Imaging Histone Decatelylase (HDAC) Inhibition in Cancer

这个项目的总体目标是开发新的化合物和方法来成像组蛋白。 十氢叶酸脱氢酶(HDAC)，与表观基因调控相关的关键酶。HDAC已经被 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和早期临床试验中具有显著的生物学效应。我们的 Group最近开发了基于有理配体和底物的类特定和PAN-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什么？2)癌细胞是否有不同的 间质细胞的表达水平？3)体内HDAC的活性水平(不仅仅是丰度)是什么？ 4)HDAC在整个器官水平的活性水平是什么？5)HDAC抑制(使用HDACi)是否可以 使用成像技术进行量化？这项研究的中心假设是新型显像剂 这将使我们既可以可视化HDAC的分布，也可以量化它们在体内的活动水平。 具体目标如下：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；以及3)成像HDAC的表达和治疗效果 HDAC在体内对卵巢癌的抑制作用。

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.