Imaging Histone Decatelylase (HDAC) Inhibition in Cancer

癌症中组蛋白癸酰酶 (HDAC) 抑制的成像

• 批准号: 8555238
• 负责人: Ralph Mazitschek
• 金额: $ 68.78万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-08-09 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8555238
• 关键词: Address; Behavior; Binding; Biochemistry; Biological; Biological Process; Biology; Biomedical Research; Boron; Cancer Center; Cathepsins; Chemicals; Chromatin; Clinical Trials; Cutaneous; Development; Drug or chemical Tissue Distribution; Dyes; Enzymes; Epigenetic Process; Fluorine; Fluorochrome; Gene Expression; Gene Expression Regulation; Generic Drugs; Goals; Histone Deacetylase; Histone Deacetylase Inhibitor; Histones; Image; Libraries; Ligands; Link; Lysine; Malignant Neoplasms; Malignant neoplasm of ovary; Metalloproteases; Methods; Molecular Biology; Organ; Pathogenesis; Peptides; Positron-Emission Tomography; Pre-Clinical Model; Protein Acetylation; Regulation; Reporting; Research; Research Personnel; Screening procedure; Seasons; Stromal Cells; T-Cell Lymphoma; Tail; Testing; Tissues; Transcription Regulatory Protein; Treatment Efficacy; Vorinostat; Work; Zolinza; base; cancer cell; cancer therapy; design; enzyme activity; enzyme substrate; in vivo; interest; molecular imaging; mouse model; novel; small molecule; therapeutic target

The overall goal of this project is to develop novel compounds and approaches to image histone decatelylases (HDACs), key enzymes associated with epigenetic gene regulation. HDACs have been linked to the pathogenesis of cancer, and small-molecule HDAC inhibitors (HDACi) have been shown to have significant biological effects in preclinical models of cancer as well as in early clinical trials. Our group has recently developed class-specific and pan-HDACi based on rational ligand and substrate design, HDAC biochemistry, and on high-content screening (Nat Chem Biol 2009;6:238-243). Based on these developments, we will now address fundamental questions regarding HDAC biology and inhibition, such as: 1) What are the tissue distribution levels of HDACs in vivo? 2) Do cancer cells have different expression levels to stromal cells? 3) What are the activity levels of HDACs (not just abundance) in vivo? 4) What are HDAC activity levels at the whole organ level? 5) Can HDAC inhibition (using HDACi) be quantitated using imaging? The central hypothesis underlying this research is that novel imaging agents will allow us to both visualize the distribution of HDACs as well as quantitate their activity levels in vivo. The specific aims are thus: 1) to develop and test small molecule HDAC ligands for imaging; 2) to validate and test imaging agents in mouse models; and 3) to image HDAC expression and therapeutic efficacy of HDAC inhibition in ovarian cancer in vivo.

该项目的总体目标是开发新的化合物和组蛋白成像方法 十氢化酶 (HDAC)，与表观遗传基因调控相关的关键酶。 HDAC 已 与癌症的发病机制有关，小分子 HDAC 抑制剂 (HDACi) 已被证明可以 在癌症的临床前模型以及早期临床试验中具有显着的生物学效应。我们的 课题组最近开发了基于合理配体和底物的类特异性和泛HDACi 设计、HDAC 生物化学和高内涵筛选（Nat Chem Biol 2009；6:238-243）。基于 这些进展，我们现在将解决有关 HDAC 生物学和抑制的基本问题， 例如：1）HDAC在体内的组织分布水平是怎样的？ 2）癌细胞有不同的吗？ 基质细胞的表达水平？ 3) 体内 HDAC 的活性水平（不仅仅是丰度）是多少？ 4) 整个器官水平的 HDAC 活性水平是多少？ 5) HDAC抑制（使用HDACi）可以吗？ 使用成像进行定量？这项研究的中心假设是新型显像剂 将使我们能够可视化 HDAC 的分布并量化它们在体内的活性水平。 因此，具体目标是：1）开发和测试用于成像的小分子 HDAC 配体； 2）验证 并在小鼠模型中测试显像剂； 3) 对 HDAC 表达和治疗效果进行成像 HDAC 在体内卵巢癌中的抑制作用。