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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Specialized Center (P50)
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Special Emphasis Panel (ZCA1-SRLB-9 (M1))
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Massachusetts General Hospital
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Pfirschke, Christina; Engblom, Camilla; Rickelt, Steffen et al. (2016) Immunogenic Chemotherapy Sensitizes Tumors to Checkpoint Blockade Therapy. Immunity 44:343-54
Ghosh, Balaram; Zhao, Wen-Ning; Reis, Surya A et al. (2016) Dissecting structure-activity-relationships of crebinostat: Brain penetrant HDAC inhibitors for neuroepigenetic regulation. Bioorg Med Chem Lett 26:1265-71
Roy, Jeremy; Kim, Bongki; Hill, Eric et al. (2016) Tyrosine kinase-mediated axial motility of basal cells revealed by intravital imaging. Nat Commun 7:10666
Wu, Juwell W; Turcotte, Raphaël; Alt, Clemens et al. (2016) Defining Clonal Color in Fluorescent Multi-Clonal Tracking. Sci Rep 6:24303
Reis, Surya A; Ghosh, Balaram; Hendricks, J Adam et al. (2016) Light-controlled modulation of gene expression by chemical optoepigenetic probes. Nat Chem Biol 12:317-23
Pucci, Ferdinando; Rickelt, Steffen; Newton, Andita P et al. (2016) PF4 Promotes Platelet Production and Lung Cancer Growth. Cell Rep 17:1764-1772
Miller, Miles A; Weissleder, Ralph (2016) Imaging the pharmacology of nanomaterials by intravital microscopy: Toward understanding their biological behavior. Adv Drug Deliv Rev :
Vinegoni, Claudio; Dubach, John M; Feruglio, Paolo Fumene et al. (2016) Two-photon Fluorescence Anisotropy Microscopy for Imaging and Direct Measurement of Intracellular Drug Target Engagement. IEEE J Sel Top Quantum Electron 22:
Meimetis, Labros G; Boros, Eszter; Carlson, Jonathan C et al. (2016) Bioorthogonal Fluorophore Linked DFO-Technology Enabling Facile Chelator Quantification and Multimodal Imaging of Antibodies. Bioconjug Chem 27:257-63
Pucci, Ferdinando; Garris, Christopher; Lai, Charles P et al. (2016) SCS macrophages suppress melanoma by restricting tumor-derived vesicle-B cell interactions. Science 352:242-6

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