Noninvasive measurement of mTORC1 signaling with (89)Zr-transferrin Journal Article

Authors: Truillet, C.; Cunningham, J. T.; Parker, M. F. L.; Huynh, L. T.; Conn, C. S.; Ruggero, D.; Lewis, J. S.; Evans, M. J.
Article Title: Noninvasive measurement of mTORC1 signaling with (89)Zr-transferrin
Abstract: Purpose: mTOR regulates many normal physiological processes and when hyperactive can drive numerous cancers and human diseases. However, it is very challenging to detect and quantify mTOR signaling noninvasively in clinically relevant animal models of disease or man. We hypothesized that a nuclear imaging tool measuring intracellular mTOR activity could address this unmet need. Experimental Design: Although the biochemical activity of mTOR is not directly amenable to nuclear imaging probe development, we show that the transferrin receptor can be used to indirectly measure intracellular changes in mTOR activity. Results: After verifying that the uptake of radiolabeled transferrin (the soluble ligand of the transferrin receptor) is stimulated by active mTORC1 in vitro, we showed that 89Zr-labeled transferrin (Tf) can measure mTORC1 signaling dynamics in normal and cancerous mouse tissues with PET. Finally, we show that 89Zr-Tf can detect the upregulation of mTORC1 by tumor cells to escape the antitumor effects of a standard-of-care antiandrogen, which is to our knowledge the first example of applying PET to interrogate the biology of treatment resistant cancer. Conclusions: In summary, we have developed the first quantitative assay to provide a comprehensive measurement of mTOR signaling dynamics in vivo, in specific normal tissues, and during tumor development in genetically engineered animal models using a nuclear imaging tool that is readily translatable to man. ©2016 AACR.
Journal Title: Clinical Cancer Research
Volume: 23
Issue: 12
ISSN: 1078-0432
Publisher: American Association for Cancer Research  
Date Published: 2017-06-01
Start Page: 3045
End Page: 3052
Language: English
DOI: 10.1158/1078-0432.ccr-16-2448
PROVIDER: scopus
PMCID: PMC5474159
PUBMED: 28007777
Notes: Article -- Export Date: 2 August 2017 -- Source: Scopus
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  1. Jason S Lewis
    242 Lewis