Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Technical Report
  • Published:

Detection of colorectal polyps in humans using an intravenously administered fluorescent peptide targeted against c-Met

Nature Medicine volume 21, pages 955–961 (2015)Cite this article

Subjects

Abstract

Colon cancer prevention currently relies on colonoscopy using white light to detect and remove polyps, but small and flat polyps are difficult to detect and frequently missed when using this technique. Fluorescence colonoscopy combined with a fluorescent probe specific for a polyp biomarker may improve polyp detection. Here we describe GE-137, a water-soluble probe consisting of a 26–amino acid cyclic peptide that binds the human tyrosine kinase c-Met conjugated to a fluorescent cyanine dye. Intravenous administration of GE-137 leads to its accumulation specifically in c-Met–expressing tumors in mice, and it is safe and well tolerated in humans. Fluorescence colonoscopy in patients receiving intravenous GE-137 enabled visualization of all neoplastic polyps that were visible with white light (38), as well as an additional nine polyps that were not visible with white light. This first-in-human pilot study shows that molecular imaging using an intravenous fluorescent agent specific for c-Met is feasible and safe, and that it may enable the detection of polyps missed by other techniques.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: GE-137 chemical and optical properties and testing in a rodent model of colon cancer.
Figure 2: Experimental system for combined WL and NIR fluorescence colonoscopy in humans.
Figure 3: Simultaneous WL and FL images of representative lesions of the various morphological and histological subtypes found.
Figure 4: c-Met expression analysis by immunohistochemistry using an antibody specific for the extracellular domain of c-Met.
Figure 5: c-Met expression in normal colon and an adenomatous polyp as detected by immunohistochemistry and GE-137.

Similar content being viewed by others

References

  1. Jemal, A. et al. Global cancer statistics. CA Cancer J. Clin. 61, 69–90 (2011).

    Article  PubMed  Google Scholar 

  2. Atkin, W.S. et al. Once-only flexible sigmoidoscopy screening in prevention of colorectal cancer: a multicentre randomised controlled trial. Lancet 375, 1624–1633 (2010).

    Article  PubMed  Google Scholar 

  3. Baxter, N.N. et al. Association of colonoscopy and death from colorectal cancer. Ann. Intern. Med. 150, 1–8 (2009).

    Article  PubMed  Google Scholar 

  4. Brenner, H. et al. Protection from right- and left-sided colorectal neoplasms after colonoscopy: population-based study. J. Natl. Cancer Inst. 102, 89–95 (2010).

    Article  PubMed  Google Scholar 

  5. Kaminski, M.F. et al. Quality indicators for colonoscopy and the risk of interval cancer. N. Engl. J. Med. 362, 1795–1803 (2010).

    Article  CAS  PubMed  Google Scholar 

  6. Kahi, C.J., Hewett, D.G., Norton, D.L., Eckert, G.J. & Rex, D.K. Prevalence and variable detection of proximal colon serrated polyps during screening colonoscopy. Clin. Gastroenterol. Hepatol. 9, 42–46 (2011).

    Article  PubMed  Google Scholar 

  7. van Rijn, J.C. et al. Polyp miss rate determined by tandem colonoscopy: a systematic review. Am. J. Gastroenterol. 101, 343–350 (2006).

    Article  PubMed  Google Scholar 

  8. Clapper, M.L. et al. Detection of colorectal adenomas using a bioactivatable probe specific for matrix metalloproteinase activity. Neoplasia 13, 685–691 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Marten, K. et al. Detection of dysplastic intestinal adenomas using enzyme-sensing molecular beacons in mice. Gastroenterology 122, 406–414 (2002).

    Article  PubMed  Google Scholar 

  10. Endlicher, E. et al. Hexaminolevulinate-induced fluorescence endoscopy in patients with rectal adenoma and cancer: a pilot study. Gastrointest. Endosc. 60, 449–454 (2004).

    Article  PubMed  Google Scholar 

  11. Hsiung, P.-L. et al. Detection of colonic dysplasia in vivo using a targeted heptapeptide and confocal microendoscopy. Nat. Med. 14, 454–458 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Fearon, E.R. & Vogelstein, B. A genetic model for colorectal tumorigenesis. Cell 61, 759–767 (1990).

    Article  CAS  PubMed  Google Scholar 

  13. Di Renzo, M.F. et al. Overexpression and amplification of the met/HGF receptor gene during the progression of colorectal cancer. Clin. Cancer Res. 1, 147–154 (1995).

    CAS  PubMed  Google Scholar 

  14. Nanjappan, A.K.S. et al. Peptides that specifically bind HGF receptor (cMet) and uses thereof. Patent no. WO 2004/078778 A2. (2004).

  15. Moestue, S. et al. Whole-body section fluorescence imaging—a novel method for tissue distribution studies of fluorescent substances. Contrast Media Mol. Imaging 4, 73–80 (2009).

