Collaborative genomic alterations and transcriptional control in prostate cancer

前列腺癌中的协同基因组改变和转录控制

基本信息

批准号：
10549377
负责人：
Christopher E Barbieri
金额：
$ 53.9万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-02-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10549377
关键词：
Affect Androgen Receptor Binding Biological Biological Models Biology CHD1 gene Cells Chromatin Clinical Course of Disease Clinical Trials Collaborations Complex DNA Sequence Alteration Data Diagnosis Disease EP300 gene Foundations Gene Expression Genes Genetic Genetic Transcription Genetically Engineered Mouse Genomic approach Growth Histologic In Vitro Malignant Neoplasms Malignant neoplasm of prostate Mediating Missense Mutation Modeling Molecular Mus Mutation Neoplasms Nucleosomes Oncogenic Pathogenesis Patients Phenotype Play Prostate Proteins Proteome Proteomics Recurrence Role Sampling Shapes Signal Transduction Specificity Testing Therapeutic Intervention Transcription Process Transcriptional Regulation cancer subtypes clinically relevant cohort functional genomics genome-wide human data human disease in vivo innovation insight men mutant new therapeutic target novel novel diagnostics novel therapeutic intervention programs prostate carcinogenesis protein expression stoichiometry targeted treatment therapeutic biomarker therapeutic target transcriptome transcriptomics translational impact ubiquitin ligase

项目摘要

PROJECT SUMMARY / ABSTRACT Molecular characterization of prostate cancer has revealed distinct subtypes, but the biologic implications and translational impact of these are still unclear. We recently defined a distinct molecular subclass of prostate cancer characterized by the combination of mutations in the ubiquitin ligase SPOP, and deletion of the nucleosome remodeler CHD1. However, the mechanisms by which SPOP mutation and CHD1 deletion collaborate to drive prostate tumorigenesis remain unknown. The overall objective of this proposal is to define the mechanisms by which SPOP mutation and CHD1 deletion collaborate to drive prostate tumorigenesis. Using novel models, our preliminary data demonstrate that SPOP mutation alters expression of proteins that are functionally and physically associated with the androgen receptor (AR), a critical driver for prostate cancer and key therapeutic target, and alters AR-driven gene expression. Furthermore, we have found that CHD1 deletion fundamentally reprograms the AR-cistrome and transcriptional program in prostate cells, diverting away from a growth suppressive AR program and towards an oncogenic program. These results suggest that mutation of SPOP stabilizes key substrates involved in AR activity, and that CHD1 deletion specifically collaborates with these changes in the AR- transcriptional complex to promote oncogenic transcription and prostate tumorigenesis. This project will elucidate the molecular details underlying these phenomena through the following Aims: 1) establishing the collaborative impact of SPOP mutation and CHD1 deletion on the pathogenesis of prostate cancer, 2) defining the alterations to the AR-transcriptional complex mediated by SPOP mutation, and 3) determining the alterations induced by SPOP mutation that are critical for collaboration with CHD1 loss and reprograming of the AR transcriptome. To accomplish this, we will leverage unique, biologically and clinically relevant model systems, innovative approaches to proteomic and transcriptomic discovery, and data from human prostate cancer samples. This project will define the critical transcriptional processes in SPOP mutant / CHD1 deleted prostate cancer and the broader applicability across prostate cancer subtypes, and provide the foundation for precision clinical trials targeting this subclass.

项目摘要 /摘要前列腺癌的分子表征揭示了不同的亚型，但生物学意义和这些翻译影响仍然不清楚。我们最近定义了前列腺的独特分子亚类癌症以泛素连接酶旋转中突变的结合，并缺失核小体重塑CHD1。但是，SPOP突变和CHD1删除的机制驱动前列腺肿瘤发生的合作仍然未知。该提议的总体目的是定义Spop突变和CHD1的机制删除协作以驱动前列腺肿瘤发生。使用新型模型，我们的初步数据证明了这种汤匙突变改变了功能和物理上与该蛋白的表达雄激素受体（AR）是前列腺癌和关键治疗靶标的关键驱动因素，并改变了AR驱动基因表达。此外，我们发现CHD1删除从根本上重新编程了AR-Cistrome 和前列腺细胞中的转录程序，脱离增长抑制性AR程序和走向致癌计划。这些结果表明，Spop的突变稳定了关键底物参与AR活动，CHD1删除专门与AR中的这些变化合作转录复合物可促进致癌转录和前列腺肿瘤发生。这个项目将通过以下目的阐明这些现象的分子细节：1）建立 SPOP突变和CHD1缺失对前列腺癌发病机理的协作影响，2）定义通过SPOP突变介导的AR转录复合物的改变，以及3）确定 SPOP突变引起的改变，这对于与CHD1损失合作至关重要 AR转录组。为此，我们将利用独特，生物学和临床相关的模型来利用系统，蛋白质组学和转录组发现的创新方法以及人类前列腺的数据癌症样本。该项目将定义Spop突变体 / CHD1中的关键转录过程前列腺癌和跨前列腺癌亚型的更广泛的适用性，并为针对此子类的精确临床试验。