Fluorescent imaging technologies for in situ measurement of drug target engagement and cell signaling pathways

Nathan P. McMahon, Allison Solanki, Jocelyn Jones, Sunjong Kwon, Young Hwan Chang, Koei Chin, Michel A. Nederlof, Joe W. Gray, Summer L. Gibbs

Research output: Chapter in Book/Report/Conference proceedingConference contribution

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.

Original languageEnglish (US)
Title of host publicationVisualizing and Quantifying Drug Distribution in Tissue IV
EditorsKin Foong Chan, Conor L. Evans
PublisherSPIE
ISBN (Electronic)9781510632011
DOIs
StatePublished - Jan 1 2020
EventVisualizing and Quantifying Drug Distribution in Tissue IV 2020 - San Francisco, United States
Duration: Feb 1 2020 → …

Publication series

NameProgress in Biomedical Optics and Imaging - Proceedings of SPIE
Volume11219
ISSN (Print)1605-7422

Conference

ConferenceVisualizing and Quantifying Drug Distribution in Tissue IV 2020
CountryUnited States
CitySan Francisco
Period2/1/20 → …

Keywords

  • Cancer heterogeneity
  • Cell signaling
  • Cyclic immunostaining
  • Fluorescence imaging
  • Paired agent imaging
  • Tyrosine kinase inhibitors

ASJC Scopus subject areas

  • Electronic, Optical and Magnetic Materials
  • Biomaterials
  • Atomic and Molecular Physics, and Optics
  • Radiology Nuclear Medicine and imaging

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  • Cite this

    McMahon, N. P., Solanki, A., Jones, J., Kwon, S., Chang, Y. H., Chin, K., Nederlof, M. A., Gray, J. W., & Gibbs, S. L. (2020). Fluorescent imaging technologies for in situ measurement of drug target engagement and cell signaling pathways. In K. F. Chan, & C. L. Evans (Eds.), Visualizing and Quantifying Drug Distribution in Tissue IV [112190O] (Progress in Biomedical Optics and Imaging - Proceedings of SPIE; Vol. 11219). SPIE. https://doi.org/10.1117/12.2546320