There is a need to develop more sensitive, specific and robust strategies capable of imaging and quantitating therapeutic targets In cancers in vivo. To date, many biological targets and processes remain largely unobserved due to a) lack of affinity ligands, b) mismatches between target abundance and the amount of imaging agent required for target visualization, c) delivery barriers, d) unfavorable pharmacokinetics, e) high background signals, f) the unavailability of appropriate affinity ligands, and/or g) the sheer numbers of targets. The goal of this project is to use a recently developed bioorthogonal platform technology (known as BIND) for the rapid development of intracellular imaging agents such as polo-lil The specific aims are: 1) to develop a library of PLK-1 and PARP1-targeted BIND agents and characterize them biochemically, using live cell imaging and intravital microscopy;2) to perform target-identification and network analysis using in vivo proteomics (SILAC);and 3) to explore the translational potential using ^^F-labeled agents in gemcitabine and PLKHnhibitor/PARPinhibitor treated mice.

Public Health Relevance

The proposed work will likely lead to more sensitive, rapid and robust generic methods for imaging and quantifying therapeutic targets in cancer. Such technologies will enable physicians to stratify patients into appropriate treatment groups and to detect emerging drug resistance.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
5P50CA086355-14
Application #
8566732
Study Section
Special Emphasis Panel (ZCA1-SRLB-9)
Project Start
Project End
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
14
Fiscal Year
2013
Total Cost
$113,851
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
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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