    Article  CAS  PubMed  Google Scholar 

  16. van den Berg, N.S., Buckle, T., Kuil, J., Wesseling, J. & van Leeuwen, F.W.B. Immunohistochemical detection of the CXCR4 expression in tumor tissue using the fluorescent peptide antagonist Ac-TZ14011-FITC. Transl. Oncol. 4, 234–240 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  17. Kiesslich, R., Goetz, M., Hoffman, A. & Galle, P.R. New imaging techniques and opportunities in endoscopy. Nat. Rev. Gastroenterol. Hepatol. 8, 547–553 (2011).

    Article  PubMed  Google Scholar 

  18. Adler, A. et al. A prospective randomised study on narrow-band imaging versus conventional colonoscopy for adenoma detection: does narrow-band imaging induce a learning effect? Gut 57, 59–64 (2008).

    Article  CAS  PubMed  Google Scholar 

  19. Kuiper, T. et al. Endoscopic trimodal imaging detects colonic neoplasia as well as standard video endoscopy. Gastroenterology 140, 1887–1894 (2011).

    Article  PubMed  Google Scholar 

  20. Mayinger, B., Neumann, F., Kastner, C., Haider, T. & Schwab, D. Hexaminolevulinate-induced fluorescence colonoscopy versus white light endoscopy for diagnosis of neoplastic lesions in the colon. Endoscopy 42, 28–33 (2010).

    Article  CAS  PubMed  Google Scholar 

  21. Keller, R., Winde, G., Terpe, H.J., Foerster, E.C. & Domschke, W. Fluorescence endoscopy using a fluorescein-labeled monoclonal antibody against carcinoembryonic antigen in patients with colorectal carcinoma and adenoma. Endoscopy 34, 801–807 (2002).

    Article  CAS  PubMed  Google Scholar 

  22. Foersch, S. et al. Molecular imaging of VEGF in gastrointestinal cancer in vivo using confocal laser endomicroscopy. Gut 59, 1046–1055 (2010).

    Article  PubMed  Google Scholar 

  23. Goetz, M. & Wang, T.D. Molecular imaging in gastrointestinal endoscopy. Gastroenterology 138, 828–833 (2010).

    Article  PubMed  CAS  Google Scholar 

  24. Wu, A.M. & Olafsen, T. Antibodies for molecular imaging of cancer. Cancer J. 14, 191–197 (2008).

    Article  CAS  PubMed  Google Scholar 

  25. Chen, K. & Chen, X. Design and development of molecular imaging probes. Curr. Top. Med. Chem. 10, 1227–1236 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Liu, Z., Miller, S.J., Joshi, B.P. & Wang, T.D. In vivo targeting of colonic dysplasia on fluorescence endoscopy with near-infrared octapeptide. Gut 62, 395–403 (2013).

    Article  PubMed  Google Scholar 

  27. Mitsunaga, M. et al. Fluorescence endoscopic detection of murine colitis-associated colon cancer by topically applied enzymatically rapid-activatable probe. Gut 62, 1179–1186 (2013).

    Article  CAS  PubMed  Google Scholar 

  28. Imaizumi, K. et al. Dual-wavelength excitation of mucosal autofluorescence for precise detection of diminutive colonic adenomas. Gastrointest. Endosc. 75, 110–117 (2012).

    Article  PubMed  Google Scholar 

  29. Rex, D.K. Reducing costs of colon polyp management. Lancet Oncol. 10, 1135–1136 (2009).

    Article  PubMed  Google Scholar 

  30. Leggett, B. & Whitehall, V. Role of the serrated pathway in colorectal cancer pathogenesis. Gastroenterology 138, 2088–2100 (2010).

    Article  CAS  PubMed  Google Scholar 

  31. Wielenga, V.J. et al. Expression of c-Met and heparan-sulfate proteoglycan forms of CD44 in colorectal cancer. Am. J. Pathol. 157, 1563–1573 (2000).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. van der Poel, H.G., Buckle, T., Brouwer, O.R., Valdes Olmos, R.A. & van Leeuwen, F.W. Intraoperative laparoscopic fluorescence guidance to the sentinel lymph node in prostate cancer patients: clinical proof of concept of an integrated functional imaging approach using a multimodal tracer. Eur. Urol. 60, 826–833 (2011).

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

The authors would like to acknowledge the contributions of T. Attramadal, E. Johannesen and H. Dirven, who were the Project Leaders at GE Healthcare in the screening, lead selection and the translational/early clinical phases of the project, respectively. GE Healthcare AS received support for the GE-137 project from The Research Council of Norway grant no. 192984/BIA and SkatteFUNN grant no. 201108. F.W.B.v.L. and T.B. were supported by the The Netherlands Organisation for Scientific Research (NWO) VIDI (grant no. STW BGT11272) and a Postdoctoral Molecular Imaging Scholarship from the Education and Research Foundation for Nuclear Medicine and Molecular Imaging.

