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Annotating MYC status with 89Zr-transferrin imaging

Nature Medicine volume 18, pages 1586–1591 (2012)Cite this article

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Abstract

A noninvasive technology that quantitatively measures the activity of oncogenic signaling pathways could have a broad impact on cancer diagnosis and treatment with targeted therapies. Here we describe the development of 89Zr-desferrioxamine–labeled transferrin (89Zr-transferrin), a new positron emission tomography (PET) radiotracer that binds the transferrin receptor 1 (TFRC, CD71) with high avidity. The use of 89Zr-transferrin produces high-contrast PET images that quantitatively reflect treatment-induced changes in MYC-regulated TFRC expression in a MYC-driven prostate cancer xenograft model. Moreover, 89Zr-transferrin imaging can detect the in situ development of prostate cancer in a transgenic MYC prostate cancer model, as well as in prostatic intraepithelial neoplasia (PIN) before histological or anatomic evidence of invasive cancer. These preclinical data establish 89Zr-transferrin as a sensitive tool for noninvasive measurement of oncogene-driven TFRC expression in prostate and potentially other cancers, with prospective near-term clinical application.

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Figure 1: PET imaging of inflammation with 89Zr-transferrin.
Figure 2: In vitro and in vivo studies on mouse 89Zr-transferrin in MycCaP prostate cancer models.
Figure 3: Co-registered PET/CT imaging and ex vivo prostate tissue studies of mouse 89Zr-transferrin in Hi-Myc (12- and 4-month-old) and WT (4-month-old) mice.

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Acknowledgements

We thank N. Pillarsetty, B. Carver, D. Ulmert and P. Zanzonico for informative discussions, V. Longo for assistance with the in vivo studies, and M. Balbas for help with in vitro experiments. We thank C. Le and D. Winkleman for recording the MRI data and B. Beattie for assistance with co-registering PET/CT data. We thank M. McDevitt for assistance with HPLC stability studies. We also thank the staff of the Radiochemistry and Cyclotron Core at MSKCC. Funded in part by the Geoffrey Beene Cancer Research Center of MSKCC (J.S.L.), the Office of Science (BER)–US Department of Energy (Award DE-SC0002456, J.S.L.) and the R25T Molecular Imaging for Training in Oncology Program (2R25-CA096945; principal investigator H. Hricak; fellows: M.J.E. and S.L.R.) from the US National Cancer Institute. Technical services provided by the MSKCC Small-Animal Imaging Core Facility were supported in part by the US National Institutes of Health (NIH) grant R24-CA83084; NIH Center grant P30-CA08748; and NIH Prostate SPORE, P50-CA92629.

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Author notes

  1. Jason P Holland

    Present address: Present address: Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.,

  2. Jason P Holland and Michael J Evans: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Radiology, Radiochemistry Service, Memorial Sloan-Kettering Cancer Center (MSKCC), New York, USA

    Jason P Holland, Samuel L Rice & Jason S Lewis

  2. Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, USA

    Michael J Evans, John Wongvipat & Charles L Sawyers

  3. Howard Hughes Medical Institute, Chevy Chase, Maryland, USA

    Charles L Sawyers

  4. Program in Molecular Pharmacology and Chemistry, Memorial Sloan-Kettering Cancer Center, New York, USA

    Jason S Lewis

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Contributions

J.P.H conducted all chemistry and radiochemistry. M.J.E. conducted all cellular assays. J.P.H., M.J.E., S.L.R. and J.W. conducted in vivo and ex vivo experiments. J.P.H., M.J.E. C.L.S and J.S.L. designed the experiments, analyzed data and wrote the paper.

Corresponding authors

Correspondence to Charles L Sawyers or Jason S Lewis.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Methods, Supplementary Figures 1–22 and Supplementary Tables 1–8 (PDF 8258 kb)

Supplementary Video 1

Maximum intensity projection (MIP) video of the 89Zr-mTf PET image of the Hi-Myc (12 month) mouse shown in Figure 3. The video shows the three-dimensional distribution of 89Zr-mTf at 16 h after administration. The prostate and bladder are visible as spatially resolved masses showing high contrast in the lower abdomen. (WMV 1009 kb)

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Holland, J., Evans, M., Rice, S. et al. Annotating MYC status with 89Zr-transferrin imaging. Nat Med 18, 1586–1591 (2012). https://doi.org/10.1038/nm.2935

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