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Fluorescent Imaging Technologies For In Situ Measurement Of Drug Target Engagement And Cell Signaling Pathways

Nathan P McMahon, Allison Solanki, Jocelyn Jones, S. Kwon, Young‐Hwan Chang, K. Chin, Michel A Nederlof, J. Gray, S. L. Gibbs
Published 2020 · Chemistry, Engineering

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Successful cancer treatment continues to elude modern medicine and its arsenal of therapeutic strategies. Therapy resistance is driven by significant tumor heterogeneity, complex interactions between malignant, microenvironmental and immune cells and cross talk between signaling pathways. Advances in molecular characterization technologies such as next generation sequencing have helped unravel this network of interactions and identify druggable therapeutic targets. Tyrosine kinase inhibitors (TKI) are a class of drugs seeking to inhibit signaling pathways critical to sustaining proliferative signaling, resisting cell death, and the other hallmarks of cancer. While tumors may initially respond to TKI therapy, disease progression is near universal due to mechanisms of acquired resistance largely involving cellular signaling pathway reprogramming. With the ultimate goal of improved TKI therapeutic efficacy our group has developed intracellular paired agent imaging (iPAI) to quantify drug target interactions and oligonucleotide conjugated antibody (Ab-oligo) cyclic immunofluorescence (cycIF) imaging to characterize perturbed signaling pathways in response to therapy. iPAI uses spectrally distinct, fluorescently labeled targeted and untargeted drug derivatives, correcting for non-specific drug distribution and facilitating quantitative assessment of the drug binding before and after therapy. Ab-oligo cycIF exploits in situ hybridization of complementary oligonucleotides for biomarker labeling while oligonucleotide modifications facilitate signal removal for sequential rounds of fluorescent tagging and imaging. Aboligo CycIF is capable of generating extreme multi-parametric images for quantifying total and phosphorylated protein expression to quantify protein activation, expression, and spatial distribution. Together iPAI and Ab-oligo cycIF can be applied to interrogate drug uptake and target binding as well as changes to heterogenous cell populations within tumors that drive variable therapeutic responses in patients.
This paper references
10.1593/NEO.08648
In vivo investigation of breast cancer progression by use of an internal control.
J. Baeten (2009)
10.1073/pnas.1300136110
Highly multiplexed single-cell analysis of formalin-fixed, paraffin-embedded cancer tissue
M. Gerdes (2013)
10.1364/OL.38.005184
Topical dual-stain difference imaging for rapid intra-operative tumor identification in fresh specimens.
S. Davis (2013)
10.1007/s11307-013-0692-1
Tumor Endothelial Marker Imaging in Melanomas Using Dual-Tracer Fluorescence Molecular Imaging
K. Tichauer (2013)
10.1038/nrclinonc.2012.159
What are we learning from the cancer genome?
E. Collisson (2012)
10.1038/s41467-017-02096-w
Target engagement imaging of PARP inhibitors in small-cell lung cancer
Brandon Carney (2017)
10.1021/acschembio.6b00346
A Modular Probe Strategy for Drug Localization, Target Identification and Target Occupancy Measurement on Single Cell Level.
A. Rutkowska (2016)
10.1117/1.JBO.18.1.016003
Dual-tracer background subtraction approach for fluorescent molecular tomography
K. Tichauer (2013)
10.1016/j.ymeth.2014.08.016
Multiplexed immunohistochemistry, imaging, and quantitation: a review, with an assessment of Tyramide signal amplification, multispectral imaging and multiplex analysis.
E. Stack (2014)
10.1038/nchembio.1197
Target validation using chemical probes.
M. Bunnage (2013)
10.1038/nrd4090
Trial Watch: Phase II and Phase III attrition rates 2011–2012
John Arrowsmith (2013)
10.1038/nprot.2013.112
