Characterization of Epigenetic Targets in Prostate Cancer

前列腺癌表观遗传靶点的表征

• 批准号: 9326820
• 负责人: Irfan Ahmed Asangani
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9326820
• 关键词: Address; Attenuated; Award; Binding; Bioinformatics; Biological Markers; Cancer Biology; Cancer cell line; Catalytic Domain; Cell Maintenance; ChIP-seq; Chromatin; Chromosomal translocation; Clinical; Data; Development; Diagnostic; Disease; Disease Progression; EZH2 gene; Embryonic Development; Environment; Enzymes; Epigenetic Process; Future; Gene Expression; Gene Expression Regulation; Gene Silencing; Genes; Genetic Transcription; Genome; Genomics; Goals; Growth; High-Throughput Nucleotide Sequencing; Histones; Human Genome; Hydralazine; Immunohistochemistry; Investigation; Isomerism; Journals; Knock-out; Lead; Lysine; Malignant Neoplasms; Malignant neoplasm of prostate; Mass Spectrum Analysis; Mediating; Methylation; Michigan; Molecular; Multiple Myeloma; Mutation; Myeloproliferative disease; Nuclear; Oncogenic; Outcome; Paper; Pathology; Pathway interactions; Pharmacologic Substance; Phenotype; Play; Property; Prostate; Prostate Cancer therapy; Prostatic Neoplasms; Protein Binding Domain; Proteins; Recurrence; Reporting; Research; Research Personnel; Role; SET Domain; Signal Transduction; Site; Solid Neoplasm; Stem cells; Sulfhydryl Compounds; Tail; Therapeutic Intervention; Tissue Sample; Transcriptional Activation; Transcriptional Regulation; Translating; Tumor Suppressor Proteins; United States National Institutes of Health; WHSC1 gene; Wolf-Hirschhorn Syndrome; Work; arginyllysine; base; cancer type; career; castration resistant prostate cancer; chromatin immunoprecipitation; chromatin modification; clinical application; clinically relevant; epigenetic drug; experience; genome integrity; high throughput technology; histone methylation; histone methyltransferase; improved; in vivo; inhibitor/antagonist; novel; outcome forecast; overexpression; prognostic; prostate cancer cell; protein expression; public health relevance; small molecule; small molecule inhibitor; therapeutic target; tool; transcriptome; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): Histone methyltransferases (HMTases) are chromatin modifiers that play an important role in normal development as well as in diseases such as cancer. Following the discovery by our group that EZH2 is overexpressed and associates with prostate cancer progression and poor prognosis (1), it has become the most well-studied HMTase in cancer with multiple research groups and pharmaceutical companies in pursuit of developing EZH2 inhibitors for clinical use. However, direct targeting of EZH2 is deemed problematic since it also has a role in stem cell maintenance and acts as a tumor suppressor in myeloid diseases. More recently, our transcriptome and protein expression analysis across multiple cancers including primary and metastatic prostate tumors revealed overexpression of another HMTase, MMSET, that paralleled EZH2 expression, function and clinical attributes (2). EZH2, which is associated with gene silencing mediated through histone H3K27 trimethylation, was found to be coordinately expressed and function upstream of MMSET, which mediates H3K36 dimethylation associated with active transcription. Given the high expression and functional significance of MMSET as an effector of EZH2-mediated oncogenesis as well as the observation that MMSET plays a critical role in prostate cancer by regulating AR signaling and gene expression, we hypothesize that MMSET potentially represents an important therapeutic target in prostate cancer. In an effort to therapeutically target MMSET we have identified a lead probe compound, 3-hydraxino-2-quinoxalinethiol (MCTP39), a thiol group containing isomer of hydralazine (a known epigenetic drug), that was found to attenuate MMSET enzymatic activity in vivo. Further, MCTP39 was shown to inhibit growth and invasive properties specifically of cancer cell lines that overexpress MMSET. Here, we propose to carry out the following Specific Aims: 1) Integrative functional study of MMSET in prostate cancer; 2) Elucidation of the role of MMSET in AR signaling; 3) Characterization of a lead MMSET inhibitor compound MCTP39. Successful completion of the Aims outlined in this proposal will improve understanding of the role of MMSET and its importance in AR-mediated prostate cancer progression, and may yield a promising small molecule inhibitor that could be further developed for clinical use. The proposed projects and the supporting preliminary data were conceived based on the applicant's original ideas. The cross-disciplinary environment provided by Dr. Chinnaiyan at the Michigan Center of Translational Pathology, which has vast experience applying high-throughput technologies and bioinformatics approaches for studying the mutational landscape of cancer and identifying associated biomarkers and therapeutic targets, serves as an ideal environment for supporting the applicant's scientific career goals. This is exemplified by the applicant's extensive preliminary data that has led to multiple first author and co-author papers in high impact journals. Dr. Chinnaiyan has extended his full support towards the applicants' career goals and has encouraged him to transfer these projects to his independent lab in the future. Overall, an NIH Pathway to Independence Award will be indispensable for the applicant to transition into an independent investigator in the field of cancer biology specifically in translating genome-based discoveries into clinical applications.

