Project 1: Resistance caused by AR pathway reactivation

项目1：AR通路重新激活引起的耐药

基本信息

批准号：
10005210
负责人：
CHARLES L. SAWYERS
金额：
$ 35.26万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-30 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10005210
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 pre-clinical preclinical study promoter prostate cancer cell line receptor expression screening small hairpin RNA tool transcriptome tumor tumor growth whole genome

项目摘要

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 摘要/摘要 MSKCC-UW/Fred Hutch 前列腺癌耐药性和敏感性中心的项目 1 重点关注由于雄激素受体（AR）途径重新激活而导致对激素治疗的获得性耐药。这项目由两个目标组成，基于两种不同的 AR 通路激活机制。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替代 AR 来驱动肿瘤生长通过旁路机制。临床数据集尽管现阶段有限，但表明这种机制可以 20-30% 的恩杂鲁胺获得性耐药是由其引起的。目标 1 中的实验将探索靶向 AR 与 GR 竞争性拮抗剂联合治疗方案的临床前活性（来自 ORIC Pharmaceuticals）或 BET 域抑制剂（来自 Constellation Pharmaceuticals）有效下调 GR 表达。目标 2 解决了更常见的情况，即更改 AR 本身负责 AR 通路重新激活，这种情况存在于超过 50% 的获得性耐药患者。这可以通过 AR 基因扩增、AR mRNA 剪接变体或 AR 突变发生，大致按照频率的顺序。 Aim 2 中的实验旨在比 AR 更有效地抑制 AR 目前可以使用恩杂鲁胺等当前拮抗剂，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）。我们还将评估一个工具我们在全基因组 shRNA 筛选中回收的针对染色质修饰剂 G9A/EHMT2 的化合物，基于与恩杂鲁胺联合的选择性抗增殖活性。最后我们将进行一次筛选用于进一步损害 AR 转录输出的药物靶标，其效果超出恩杂鲁胺所见。总共，我们将评估四种 AR 联合治疗方案，其中三种涉及目前处于临床阶段的药物发展或很快就会。总之，该项目有潜力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方法选择患者的见解生物标志物。此外，这些发现可能与其他激素受体依赖性药物更广泛地相关。乳腺癌等疾病。