Imaging Histone Decatelylase (HDAC) Inhibition in Cancer

该项目的总体目标是开发新的化合物和方法来成像组蛋白 十烷基化酶（HDAC），与表观遗传基因调控相关的关键酶。HDAC已经 与癌症的发病机制有关，小分子HDAC抑制剂（HDACi）已被证明 在癌症的临床前模型以及早期临床试验中具有显著的生物学效应。我们 小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生物化学和高含量筛选（Nat Chem Biol 2009;6：238-243）。基于 这些发展，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如何？2)癌细胞有不同的 基质细胞的表达水平？3)HDAC在体内的活性水平（不仅仅是丰度）是多少？ 4)HDAC在整个器官水平上的活性水平是多少？5)HDAC抑制（使用HDACi）是否可以 使用成像进行定量？这项研究的核心假设是， 将允许我们可视化HDAC的分布以及定量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 和测试小鼠模型中的成像剂;和3）对HDAC表达和治疗功效进行成像， HDAC在体内卵巢癌中的抑制。

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.