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:

Intraoperative tumor-specific fluorescence imaging in ovarian cancer by folate receptor-α targeting: first in-human results

Nature Medicine volume 17, pages 1315–1319 (2011)Cite this article

Subjects

Abstract

The prognosis in advanced-stage ovarian cancer remains poor. Tumor-specific intraoperative fluorescence imaging may improve staging and debulking efforts in cytoreductive surgery and thereby improve prognosis. The overexpression of folate receptor-α (FR-α) in 90–95% of epithelial ovarian cancers prompted the investigation of intraoperative tumor-specific fluorescence imaging in ovarian cancer surgery using an FR-α–targeted fluorescent agent. In patients with ovarian cancer, intraoperative tumor-specific fluorescence imaging with an FR-α–targeted fluorescent agent showcased the potential applications in patients with ovarian cancer for improved intraoperative staging and more radical cytoreductive surgery.

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: The tumor-specific fluorescent agent folate-FITC.
Figure 2: Intra-operative multispectral imaging system.
Figure 3: Quantification of tumor deposits ex vivo.
Figure 4: Microphotographs of different ovarian tumors.

Similar content being viewed by others

References

  1. Jemal, A. et al. Cancer statistics, 2008. CA Cancer J. Clin. 58, 71–96 (2008).

    Article  Google Scholar 

  2. Gondos, A., Bray, F., Hakulinen, T. & Brenner, H. Trends in cancer survival in 11 European populations from 1990 to 2009: a model-based analysis. Ann. Oncol. 20, 564–573 (2009).

    Article  CAS  Google Scholar 

  3. Aletti, G.D., Gallenberg, M.M., Cliby, W.A., Jatoi, A. & Hartmann, L.C. Current management strategies for ovarian cancer. Mayo Clin. Proc. 82, 751–770 (2007).

    Article  Google Scholar 

  4. Winter, W.E. III et al. Tumor residual after surgical cytoreduction in prediction of clinical outcome in stage IV epithelial ovarian cancer: a Gynecologic Oncology Group Study. J. Clin. Oncol. 26, 83–89 (2008).

    Article  Google Scholar 

  5. Ibeanu, O.A. & Bristow, R.E. Predicting the outcome of cytoreductive surgery for advanced ovarian cancer: a review. Int. J. Gynecol. Cancer 20 (suppl. 1), S1–S11 (2010).

    Article  Google Scholar 

  6. Troyan, S.L. et al. The FLARE intraoperative near-infrared fluorescence imaging system: a first-in-human clinical trial in breast cancer sentinel lymph node mapping. Ann. Surg. Oncol. 16, 2943–2952 (2009).

    Article  Google Scholar 

  7. Luker, G.D. & Luker, K.E. Optical imaging: current applications and future directions. J. Nucl. Med. 49, 1–4 (2008).

    Article  Google Scholar 

  8. Tromberg, B.J. et al. Assessing the future of diffuse optical imaging technologies for breast cancer management. Med. Phys. 35, 2443–2451 (2008).

    Article  Google Scholar 

  9. Kirsch, D.G. et al. A spatially and temporally restricted mouse model of soft tissue sarcoma. Nat. Med. 13, 992–997 (2007).

    Article  CAS  Google Scholar 

  10. von Burstin, J. et al. Highly sensitive detection of early-stage pancreatic cancer by multimodal near-infrared molecular imaging in living mice. Int. J. Cancer 123, 2138–2147 (2008).

    Article  CAS  Google Scholar 

  11. Sevick-Muraca, E.M. et al. Imaging of lymph flow in breast cancer patients after microdose administration of a near-infrared fluorophore: feasibility study. Radiology 246, 734–741 (2008).

    Article  Google Scholar 

  12. Tagaya, N. et al. Intraoperative identification of sentinel lymph nodes by near-infrared fluorescence imaging in patients with breast cancer. Am. J. Surg. 195, 850–853 (2008).

