Characterization of Epigenetic Targets in Prostate Cancer

前列腺癌表观遗传靶点的表征

• 批准号: 9148273
• 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/9148273
• 关键词: Address; Attenuated; Award; Binding; Binding Proteins; 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 Profile; Gene Expression Regulation; Gene Silencing; Genes; Genetic Transcription; Genome; Genomics; Goals; Growth; Health; 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; Myeloproliferative disease; Nuclear; Oncogenic; Outcome; Paper; Pathology; Pathway interactions; Pharmaceutical Preparations; Pharmacologic Substance; Phenotype; Play; Property; Prostate; Prostate Cancer therapy; Prostatic Neoplasms; 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; Wolf-Hirschhorn Syndrome; Work; arginyllysine; base; cancer type; career; castration resistant prostate cancer; chromatin immunoprecipitation; chromatin modification; clinical application; clinically relevant; 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; small molecule; therapeutic target; tool; 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（HMTase）是染色质修饰剂，在正常发育以及癌症等疾病中发挥重要作用。继我们小组发现 EZH2 过度表达并与前列腺癌进展和不良预后相关 (1) 后，它已成为癌症中研究最充分的 HMTase，多个研究小组和制药公司都在寻求开发用于临床的 EZH2 抑制剂。然而，直接靶向 EZH2 被认为是有问题的，因为它还在干细胞维持中发挥作用，并在骨髓疾病中充当肿瘤抑制因子。最近，我们对多种癌症（包括原发性和转移性前列腺肿瘤）的转录组和蛋白质表达分析揭示了另一种 HMTase MMSET 的过度表达，其与 EZH2 表达、功能和临床属性相似 (2)。 EZH2 与组蛋白 H3K27 三甲基化介导的基因沉默相关，被发现在 MMSET 上游协调表达和发挥作用，MMSET 介导与活性转录相关的 H3K36 二甲基化。鉴于 MMSET 作为 EZH2 介导的肿瘤发生效应物的高表达和功能意义，以及观察到 MMSET 通过调节 AR 信号传导和基因表达在前列腺癌中发挥关键作用，我们假设 MMSET 可能代表前列腺癌的重要治疗靶点。为了以 MMSET 为治疗目标，我们鉴定了一种先导探针化合物 3-Hydraxino-2-quinoxalinethiol (MCTP39)，这是一种含有肼基异构体的硫醇基团（一种已知的表观遗传药物），被发现可以减弱体内 MMSET 酶活性。此外，MCTP39 显示可抑制生长和侵袭特性，特别是过度表达 MMSET 的癌细胞系。在此，我们建议开展以下具体目标：1）MMSET在前列腺癌中的综合功能研究； 2）阐明MMSET在AR信令中的作用； 3) 主要 MMSET 抑制剂化合物 MCTP39 的表征。成功完成本提案中概述的目标将提高对 MMSET 的作用及其在 AR 介导的前列腺癌进展中的重要性的理解，并可能产生一种有前途的小分子抑制剂，可进一步开发用于临床使用。拟议的项目和支持的初步数据是根据申请人的原始想法构思的。密歇根转化病理学中心的 Chinnaiyan 博士提供的跨学科环境，在应用高通量技术和生物信息学方法来研究癌症突变情况和识别相关生物标志物和治疗靶点方面拥有丰富的经验，为支持申请人的科学职业目标提供了理想的环境。申请人广泛的初步数据就证明了这一点，这些数据已在高影响力期刊上发表了多篇第一作者和共同作者论文。 Chinnaiyan博士对申请者的职业目标表示全力支持，并鼓励他将来将这些项目转移到自己的独立实验室。总体而言，NIH 独立之路奖对于申请人转变为癌症生物学领域的独立研究者（特别是将基于基因组的发现转化为临床应用）是必不可少的。