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Proceedings Paper

Intracellular paired agent imaging enables improved evaluation of tyrosine kinase inhibitor target engagement
Author(s): Allison Solanki; Lei Wang; Jesse Korber; Nathan McMahon; Kenneth Tichauer; Kimberley S. Samkoe; Summer L. Gibbs
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Paper Abstract

Targeting the aberrant epidermal growth factor receptor (EGFR) signaling pathway is an attractive choice for many cancers (e.g., non-small cell lung carcinoma (NSCLC) and head and neck squamous cell carcinoma (HNSCC)). Despite the development of promising therapeutics, incomplete target engagement and acquired resistance (e.g., mutagenesis and intracellular signaling pathway rewiring) ensure that curative options still elude patients. To address limitations posed by standard drug evaluation assays (e.g., western blot, bulk plasma monitoring, immunohistochemistry), we have developed a novel dynamic, fluorescence-based platform termed intracellular paired agent imaging (iPAI). iPAI quantifies intracellular protein target engagement using two matched small-molecule, cell membrane-permeable agents: one targeted to the protein of interest and one untargeted, which accounts for non-specific therapeutic uptake. Currently, our iPAI panel includes successfully characterized tyrosine kinase inhibitors targeting the kinase binding domain of numerous proteins in the EGFR pathway, including erlotinib (EGFR). Here, we present a pharmacokinetic uptake study using our novel iPAI erlotinib reagents: a targeted erlotinib probed conjugated to silicon tetramethylrhodamine (Erl- SiTMR-T) and an untargeted reagent conjugated to tetramethylrhodaime (Erl-TMR-UT). An initial uptake study in a cell derived xenograft (CDX) model of NSCLC was performed by administering the Erl iPAI reagents systemically via tail vein injection, where drug uptake was quantified in the tumor over time. Excitingly, evidence of heterogeneous uptake was observed in the iPAI injected cohort, displaying distinct drug-uptake within a single tumor. Characterization of additional iPAI agents targeting downstream effectors (e.g., AKT, PI3K, MEK and ERK) is ongoing and will allow us to visualize complex drug-target interactions and quantify their downstream signaling partners during treatment regimens for NSCLC and other cancers. Together, we anticipate these iPAI probes will improve understanding of current limitations in personalized cancer therapy.

Paper Details

Date Published: 19 February 2020
PDF: 6 pages
Proc. SPIE 11219, Visualizing and Quantifying Drug Distribution in Tissue IV, 112190F (19 February 2020); doi: 10.1117/12.2546234
Show Author Affiliations
Allison Solanki, Oregon Health & Science Univ. (United States)
Lei Wang, Oregon Health & Science Univ. (United States)
Jesse Korber, Oregon Health & Science Univ. (United States)
Nathan McMahon, Oregon Health & Science Univ. (United States)
Kenneth Tichauer, Illinois Institute of Technology (United States)
Kimberley S. Samkoe, Dartmouth-Hitchcock Medical Ctr. (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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