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.
Histone decatelylases (HDACs) have been linked to the pathogenesis of cancer, and small-molecule HDAC inhibitors (HDACi) have been shown to have significant biological effects in both preclinical models as well as in early clinical trials of cancer Thus, having the ability to image HDAC function in vivo in both normal and diseased tissue will likely have wide-ranging implications for both basic and applied biomedical research.
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