Skip to main content

Advertisement

SpringerLink
Log in

Baseline [18F]FMISO μPET as a Predictive Biomarker for Response to HIF-1α Inhibition Combined with 5-FU Chemotherapy in a Human Colorectal Cancer Xenograft Model

  • Research Article
  • Published:
Molecular Imaging and Biology Aims and scope Submit manuscript

Abstract

Purpose

The purpose of this study was to characterize imaging biomarkers for the potential benefit of hypoxia-inducible factor-1 (HIF-1)α inhibition (by PX-12) during 5-fluorouracil (5-FU) chemotherapy in the treatment of colorectal cancer (CRC).

Procedures

Therapy response to 5-FU ± PX-12 was assessed with baseline [18F]fluoromisonidazole ([18F]FMISO) and longitudinal 2-deoxy-2-[18F]fluoro-d-glucose ([18F]FDG) positron emission computed tomography (μPET/CT) in CRC xenograft model (n = 36) during breathing of a hypoxic (10 % O2) or normoxic (21 % O2) atmosphere. Ex vivo, immunohistochemistry was performed.

Results

Baseline [18F]FMISO uptake and relative tumor volume (RTV) 2 days after 5-FU or 5-FU + PX-12 administration correlated significantly (p ≤ 0.01). Under hypoxic breathing conditions, [18F]FDG uptake (−53.1 ± 8.4 %) and Ki67 expression (−16 %) decreased and RTV stagnated in the 5-FU + PX-12 treatment group, but not in 5-FU alone-treated tumors. Under normoxic breathing, [18F]FDG uptake (−23.5 ± 15.2 % and −72.8 ± 7.1 %) and Ki67 expression (−5 % and −19 %) decreased and RTV stagnated in both the 5-FU and the combination treatment group, respectively.

Conclusion

Baseline [18F]FMISO μPET may predict the beneficial effect of HIF-1α inhibition during 5-FU chemotherapy in CRC.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Nagaraju GP, Bramhachari PV, Raghu G, El-Rayes BF (2015) Hypoxia inducible factor-1α: its role in colorectal carcinogenesis and metastasis. Cancer Lett 366:11–18

    Article  CAS  PubMed  Google Scholar 

  2. Vaupel P, Mayer A (2007) Hypoxia in cancer: significance and impact on clinical outcome. Cancer Metastasis Rev 26:225–239

    Article  CAS  PubMed  Google Scholar 

  3. Bertout JA, Patel SA, Simon MC (2008) The impact of O2 availability on human cancer. Nat Rev Cancer 8:967–975

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Ruan K, Song G, Ouyang G (2009) Role of hypoxia in the hallmarks of human cancer. J Cell Biochem 107:1053–1062

    Article  CAS  PubMed  Google Scholar 

  5. Ravizza R, Molteni R, Gariboldi MB et al (2009) Effect of HIF-1 modulation on the response of two- and three-dimensional cultures of human colon cancer cells to 5-fluorouracil. Eur J Cancer 45:890–898

    Article  CAS  PubMed  Google Scholar 

  6. Gustavsson B, Carlsson G, Machover D et al (2015) A review of the evolution of systemic chemotherapy in the management of colorectal cancer. Clin Colorectal Cancer 14:1–10

    Article  CAS  PubMed  Google Scholar 

  7. Semenza GL (2006) Development of novel therapeutic strategies that target HIF-1. Expert Opin Ther Targets 10:267–280

    Article  CAS  PubMed  Google Scholar 

  8. Semenza GL (2003) Targeting HIF-1 for cancer therapy. Nat Rev Cancer 3:721–732

    Article  CAS  PubMed  Google Scholar 

  9. Krohn KA, Link JM, Mason RP (2008) Molecular imaging of hypoxia. J Nucl Med 49:129S–148S

    Article  CAS  PubMed  Google Scholar 

  10. Rajendran JG, Krohn KA (2015) F-18 fluoromisonidazole for imaging tumor hypoxia: imaging the microenvironment for personalized cancer therapy. Sem Nucl Med 45:151–162

    Article  Google Scholar 

  11. Gambhir SS (2002) Molecular imaging of cancer with positron emission tomography. Nat Rev Cancer 2:683–693

    Article  CAS  PubMed  Google Scholar 

  12. Gatenby RA, Gillies RJ (2004) Why do cancers have high aerobic glycolysis? Nat Rev Cancer 4:891–899

    Article  CAS  PubMed  Google Scholar 

  13. Kim J-W, Gao P, Dang CV (2007) Effects of hypoxia on tumor metabolism. Cancer Metastasis Rev 26:291–298

    Article  PubMed  Google Scholar 

  14. Denko NC (2008) Hypoxia, HIF1 and glucose metabolism in the solid tumour. Nat Rev Cancer 8:705–713

    Article  CAS  PubMed  Google Scholar 

  15. Wijsman R, Kaanders JHAM, Oyen WJG, Bussink J (2013) Hypoxia and tumor metabolism in radiation oncology: targets visualized by positron emission tomography. Q J Nucl Med Mol Imaging 57:244–256

    CAS  PubMed  Google Scholar 

  16. Vander Heiden MG, Cantley LC, Thompson CB (2009) Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324:1029–1033

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Bentzen L, Keiding S, Horsman MR et al (2000) Feasibility of detecting hypoxia in experimental mouse tumours with 18F-fluorinated tracers and positron emission tomography. Acta Oncol 39:629–637

    Article  CAS  PubMed  Google Scholar 

  18. Mees G, Dierckx R, Vangestel C et al (2013) Pharmacologic activation of tumor hypoxia: a means to increase tumor 2-deoxy-2-[18F]fluoro-D-glucose uptake? Mol Imaging 12:49–58

    CAS  PubMed  Google Scholar 

  19. Powis G, Kirkpatrick DL (2007) Thioredoxin signaling as a target for cancer therapy. Curr Opin Pharmacol 7:392–397

    Article  CAS  PubMed  Google Scholar 

  20. Welsh SJ, Williams RR, Birmingham A et al (2003) The thioredoxin redox inhibitors 1-methylpropyl 2-imidazolyl disulfide and pleurotin inhibit hypoxia-induced factor 1alpha and vascular endothelial growth factor formation. Mol Cancer Ther 2:235–243

    CAS  PubMed  Google Scholar 

  21. Kim YH, Coon A, Baker AF, Powis G (2010) Antitumor agent PX-12 inhibits HIF-1α protein levels through an Nrf2/PMF-1-mediated increase in spermidine/spermine acetyl transferase. Cancer Chemother Pharmacol 68:405–413

    Article  PubMed  PubMed Central  Google Scholar 

  22. Wouters A, Pauwels B, Lambrechts HAJ et al (2009) Chemoradiation interactions under reduced oxygen conditions: cellular characteristics of an in vitro model. Cancer Lett 286:180–188

    Article  CAS  PubMed  Google Scholar 

  23. Adamsen TCH, Grierson JR, Krohn KA (2005) A new synthesis of the labeling precursor for [18F]-fluoromisonidazole. J Label Compd Radiopharm 48:923–927

    Article  CAS  Google Scholar 

  24. De Bruycker S, Vangestel C, Verbrugghen T et al (2014) Baseline [18F]FMISO and early [18F]FDG μPET changes as imaging biomarkers for HIF-1α inhibition combined with 5-FU in colorectal cancer [abstract]. European Molecular Imaging Meeting

    Google Scholar 

  25. Dubois L, Lieuwes NG, Janssen MH et al (2011) Preclinical evaluation and validation of [18F]HX4, a promising hypoxia marker for PET imaging. Proc Natl Acad Sci U S A 108:14620–14625

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Babsky AM, Zhang H, Hekmatyar SK et al (2007) Monitoring chemotherapeutic response in RIF-1 tumors by single-quantum and triple-quantum-filtered 23Na MRI, 1H diffusion-weighted MRI and PET imaging. Magn Reson Imaging 25:1015–1023

    Article  CAS  PubMed  Google Scholar 

  27. Barthel H, Cleij MC, Collingridge DR et al (2003) 3“-deoxy-3-”[18F]fluorothymidine as a new marker for monitoring tumor response to antiproliferative therapy in vivo with positron emission tomography. Cancer Res 63:3791–3798

    CAS  PubMed  Google Scholar 

  28. Kamm YJL, Peters GJ, Hull WE et al (2003) Correlation between 5-fluorouracil metabolism and treatment response in two variants of C26 murine colon carcinoma. Br J Cancer 89:754–762

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Choudhury KR, Yagle KJ, Swanson PE et al (2010) A robust automated measure of average antibody staining in immunohistochemistry images. J Histochem Cytochem 58:95–107

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Beck R, Roper B, Carlsen JM et al (2007) Pretreatment 18F-FAZA PET predicts success of hypoxia-directed radiochemotherapy using tirapazamine. J Nucl Med 48:973–980

    Article  CAS  PubMed  Google Scholar 

  31. Wyss MT, Honer M, Schubiger PA, Ametamey SM (2005) NanoPET imaging of [18F]fluoromisonidazole uptake in experimental mouse tumours. Eur J Nucl Med Mol Imaging 33:311–318

    Article  PubMed  Google Scholar 

  32. Troost EGC, Laverman P, Kaanders JHAM et al (2006) Imaging hypoxia after oxygenation-modification: comparing [18F]FMISO autoradiography with pimonidazole immunohistochemistry in human xenograft tumors. Radiother Oncol 80:157–164

    Article  CAS  PubMed  Google Scholar 

  33. Campanile C, Arlt MJE, Kramer SD et al (2013) Characterization of different osteosarcoma phenotypes by PET imaging in preclinical animal models. J Nucl Med 54:1362–1368

