Abstract
Molecular imaging biomarkers of proliferation hold great promise for quantifying response to personalized medicine. One such approach utilizes the positron emission tomography (PET) tracer 3′-deoxy-3′[18F]-fluorothymidine ([18F]FLT), an investigational agent whose uptake reflects thymidine salvage-dependent DNA synthesis. The goal of this study was to evaluate [18F]FLT-PET in the setting of Ménétrier’s disease (MD), a rare, premalignant hyperproliferative disorder of the stomach treatable with cetuximab therapy. Over 15 months, a patient with confirmed MD underwent cetuximab therapy and was followed with sequential [18F]FLT-PET. For comparison to MD, an [18F]FLT-PET study was conducted in another patient to quantify uptake in a normal stomach. Prior to cetuximab therapy, stomach tissue in MD was easily visualized with [18F]FLT-PET, with pre-treatment uptake levels exceeding normal stomach uptake by approximately fourfold. Diminished [18F]FLT-PET in MD was observed following the initial and subsequent doses of cetuximab and correlated with clinical resolution of the disease. To our knowledge, this study reports the first clinical use of [18F]FLT-PET to assess proliferation in a premalignant disorder. We illustrate that the extent of MD involvement throughout the stomach could be easily visualized using [18F]FLT-PET, and that response to cetuximab could be followed quantitatively and non-invasively in sequential [18F]FLT-PET studies. Thus, [18F]FLT-PET appears to have potential to monitor response to treatment in this and potentially other hyperproliferative disorders.
References
Czernin J, Weber WA, Herschman HR. Molecular imaging in the development of cancer therapeutics. Annu Rev Med. 2006;57:99–118.
DeNardo SJ. Combined molecular targeting for cancer therapy: a new paradigm in need of molecular imaging. J Nucl Med. 2006;47:4–5.
Rudin M, Weissleder R. Molecular imaging in drug discovery and development. Nat Rev Drug Discov. 2003;2:123–31.
Shields AF, Grierson JR, Dohmen BM, Machulla HJ, Stayanoff JC, Lawhorn-Crews JM, et al. Imaging proliferation in vivo with [F-18]FLT and positron emission tomography. Nat Med. 1998;4:1334–6.
Mankoff DA, Eary JF, Link JM, Muzi M, Rajendran JG, Spence AM, et al. Tumor-specific positron emission tomography imaging in patients: [18F] fluorodeoxyglucose and beyond. Clin Cancer Res. 2007;13:3460–9.
Schwartz JL, Tamura Y, Jordan R, Grierson JR, Krohn KA. Monitoring tumor cell proliferation by targeting DNA synthetic processes with thymidine and thymidine analogs. J Nucl Med. 2003;44:2027–32.
Been LB, Suurmeijer AJ, Cobben DC, Jager PL, Hoekstra HJ, Elsinga PH. [18F]FLT-PET in oncology: current status and opportunities. Eur J Nucl Med Mol Imaging. 2004;31:1659–72.
Chen W, Cloughesy T, Kamdar N, Satyamurthy N, Bergsneider M, Liau L, et al. Imaging proliferation in brain tumors with 18F-FLT PET: comparison with 18F-FDG. J Nucl Med. 2005;46:945–52.
Wagner M, Seitz U, Buck A, Neumaier B, Schultheiss S, Bangerter M, et al. 3′-[18F]fluoro-3′-deoxythymidine ([18F]-FLT) as positron emission tomography tracer for imaging proliferation in a murine B-Cell lymphoma model and in the human disease. Cancer Res. 2003;63:2681–7.
Coffey RJ, Washington MK, Corless CL, Heinrich MC. Menetrier disease and gastrointestinal stromal tumors: hyperproliferative disorders of the stomach. J Clin Invest. 2007;117:70–80.
Bluth RF, Carpenter HA, Pittelkow MR, Page DL, Coffey RJ. Immunolocalization of transforming growth factor-alpha in normal and diseased human gastric mucosa. Hum Pathol. 1995;26:1333–40.
Dempsey PJ, Goldenring JR, Soroka CJ, Modlin IM, McClure RW, Lind CD, et al. Possible role of transforming growth factor alpha in the pathogenesis of Menetrier’s disease: supportive evidence form humans and transgenic mice. Gastroenterology. 1992;103:1950–63.
van den Berg M, Stokkers P, Rings E, Buller H. Transforming growth factor alpha in Menetrier’s disease. J Pediatr Gastroenterol Nutr. 1993;17:230–2.
Burdick JS, Chung E, Tanner G, Sun M, Paciga JE, Cheng JQ, et al. Treatment of Menetrier’s disease with a monoclonal antibody against the epidermal growth factor receptor. N Engl J Med. 2000;343:1697–701.
Fiske WH, Tanksley J, Nam KT, Goldenring JR, Slebos RJ, Liebler DC, et al. Efficacy of cetuximab in the treatment of Menetrier’s disease. Sci Transl Med. 2009;1:8ra18.
Settle SH, Washington K, Lind C, Itzkowitz S, Fiske WH, Burdick JS, et al. Chronic treatment of Menetrier’s disease with Erbitux: clinical efficacy and insight into pathophysiology. Clin Gastroenterol Hepatol. 2005;3:654–9.
Machulla HJ, Blocher A, Wei R, Whrllichmann W, Juntzsch M, Solbach C, Dohmen BM, Reischl G. Procedure for routine synthesis of [18F]FLT in high activities. J Nucl Med. 2001;42:257.
Manning HC, Merchant NB, Foutch AC, Virostko JM, Wyatt SK, Shah C, et al. Molecular imaging of therapeutic response to epidermal growth factor receptor blockade in colorectal cancer. Clin Cancer Res. 2008;14:7413–22.
Arner ES, Eriksson S. Mammalian deoxyribonucleoside kinases. Pharmacol Ther. 1995;67:155–86.
Acknowledgments
The authors wish to acknowledge Mr. M. Sib Ansari, Dr. Ronald M. Baldwin and Dr. Michael L. Nickels of the VUIIS Research Radiochemistry Core Facility for production of [18F]FLT, Mr. Frank Revetta of the Vanderbilt University Department of Pathology for histological expertise and funding from P50-951903, R01-CA140628, K25-CA127349, RC1-CA145138, R01-CA46413, and The Kleberg Foundation
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
McKinley, E.T., Smith, R.A., Tanksley, J.P. et al. [18F]FLT-PET to predict pharmacodynamic and clinical response to cetuximab therapy in Ménétrier’s disease. Ann Nucl Med 26, 757–763 (2012). https://doi.org/10.1007/s12149-012-0636-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12149-012-0636-x