Multicolor multicycle molecular profiling with quantum dots for single-cell analysis
P. Zrazhevskiy (2013)
10.1038/nm.3488
Multiplexed ion beam imaging of human breast tumors
M. Angelo (2014)
10.1002/9780470559277.ch110180
Target Identification Using Drug Affinity Responsive Target Stability (DARTS)
Brett Lomenick (2011)
10.1369/jhc.2009.953612
Simple: A Sequential Immunoperoxidase Labeling and Erasing Method
George Glass (2009)
10.1016/j.ccell.2018.03.025
A Convergence-Based Framework for Cancer Drug Resistance.
D. Konieczkowski (2018)
10.1038/nchembio.1211
Determining target engagement in living systems.
G. Simon (2013)
10.1038/NCHEMBIO859
A clickable inhibitor reveals context-dependent autoactivation of p90 RSK.
M. Cohen (2007)
10.1016/j.cell.2013.03.002
Lessons from the Cancer Genome
L. Garraway (2013)
10.1016/S0065-230X(08)60983-5
MECHANISMS OF RESISTANCE TO ANTICANCER AGENTS.
R. W. Brockman (1963)
10.1038/nmeth.2869
Highly multiplexed imaging of tumor tissues with subcellular resolution by mass cytometry
C. Giesen (2014)
10.1038/ncomms9390
Highly multiplexed imaging of single cells using a high-throughput cyclic immunofluorescence method
Jia-Ren Lin (2015)
10.1002/path.5223
New tools for pathology: a user's review of a highly multiplexed method for in situ analysis of protein and RNA expression in tissue
Jérémie Decalf (2019)
10.1038/nbt.2083
Reinventing clinical trials
M. Allison (2012)
10.1038/ncomms9692
Tumour-associated macrophages act as a slow-release reservoir of nano-therapeutic Pt(IV) pro-drug
Miles A. Miller (2015)
10.12968/chca.2008.5.10.31383
The next generation.
G. Collins (2006)
10.1111/j.1365-2125.2011.04085.x
Positron emission tomography molecular imaging for drug development.
P. Matthews (2012)
10.1016/j.cell.2011.02.013
Hallmarks of Cancer: The Next Generation
D. Hanahan (2011)
10.1038/nchembio.2248
Quantitating drug-target engagement in single cells in vitro and in vivo.
J. Dubach (2017)
The use of paired labeling in the determination of tumor-localizing antibodies.
D. Pressman (1957)
10.1126/scitranslmed.3007361
Cancer Cell Profiling by Barcoding Allows Multiplexed Protein Analysis in Fine-Needle Aspirates
Adeeti V. Ullal (2014)
10.1038/labinvest.2015.2
Immunohistochemistry and mass spectrometry for highly multiplexed cellular molecular imaging
R. Levenson (2015)
10.1126/sciimmunol.aaf6925
In-depth tissue profiling using multiplexed immunohistochemical consecutive staining on single slide
R. Remark (2016)
10.1126/sciadv.aax5851
MIBI-TOF: A multiplexed imaging platform relates cellular phenotypes and tissue structure
Leeat Keren (2019)
A Sequential Immunoperoxidase Labeling and Erasing Method
G. Glass (2010)
10.7150/thno.21527
Optimizing fresh specimen staining for rapid identification of tumor biomarkers during surgery
C. Barth (2017)
10.1038/ncomms10690
Diverse drug-resistance mechanisms can emerge from drug-tolerant cancer persister cells
M. Ramirez (2016)
10.1038/ncomms2635
Quantum dot imaging platform for single-cell molecular profiling
P. Zrazhevskiy (2013)
10.1200/JCO.2011.37.6418
Development of therapeutic combinations targeting major cancer signaling pathways.
T. Yap (2013)
10.1021/ac500038j
Label-free in situ monitoring of histone deacetylase drug target engagement by matrix-assisted laser desorption ionization-mass spectrometry biotyping and imaging.
B. Munteanu (2014)
10.1053/j.seminoncol.2016.06.005
Using reverse-phase protein arrays as pharmacodynamic assays for functional proteomics, biomarker discovery, and drug development in cancer.
Y. Lu (2016)
10.1016/j.bmc.2017.09.034
Synthesis and photophysical properties of a fluorescent cyanoquinoline probe for profiling ERBB2 kinase inhibitor response.
H. Lee (2017)
10.1038/nature08960
Chemical genetics strategy identifies an HCV NS5A inhibitor with a potent clinical effect
M. Gao (2010)



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