title: Noninvasive Measurement of mTORC1 Signaling with89Zr-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 mTORC1in vitro, we showed that89Zr-labeled transferrin (Tf) can measure mTORC1 signaling dynamics in normal and cancerous mouse tissues with PET. Finally, we show that89Zr-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 dynamicsin 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.Clin Cancer Res; 23(12); 3045-52. ©2016 AACR.
authors.affiliation: Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, California.
authors.forename: Charles
authors.initials: C
authors.lastname: Truillet
authors.affiliation: Department of Urology, University of California San Francisco, San Francisco, California.
authors.forename: John T
authors.initials: JT
authors.lastname: Cunningham
authors.affiliation: Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, California.
authors.forename: Matthew F L
authors.initials: MFL
authors.lastname: Parker
authors.affiliation: Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, California.
authors.forename: Loc T
authors.initials: LT
authors.lastname: Huynh
authors.affiliation: Department of Urology, University of California San Francisco, San Francisco, California.|Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California.
authors.forename: Crystal S
authors.initials: CS
authors.lastname: Conn
authors.affiliation: Department of Urology, University of California San Francisco, San Francisco, California.|Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California.
authors.forename: Davide
authors.initials: D
authors.lastname: Ruggero
authors.affiliation: Department of Radiology and the Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York. michael.evans@ucsf.edu lewisj2@mskcc.org.|Departments of Radiology and Pharmacology, Weill Cornell Medical College, New York.
authors.forename: Jason S
authors.initials: JS
authors.lastname: Lewis
authors.affiliation: Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, California. michael.evans@ucsf.edu lewisj2@mskcc.org.|Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Evans
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1 / Q000235:genetics / Q000302:isolation & purification*; D051379:Mice; D057054:Molecular Imaging / Q000379:methods*; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals / Q000737:chemistry; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000302:isolation & purification* / Q000378:metabolism; D014168:Transferrin / Q000737:chemistry*; D023041:Xenograft Model Antitumor Assays; D015040:Zirconium / Q000737:chemistry
chemical_list: D019275:Radiopharmaceuticals; D014168:Transferrin; D015040:Zirconium; C546842:MTOR protein, human; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases