Abstract

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 18F-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.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
5P50CA086355-15
Application #
8693587
Study Section
Special Emphasis Panel (ZCA1-SRLB-9)
Project Start
Project End
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
15
Fiscal Year
2014
Total Cost
$108,868
Indirect Cost

  Institution

Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199

  Publications

Iaconelli, Jonathan; Lalonde, Jasmin; Watmuff, Bradley et al. (2017) Lysine Deacetylation by HDAC6 Regulates the Kinase Activity of AKT in Human Neural Progenitor Cells. ACS Chem Biol 12:2139-2148
Arlauckas, Sean P; Garris, Christopher S; Kohler, Rainer H et al. (2017) In vivo imaging reveals a tumor-associated macrophage-mediated resistance pathway in anti-PD-1 therapy. Sci Transl Med 9:
Miller, Miles A; Weissleder, Ralph (2017) Imaging the pharmacology of nanomaterials by intravital microscopy: Toward understanding their biological behavior. Adv Drug Deliv Rev 113:61-86
Engblom, Camilla; Pfirschke, Christina; Zilionis, Rapolas et al. (2017) Osteoblasts remotely supply lung tumors with cancer-promoting SiglecFhigh neutrophils. Science 358:
Miller, Miles A; Askevold, Bjorn; Mikula, Hannes et al. (2017) Nano-palladium is a cellular catalyst for in vivo chemistry. Nat Commun 8:15906
Dubach, J Matthew; Kim, Eunha; Yang, Katherine et al. (2017) Quantitating drug-target engagement in single cells in vitro and in vivo. Nat Chem Biol 13:168-173
Vinegoni, Claudio; Fumene Feruglio, Paolo; Brand, Christian et al. (2017) Measurement of drug-target engagement in live cells by two-photon fluorescence anisotropy imaging. Nat Protoc 12:1472-1497
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
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
Pfirschke, Christina; Engblom, Camilla; Rickelt, Steffen et al. (2016) Immunogenic Chemotherapy Sensitizes Tumors to Checkpoint Blockade Therapy. Immunity 44:343-54

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