18FDG-PET Predicts Pharmacodynamic Response to OSI-906, a Dual IGF-1R/IR Inhibitor, in Preclinical Mouse Models of Lung Cancer

  • Eliot T. McKinley
    Authors' Affiliations: 1Department of Biomedical Engineering, 2The Vanderbilt University Institute of Imaging Science (VUIIS), 3Department of Radiology and Radiological Sciences, 4Program in Chemical and Physical Biology, 5Department of Neurosurgery, Vanderbilt University Medical Center, Nashville, Tennessee; and 6OSI Pharmaceuticals, In Vivo Pharmacology, Boulder, Colorado
  • Joseph E. Bugaj
    Authors' Affiliations: 1Department of Biomedical Engineering, 2The Vanderbilt University Institute of Imaging Science (VUIIS), 3Department of Radiology and Radiological Sciences, 4Program in Chemical and Physical Biology, 5Department of Neurosurgery, Vanderbilt University Medical Center, Nashville, Tennessee; and 6OSI Pharmaceuticals, In Vivo Pharmacology, Boulder, Colorado
  • Ping Zhao
    Authors' Affiliations: 1Department of Biomedical Engineering, 2The Vanderbilt University Institute of Imaging Science (VUIIS), 3Department of Radiology and Radiological Sciences, 4Program in Chemical and Physical Biology, 5Department of Neurosurgery, Vanderbilt University Medical Center, Nashville, Tennessee; and 6OSI Pharmaceuticals, In Vivo Pharmacology, Boulder, Colorado
  • Saffet Guleryuz
    Authors' Affiliations: 1Department of Biomedical Engineering, 2The Vanderbilt University Institute of Imaging Science (VUIIS), 3Department of Radiology and Radiological Sciences, 4Program in Chemical and Physical Biology, 5Department of Neurosurgery, Vanderbilt University Medical Center, Nashville, Tennessee; and 6OSI Pharmaceuticals, In Vivo Pharmacology, Boulder, Colorado
  • Christine Mantis
    Authors' Affiliations: 1Department of Biomedical Engineering, 2The Vanderbilt University Institute of Imaging Science (VUIIS), 3Department of Radiology and Radiological Sciences, 4Program in Chemical and Physical Biology, 5Department of Neurosurgery, Vanderbilt University Medical Center, Nashville, Tennessee; and 6OSI Pharmaceuticals, In Vivo Pharmacology, Boulder, Colorado
  • Prafulla C. Gokhale
    Authors' Affiliations: 1Department of Biomedical Engineering, 2The Vanderbilt University Institute of Imaging Science (VUIIS), 3Department of Radiology and Radiological Sciences, 4Program in Chemical and Physical Biology, 5Department of Neurosurgery, Vanderbilt University Medical Center, Nashville, Tennessee; and 6OSI Pharmaceuticals, In Vivo Pharmacology, Boulder, Colorado
  • Robert Wild
    Authors' Affiliations: 1Department of Biomedical Engineering, 2The Vanderbilt University Institute of Imaging Science (VUIIS), 3Department of Radiology and Radiological Sciences, 4Program in Chemical and Physical Biology, 5Department of Neurosurgery, Vanderbilt University Medical Center, Nashville, Tennessee; and 6OSI Pharmaceuticals, In Vivo Pharmacology, Boulder, Colorado
  • H. Charles Manning
    Authors' Affiliations: 1Department of Biomedical Engineering, 2The Vanderbilt University Institute of Imaging Science (VUIIS), 3Department of Radiology and Radiological Sciences, 4Program in Chemical and Physical Biology, 5Department of Neurosurgery, Vanderbilt University Medical Center, Nashville, Tennessee; and 6OSI Pharmaceuticals, In Vivo Pharmacology, Boulder, Colorado

抄録

<jats:title>Abstract</jats:title> <jats:p>Purpose: To evaluate 2-deoxy-2-[18F]fluoro-d-glucose positron emission tomography imaging (18FDG-PET) as a predictive, noninvasive, pharmacodynamic (PD) biomarker of response following administration of a small-molecule insulin-like growth factor-1 receptor and insulin receptor (IGF-1R/IR) inhibitor, OSI-906.</jats:p> <jats:p>Experimental Design: In vitro uptake studies of 3H-2-deoxy glucose following OSI-906 exposure were conducted evaluating correlation of dose with inhibition of IGF-1R/IR as well as markers of downstream pathways and glucose metabolism. Similarly, in vivo PD effects were evaluated in human tumor cell line xenografts propagated in athymic nude mice by 18FDG-PET at 2, 4, and 24 hours following a single treatment of OSI-906 for the correlation of inhibition of receptor targets and downstream markers.</jats:p> <jats:p>Results: Uptake of 3H-2-deoxy glucose and 18FDG was significantly diminished following OSI-906 exposure in sensitive tumor cells and subcutaneous xenografts (NCI-H292) but not in an insensitive model lacking IGF-1R expression (NCI-H441). Diminished PD 18FDG-PET, collected immediately following the initial treatment agreed with inhibition of pIGF-1R/pIR, reduced PI3K (phosphoinositide 3-kinase) and MAPK (mitogen activated protein kinase) pathway activity, and predicted tumor growth arrest as measured by high-resolution ultrasound imaging.</jats:p> <jats:p>Conclusion: 18FDG-PET seems to serve as a rapid, noninvasive PD marker of IGF-1R/IR inhibition following a single dose of OSI-906 and should be explored clinically as a predictive clinical biomarker in patients undergoing IGF-1R/IR–directed cancer therapy. Clin Cancer Res; 17(10); 3332–40. ©2011 AACR.</jats:p>

収録刊行物

  • Clinical Cancer Research

    Clinical Cancer Research 17 (10), 3332-3340, 2011-05-15

    American Association for Cancer Research (AACR)

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