    Article  Google Scholar 

  13. Stummer, W. et al. Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial. Lancet Oncol. 7, 392–401 (2006).

    Article  CAS  Google Scholar 

  14. Kalli, K.R. et al. Folate receptor alpha as a tumor target in epithelial ovarian cancer. Gynecol. Oncol. 108, 619–626 (2008).

    Article  CAS  Google Scholar 

  15. Markert, S. et al. Alpha-folate receptor expression in epithelial ovarian carcinoma and non-neoplastic ovarian tissue. Anticancer Res. 28, 3567–3572 (2008).

    PubMed  Google Scholar 

  16. Mathias, C.J. et al. Indium-111-DTPA-folate as a potential folate-receptor-targeted radiopharmaceutical. J. Nucl. Med. 39, 1579–1585 (1998).

    CAS  PubMed  Google Scholar 

  17. Armstrong, D.K. et al. Exploratory phase II efficacy study of MORAb-003, a monoclonal antibody against folate receptor alpha, in platinum-sensitive ovarian cancer in first relapse. J. Clin. Oncol. 26, 5500 (2008).

    Article  Google Scholar 

  18. Kennedy, M.D., Jallad, K.N., Thompson, D.H., Ben Amotz, D. & Low, P.S. Optical imaging of metastatic tumors using a folate-targeted fluorescent probe. J. Biomed. Opt. 8, 636–641 (2003).

    Article  Google Scholar 

  19. Leamon, C.P. et al. Synthesis and biological evaluation of EC20: a new folate-derived, 99mTc-based radiopharmaceutical. Bioconjug. Chem. 13, 1200–1210 (2002).

    Article  CAS  Google Scholar 

  20. Themelis, G., Yoo, J.S., Soh, K.S., Schulz, R. & Ntziachristos, V. Real-time intraoperative fluorescence imaging system using light-absorption correction. J. Biomed. Opt. 14, 064012 (2009).

    Article  Google Scholar 

  21. Sega, E.I. & Low, P.S. Tumor detection using folate receptor-targeted imaging agents. Cancer Metastasis Rev. 27, 655–664 (2008).

    Article  CAS  Google Scholar 

  22. Crane, L.M.A. et al. The effect of chemotherapy on expression of folate receptor-α in ovarian cancer. Cell. Oncol. 34. Published online, doi: 10.1007/s13402-011-0052-6.

    Article  Google Scholar 

  23. Vergote, I. et al. Timing of debulking surgery in advanced ovarian cancer. Int. J. Gynecol. Cancer 18 ( suppl. 1), 11–19 (2008).

    Article  Google Scholar 

  24. Aletti, G.D. et al. Aggressive surgical effort and improved survival in advanced-stage ovarian cancer. Obstet. Gynecol. 107, 77–85 (2006).

    Article  Google Scholar 

  25. Koppe, M.J., Boerman, O.C., Oyen, W.J. & Bleichrodt, R.P. Peritoneal carcinomatosis of colorectal origin: incidence and current treatment strategies. Ann. Surg. 243, 212–222 (2006).

    Article  Google Scholar 

  26. Low, P.S. & Antony, A.C. Folate receptor-targeted drugs for cancer and inflammatory diseases. Adv. Drug Deliv. Rev. 56, 1055–1058 (2004).

    Article  CAS  Google Scholar 

  27. Parker, N. et al. Folate receptor expression in carcinomas and normal tissues determined by a quantitative radioligand binding assay. Anal. Biochem. 338, 284–293 (2005).

    Article  CAS  Google Scholar 

  28. Troy, T., Jekic-McMullen, D., Sambucetti, L. & Rice, B. Quantitative comparison of the sensitivity of detection of fluorescent and bioluminescent reporters in animal models. Mol. Imaging 3, 9–23 (2004).

    Article  CAS  Google Scholar 

  29. Benedet, J.L., Bender, H., Jones, H. III, Ngan, H.Y. & Pecorelli, S. FIGO staging classifications and clinical practice guidelines in the management of gynecologic cancers. FIGO Committee on Gynecologic Oncology. Int. J. Gynaecol. Obstet. 70, 209–262 (2000).

