Project 1: Resistance caused by AR pathway reactivation

项目1：AR通路重新激活引起的耐药

• 批准号: 10250361
• 负责人: CHARLES L. SAWYERS
• 金额: $ 33.02万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-30 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10250361
• 关键词: AR gene; Ablation; Address; Agonist; Androgen Receptor; Biological Assay; Biological Markers; Bypass; CRISPR library; Cell Line; Cells; Chromatin Remodeling Factor; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Combined Modality Therapy; Data; Data Set; Dependence; Disease; Drug Screening; Drug Targeting; EP300 gene; Enhancers; Evaluation; Frequencies; G9a histone methyltransferase; Gene Amplification; Gene Expression; Genes; Genetic; Genetic Transcription; Glucocorticoid Receptor; Growth; Hormone Receptor; Impairment; Libraries; Malignant neoplasm of prostate; Memorial Sloan-Kettering Cancer Center; Messenger RNA; Mifepristone; Modeling; Mutation; Outcome; Output; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; RNA Splicing; Receptor Inhibition; Regimen; Regulation; Reporter; Residual state; Resistance; Scientist; Technology; Testing; Therapy Clinical Trials; Treatment Protocols; VCaP; Variant; base; biomarker discovery; cancer drug resistance; clinical development; design; drug sensitivity; druggable target; experimental study; hormone therapy; improved; inhibitor/antagonist; insight; interest; malignant breast neoplasm; patient derived xenograft model; pre-clinical; preclinical study; promoter; prostate cancer cell line; receptor expression; screening; small hairpin RNA; tool; transcriptome; tumor; tumor growth; whole genome

Project 1 Summary/Abstract Project 1 of the MSKCC-UW/Fred Hutch Prostate Cancer Drug Resistance and Sensitivity Center focuses on acquired resistance to hormone therapy that is caused by androgen receptor (AR) pathway reactivation. The project consists of two Aims, based on two different mechanisms of AR pathway activation. Aim 1 focuses on the glucocorticoid receptor, which we and others have shown can substitute for AR to drive tumor growth through a bypass mechanism. Clinical datasets, albeit limited at this stage, suggest that this mechanism could be responsible for 20-30% of acquired resistance to enzalutamide. The experiments in Aim 1 will explore the preclinical activity of treatment regimens that target AR in combination with a competitive antagonist of GR (from ORIC Pharmaceuticals) or with a BET domain inhibitor (from Constellation Pharmaceuticals) that potently downregulates GR expression. Aim 2 addresses the more common circumstance where alteration of AR itself is responsible for AR pathway reactivation, a circumstance present in more than 50% of acquired resistance patients. This can occur through AR gene amplification, AR mRNA splice variants or AR mutations, roughly in that order of frequency. Experiments in Aim 2 are designed to inhibit AR more potently than is currently possible with current antagonists such as enzalutamide, first by interfering with the transcription of AR and its downstream target genes using a CBP/p300 inhibitor (from AbbVie). We will also evaluate a tool compound targeting the chromatin modifier G9A/EHMT2 that we recovered in a whole genome shRNA screen, based on selective antiproliferative activity in combination with enzalutamide. Finally, we will conduct a screen for drug targets that further impair AR transcriptional output beyond that seen with enzalutamide. In total, we will evaluate four AR combination therapy regimens, three of which involve drugs that are currently in clinical development or soon will be. In summary, this Project has the potential to generate multiple mechanism-based combination therapy clinical trials together with insights into how to select patients using clinically feasible biomarkers. Furthermore, the findings could be more broadly relevant to other hormone receptor dependent diseases such as breast cancer.

项目1概要/摘要 MSKCC-UW/Fred Hutch前列腺癌耐药性和敏感性中心的项目1侧重于 雄激素受体（AR）通路再激活引起的对激素治疗的获得性抵抗。的 该项目由两个目标组成，基于AR途径激活的两种不同机制。目标1侧重于 我们和其他人已经证明糖皮质激素受体可以取代AR来驱动肿瘤生长 通过旁路机制。临床数据集，虽然在这个阶段有限，表明这种机制可能 导致20-30%的获得性Enzalutamide耐药。目标1中的实验将探索 靶向AR与GR竞争性拮抗剂组合的治疗方案的临床前活性 (from ORIC Pharmaceuticals）或BET结构域抑制剂（来自Constellation Pharmaceuticals）， 有效下调GR表达。目标2针对的是更常见的情况， AR本身负责AR通路的再激活，这种情况存在于超过50%的获得性 抵抗患者这可以通过AR基因扩增、AR mRNA剪接变体或AR突变发生， 大概是这个频率目标2中的实验旨在比预期更有效地抑制AR。 目前可能使用当前的拮抗剂如恩杂鲁胺，首先通过干扰AR的转录， 及其下游靶基因，使用CBP/p300抑制剂（来自AbbVie）。我们还将评估一种工具， 靶向我们在全基因组shRNA筛选中回收的染色质修饰剂G9 A/EHMT 2的化合物， 基于与恩杂鲁胺组合的选择性抗增殖活性。最后，我们将进行屏幕 对于进一步损害AR转录输出的药物靶点，超过了Enzalutamide。我们总共 将评估四种AR联合治疗方案，其中三种涉及目前临床上正在使用的药物， 发展，或将很快。总之，该项目有可能产生多种基于机制的 联合治疗临床试验以及如何使用临床可行的 生物标志物。此外，这些发现可能与其他激素受体依赖性更广泛相关。 乳腺癌等疾病。