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Proceedings Paper

Fluorescent imaging technologies for in situ measurement of drug target engagement and cell signaling pathways
Author(s): Nathan P. McMahon; Allison Solanki; Jocelyn Jones; Sunjong Kwon; Young-Hwan Chang; Koei Chin; Michel A. Nederlof; Joe W. Gray; Summer L. Gibbs
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Paper Abstract

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.

Paper Details

Date Published: 19 February 2020
PDF: 9 pages
Proc. SPIE 11219, Visualizing and Quantifying Drug Distribution in Tissue IV, 112190O (19 February 2020); doi: 10.1117/12.2546320
Show Author Affiliations
Nathan P. McMahon, Oregon Health & Science Univ. (United States)
Allison Solanki, Oregon Health & Science Univ. (United States)
Jocelyn Jones, Oregon Health & Science Univ. (United States)
Sunjong Kwon, Oregon Health & Science Univ. (United States)
Young-Hwan Chang, Oregon Health & Science Univ. (United States)
Koei Chin, Oregon Health & Science Univ. (United States)
Michel A. Nederlof, Quantitative Imaging Systems (United States)
Joe W. Gray, Oregon Health & Science Univ. (United States)
Summer L. Gibbs, Oregon Health & Science Univ. (United States)

Published in SPIE Proceedings Vol. 11219:
Visualizing and Quantifying Drug Distribution in Tissue IV
Kin Foong Chan; Conor L. Evans, Editor(s)

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