Author information

Authors and Affiliations

  1. Centre for Human Drug Research, Leiden, the Netherlands

    Jacobus Burggraaf, Ingrid M C Kamerling, Lenneke Schrier, Marieke L de Kam & Andrea J Kales

  2. GE Healthcare, Oslo, Norway

    Paul B Gordon, Ragnar Bendiksen, Bård Indrevoll, Roger M Bjerke, Siver A Moestue, Marit Swaerd-Nordmo, Geir Torheim, Liv-Ingrid Ødegårdstuen & Andrew Healey

  3. GE Global Research Centre, Niskayuna, New York, USA

    Siavash Yazdanfar

  4. Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, the Netherlands

    Alexandra M J Langers, Philip W Voorneveld & James C H Hardwick

  5. Pathology Diagnostics Ltd., St. John's Innovation Centre, Cambridge, UK

    Madhuri V Warren

  6. Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands

    Hans Morreau

  7. Department of Radiology, Leiden University Medical Center, Leiden, the Netherlands

    Tessa Buckle & Fijs W B van Leeuwen

  8. GE Healthcare, Amersham, UK

    Grethe T Dalsgaard

Authors
  1. Jacobus Burggraaf
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ingrid M C Kamerling
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Paul B Gordon
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lenneke Schrier
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Marieke L de Kam
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Andrea J Kales
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ragnar Bendiksen
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Bård Indrevoll
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Roger M Bjerke
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Siver A Moestue
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Siavash Yazdanfar
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Alexandra M J Langers
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Marit Swaerd-Nordmo
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Geir Torheim
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Madhuri V Warren
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Hans Morreau
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Philip W Voorneveld
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Tessa Buckle
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Fijs W B van Leeuwen
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Liv-Ingrid Ødegårdstuen
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Grethe T Dalsgaard
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. Andrew Healey
    View author publications

    You can also search for this author in PubMed Google Scholar

  23. James C H Hardwick
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

J.B., I.M.C.K. and P.B.G. designed the pharmacological studies; B.I., M.S.-N. and L.-I.Ø. developed the probe and the drug product; and R.B., R.M.B., S.A.M., A.H. and G.T.D. conducted the preclinical testing. L.S. and A.J.K. performed recruitment and safety testing for the clinical studies. M.L.d.K. performed the statistical analyses. H.M. performed the histopathological analysis of polyps. M.V.W. performed the c-Met immunohistochemical analysis. F.W.B.v.L., P.W.V. and T.B. performed the ex vivo direct fluorescence imaging studies. A.H., S.Y. and G.T. designed the method for assessing the imaging characteristics of the probe and developed the colonoscopy system. P.B.G., A.M.J.L. and J.C.H.H. designed the clinical studies, A.M.J.L. and J.C.H.H. performed the clinical studies, and J.C.H.H. wrote the manuscript.

Corresponding author

Correspondence to James C H Hardwick.

Ethics declarations

Competing interests

P.B. Gordon, R. Bendiksen, B. Indrevoll, R.M. Bjerke, S.A. Moestue, S. Yazdanfar, G. Torheim, M. Swaerd-Nordmo, G.T. Dalsgaard, L.-I. Ødegårdstuen and A. Healey are all currently employed by GE Healthcare or were employed by GE Healthcare during the study. The following authors declare no conflict of interest: J. Burggraaf, I.M.C. Kamerling, L. Schrier, M.L. de Kam, A.J. Kales, A.M.J. Langers, M.V. Warren, H. Morreau, P.W. Voorneveld, T. Buckle, F.W.B. van Leeuwen, and J.C.H. Hardwick.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–6, Supplementary Tables 1–4 & Supplementary Methods (PDF 4164 kb)

Supplementary Video 1

Video showing the two endoscopic images obtained simultaneously with white light and with near infrared fluorescence imaging (Green image) from a patient at colonoscopy. The first frame of the video details the characteristics of the colonic polyp shown in the video. (AVI 2485 kb)

Supplementary Video 2

Video showing the two endoscopic images obtained simultaneously with white light and with near infrared fluorescence imaging (Green image) from a patient at colonoscopy. The first frame of the video details the characteristics of the colonic polyp shown in the video (AVI 2531 kb)

Supplementary Video 3

Video showing the two endoscopic images obtained simultaneously with white light and with near infrared fluorescence imaging (Green image) from a patient at colonoscopy. The first frame of the video details the characteristics of the colonic polyp shown in the video (AVI 2577 kb)

Supplementary Video 4

Video showing the two endoscopic images obtained simultaneously with white light and with near infrared fluorescence imaging (Green image) from a patient at colonoscopy. The first frame of the video details the characteristics of the colonic polyp shown in the video (AVI 2368 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Burggraaf, J., Kamerling, I., Gordon, P. et al. Detection of colorectal polyps in humans using an intravenously administered fluorescent peptide targeted against c-Met. Nat Med 21, 955–961 (2015). https://doi.org/10.1038/nm.3641

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm.3641

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research