    Article  CAS  Google Scholar 

  30. Lu, Y. & Low, P.S. Folate targeting of haptens to cancer cell surfaces mediates immunotherapy of syngeneic murine tumors. Cancer Immunol. Immunother. 51, 153–162 (2002).

    Article  CAS  Google Scholar 

  31. Lu, Y. et al. Strategy to prevent drug-related hypersensitivity in folate-targeted hapten immunotherapy of cancer. AAPS J. 11, 628–638 (2009).

    Article  CAS  Google Scholar 

  32. Themelis, G., Yoo, J.S. & Ntziachristos, V. Multispectral imaging using multiple-bandpass filters. Opt. Lett. 33, 1023–1025 (2008).

    Article  Google Scholar 

Download references

Acknowledgements

The authors wish to thank W. Sluiter for help with statistical analyses, I. Wesselman for training the operating room personnel in using the camera system and B. Molmans (Department of Hospital Pharmacy, University Medical Center Groningen) for pharmaceutical expertise and support. Monoclonal antibody mAb343 was kindly provided by W. Franklin (University of Colorado Health Science Center).

Author information

Authors and Affiliations

  1. Department of Surgery, Division of Surgical Oncology, BioOptical Imaging Center, University of Groningen, Groningen, The Netherlands

    Gooitzen M van Dam, Lucia M A Crane, Niels J Harlaar, Rick G Pleijhuis, Wendy Kelder & Johannes S de Jong

  2. Technische Universität München & Helmholtz Zentrum, München, Germany

    George Themelis, Niels J Harlaar, Athanasios Sarantopoulos & Vasilis Ntziachristos

  3. Department of Gynaecology, Division of Gynaecological Oncology, University of Groningen, Groningen, The Netherlands

    Henriette J G Arts & Ate G J van der Zee

  4. Department of Pathology and Molecular Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

    Joost Bart

  5. Department of Chemistry, Purdue University, West Lafayette, Indiana, USA

    Philip S Low

Authors
  1. Gooitzen M van Dam
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. George Themelis
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lucia M A Crane
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Niels J Harlaar
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Rick G Pleijhuis
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Wendy Kelder
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Athanasios Sarantopoulos
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Johannes S de Jong
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Henriette J G Arts
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Ate G J van der Zee
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Joost Bart
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Philip S Low
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Vasilis Ntziachristos
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

G.M.v.D. supervised the project, designed and performed the study, interpreted data and wrote the manuscript. G.T. designed the camera system, performed the study, interpreted data with technical and computer analyses support and wrote the manuscript. L.M.A.C. designed and performed the study, interpreted data and wrote the manuscript. N.J.H. performed the study and interpreted data. R.G.P. performed the study and interpreted data. W.K. performed the study and interpreted data. A.S. designed the camera system, performed the study and interpreted data with technical and computer analysis support. J.S.d.J. performed the study and interpreted data. H.J.G.A. designed and performed the study, interpreted data and wrote the manuscript. A.G.J.v.d.Z. designed and performed the study, interpreted data and wrote the manuscript. J.B. designed and performed the study, interpreted data, performed the pathology analyses and wrote the manuscript. P.S.L. designed and performed the study, and interpreted data. V.N. supervised the project, designed and performed the study, designed and provided the camera system and interpreted data, and wrote the manuscript.

Corresponding authors

Correspondence to Gooitzen M van Dam or Vasilis Ntziachristos.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figure 1 and Supplementary Methods (PDF 220 kb)

Supplementary Video 1

Intraoperative application of the multispectral intraoperative fluorescence camera system (MOV 35948 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

van Dam, G., Themelis, G., Crane, L. et al. Intraoperative tumor-specific fluorescence imaging in ovarian cancer by folate receptor-α targeting: first in-human results. Nat Med 17, 1315–1319 (2011). https://doi.org/10.1038/nm.2472

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm.2472

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer