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

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

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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 Prostate癌症耐药性和敏感性中心的项目1关注获得的对激素治疗的耐药性是由雄激素受体（AR）途径重新激活引起的。这项目由两个目标组成，基于AR途径激活的两个不同机制。 AIM 1专注于糖皮质激素受体（我们和其他人都可以替代AR）驱动肿瘤生长通过旁路机制。临床数据集，尽管在此阶段有限，但表明这种机制可以负责20-30％获得的对恩扎拉胺的抗性。 AIM 1中的实验将探索靶向AR与GR的竞争性拮抗剂的临床前活性（来自Oric Pharmaceuticals）或使用BET域抑制剂（来自星座药物）有力下调GR表达。 AIM 2解决了更常见的情况 AR本身负责AR途径重新激活，这是一种以上被收购的情况下存在的情况抵抗患者。这可以通过AR基因扩增，AR mRNA剪接变体或AR突变发生，即大致按频率顺序。 AIM 2中的实验旨在比IS更有效地抑制AR 目前可以与当前拮抗剂（例如恩扎拉氨酰胺），首先通过干扰AR的转录并使用CBP/P300抑制剂（来自AbbVie）的下游靶基因。我们还将评估工具我们在整个基因组shrna筛选中恢复的染色质修饰剂G9A/EHMT2的化合物，基于选择性抗增生活性与恩扎拉酰胺的结合。最后，我们将进行屏幕对于进一步损害AR转录输出的药物靶标超出了enzalutamide所见。总共，我们将评估四种AR组合治疗方案，其中三种涉及目前正在临床的药物开发或很快就会。总而言之，该项目有可能生成多种基于机制的项目联合疗法临床试验以及如何使用临床可行的洞察力选择患者生物标志物。此外，这些发现可能与其他激素受体更广泛地相关乳腺癌等疾病。