相关的糖皮质激素的AR信号传导旁路 受体的这项工作在研究策略的进度报告部分和 在进度报告出版物列表中引用的论文。在这里，我们将注意力转移到第三种机制， 我们最近报道称之为谱系可塑性的获得性抵抗， 通过将它们的身份从AR依赖性管腔谱系表型改变为AR 独立的非管腔谱系。这种耐药机制主要发生在肿瘤中缺乏 抑制基因TP 53和RB 1（约占CRPC的15%），部分原因是 重编程因子SOX 2使管腔上皮细胞获得基底细胞的特征， 上皮细胞、间充质细胞和神经内分泌细胞不再依赖于AR信号传导存活。 我们已经开发了基因定义的小鼠和人类前列腺癌模型（使用类器官 技术、异种移植物和原位肿瘤模型），其概括了谱系可塑性的所有表型 在CRPC患者中观察到的具有可重现的、确定的动力学，使得这些模型适合于详细研究 机械调查。在目标1中，我们将确定这些谱系转换的调节器，从 使用RNA-seq、ATAC-seq、染色质ChIP-seq和单细胞RNA-seq的一系列时程实验， 定义与这些变化的表型相关的转录组和染色质景观变化。目的 2将解决抗雄激素治疗可以加速谱系发展的机制 可塑性，我们假设是通过破坏AR驱动的转录程序， 管腔同一性这些结果可能会对激素治疗的时机和背景产生影响。 临床使用。在目标3中，我们将确定阻断谱系可塑性发展的候选药物靶点 通过对专门关注染色质修饰酶的文库进行合并的CRISPR筛选， （基于我们最近的数据选择，该数据暗示EZH 2是一个这样的靶标）。我们将描述来自 该筛查的长期目标是开发联合治疗方案（与抗雄激素治疗） 防止抵抗总之，这个应用程序将产生新的机制洞察血统 前列腺癌的可塑性，对耐药性的临床挑战有明显的影响。这些发现 也可能与其他上皮肿瘤类型有关，如肺癌、乳腺癌和 黑色素瘤，其中也出现了暗示谱系可塑性作为耐药性原因的证据。