描述（由申请人提供）：组蛋白甲基转移酶（HMTases）是染色质修饰剂，在正常发育以及癌症等疾病中起重要作用。在我们小组发现EZH2过表达并与前列腺癌的进展和预后不良相关之后（1），它已成为癌症中最精心研究的HMTase，其中多个研究小组和制药公司追求开发EZH2抑制剂以进行临床使用。但是，直接靶向EZH2是有问题的，因为它在干细胞维持中也具有作用，并且在髓样疾病中起抑制肿瘤。最近，我们跨多种癌症（包括原发性前列腺肿瘤和转移性前列腺肿瘤）的转录组和蛋白质表达分析表明，另一种HMTase Mmset的过表达与EZH2表达，功能和临床属性平行（2）。 EZH2与通过组蛋白H3K27三甲基化介导的基因沉默相关，它被发现是协调表达的，并在MMSET的上游功能，该甲基化介导了与活性转录相关的H3K36二甲基化。鉴于MMSET作为EZH2介导的肿瘤发生的效应因子的高表达和功能意义，并且观察到MMSET通过调节AR信号传导和基因表达在前列腺癌中起关键作用，我们假设MMSET可能代表了前列腺癌中重要的治疗靶标。为了通过治疗靶向MMSET，我们已经鉴定出铅探针化合物3-羟基2- Quinoxaliniol（MCTP39），这是一种含有氢吡嗪（一种已知表观遗传药物）的硫醇基，被发现减弱了MMSET酶促活性在体内。此外，显示MCTP39可抑制过表达MMSET的癌细胞系的生长和侵入性。在这里，我们建议执行以下特定目的：1）前列腺癌中MMSET的综合功能研究； 2）阐明MMSET在AR信号传导中的作用； 3）表征铅MMSET抑制剂化合物MCTP39。该提案中概述的目标的成功完成将提高人们对MMSET的作用及其在AR介导的前列腺癌进展中的重要性，并可能产生有希望的小分子抑制剂，这可以进一步开发供临床使用。拟议的项目和支持的初步数据是根据申请人的原始想法来构想的。密歇根州转化病理中心Chinnaiyan博士提供的跨学科环境，该中心采用高通量技术和生物信息学方法的丰富经验，用于研究癌症的突变景观并识别相关的生物标志物和治疗目标，是支持申请人科学职业的理想环境。申请人的广泛初步数据为这一点举例说明了这一点，该数据导致了高影响期刊的多个第一作者和合着者论文。 Chinnaiyan博士已全力支持申请人的职业目标，并鼓励他将来将这些项目转移到他的独立实验室。总体而言，NIH独立奖是必不可少的，对于申请人过渡到癌症生物学领域的独立研究者，专门将基于基因组的发现转化为临床应用。