    Article  CAS  PubMed  Google Scholar 

  34. Busk M, Horsman MR, Kristjansen PEG et al (2008) Aerobic glycolysis in cancers: implications for the usability of oxygen-responsive genes and fluorodeoxyglucose-PET as markers of tissue hypoxia. Int J Cancer 122:2726–2734

    Article  CAS  PubMed  Google Scholar 

  35. Rajendran JG, Mankoff DA, O'Sullivan F et al (2004) Hypoxia and glucose metabolism in malignant tumors: evaluation by [18F]fluoromisonidazole and [18F]fluorodeoxyglucose positron emission tomography imaging. Clin Cancer Res 10:2245–2252

    Article  CAS  PubMed  Google Scholar 

  36. Jordan BF, Runquist M, Raghunand N et al (2005) The thioredoxin-1 inhibitor 1-methylpropyl 2-imidazolyl disulfide (PX-12) decreases vascular permeability in tumor xenografts monitored by dynamic contrast enhanced magnetic resonance imaging. Clin Cancer Res 11:529–536

    CAS  PubMed  Google Scholar 

  37. Ramanathan RK, Kirkpatrick DL, Belani CP et al (2007) A phase I pharmacokinetic and pharmacodynamic study of PX-12, a novel inhibitor of thioredoxin-1, in patients with advanced solid tumors. Clin Cancer Res 13:2109–2114

    Article  CAS  PubMed  Google Scholar 

  38. Dupuis NP, Kusumoto T, Robinson MF et al (1995) Restoration of tumor oxygenation after cytotoxic therapy by a perflubron emulsion/carbogen breathing. Artif Cells Blood Substit Immobil Biotechnol 23:423–429

    Article  CAS  PubMed  Google Scholar 

  39. Grassetto G, Capirci C, Marzola MC et al (2011) Colorectal cancer: prognostic role of 18F-FDG-PET/CT. Abdom Imaging 37:575–579

    Article  Google Scholar 

  40. Keen H, Pichler B, Kukuk D et al (2011) An evaluation of 2-deoxy-2-[18F]-fluoro-D-glucose and 3′-deoxy-3′-[18F]-fluorothymidine uptake in human tumor xenograft models. Mol Imaging Biol 14:355–365

    Article  Google Scholar 

  41. Sharma RI, Smith TAD (2008) Colorectal tumor cells treated with 5-FU, oxaliplatin, irinotecan, and cetuximab exhibit changes in 18F-FDG incorporation corresponding to hexokinase activity and glucose transport. J Nucl Med 49:1386–1394

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We gratefully acknowledge Philippe Joye and Caroline Berghmans of the Molecular Imaging Center Antwerp (MICA) and Christophe Hermans of the Center for Oncological Research (CORE) for their excellent technical assistance, and Thomas Verbrugghen of MICA for the [18F]FMISO productions. This work was funded by the University of Antwerp, Belgium through a PhD grant for Sven De Bruycker, an associate professor position for Patrick Pauwels and Steven Staelens, and a full professor position for Sigrid Stroobants; by Antwerp University Hospital, Belgium, through a postdoctoral position for Christel Vangestel (Innovative Medicines Initiative, Quic-Concept), a full-time position for Leonie wyffels, and a departmental position for Tim Van den Wyngaert, Patrick Pauwels, and Sigrid Stroobants; and by the Research Foundation Flanders, Belgium (FWO Vlaanderen) through a postdoctoral fellowship for An Wouters.

Author information

Authors and Affiliations

  1. Molecular Imaging Center Antwerp (MICA), University of Antwerp, Universiteitsplein 1, Wilrijk, Antwerp, Belgium

    Sven De Bruycker, Christel Vangestel, Tim Van den Wyngaert, Leonie wyffels, Steven Staelens & Sigrid Stroobants

  2. Department of Nuclear Medicine, Antwerp University Hospital, Wilrijkstraat 10, 2650, Edegem, Antwerp, Belgium

    Christel Vangestel, Tim Van den Wyngaert, Leonie wyffels & Sigrid Stroobants

  3. Center for Oncological Research (CORE), University of Antwerp, Universiteitsplein 1, Wilrijk, Antwerp, Belgium

    An Wouters & Patrick Pauwels

Authors
  1. Sven De Bruycker
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Christel Vangestel
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tim Van den Wyngaert
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Leonie wyffels
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. An Wouters
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Patrick Pauwels
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Steven Staelens
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Sigrid Stroobants
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sigrid Stroobants.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Electronic Supplementary Material

Below is the link to the electronic supplementary material.

Fig. S1

(PDF 198 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

De Bruycker, S., Vangestel, C., Van den Wyngaert, T. et al. Baseline [18F]FMISO μPET as a Predictive Biomarker for Response to HIF-1α Inhibition Combined with 5-FU Chemotherapy in a Human Colorectal Cancer Xenograft Model. Mol Imaging Biol 18, 606–616 (2016). https://doi.org/10.1007/s11307-015-0926-5

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11307-015-0926-5

Key words

Search

Navigation