Skip to main content

[18F]FET PET is a useful tool for treatment evaluation and prognosis prediction of anti-angiogenic drug in an orthotopic glioblastoma mouse model

Abstract

O-2-18F-fluoroethyl-l-tyrosine ([18F]FET) has been widely used for glioblastomas (GBM) in clinical practice, although evaluation of its applicability in non-clinical research is still lacking. The objective of this study was to examine the value of [18F]FET for treatment evaluation and prognosis prediction of anti-angiogenic drug in an orthotopic mouse model of GBM. Human U87MG cells were implanted into nude mice and then bevacizumab, a representative anti-angiogenic drug, was administered. We monitored the effect of anti-angiogenic agents using multiple imaging modalities, including bioluminescence imaging (BLI), magnetic resonance imaging (MRI), and positron emission tomography-computed tomography (PET/CT). Among these imaging methods analyzed, only [18F]FET uptake showed a statistically significant decrease in the treatment group compared to the control group (P=0.02 and P=0.03 at 5 and 20 mg/kg, respectively). This indicates that [18F]FET PET is a sensitive method to monitor the response of GBM bearing mice to anti-angiogenic drug. Moreover, [18F]FET uptake was confirmed to be a significant parameter for predicting the prognosis of anti-angiogenic drug (P=0.041 and P=0.007, on Days 7 and 12, respectively, on Pearson’s correlation; P=0.048 and P=0.030, on Days 7 and 12, respectively, on Cox regression analysis). However, results of BLI or MRI were not significantly associated with survival time. In conclusion, this study suggests that [18F]FET PET imaging is a pertinent imaging modality for sensitive monitoring and accurate prediction of treatment response to anti-angiogenic agents in an orthotopic model of GBM.

References

  1. 1.

    Gallego O. Nonsurgical treatment of recurrent glioblastoma. Curr Oncol 2015; 22(4): e273–281.

    CAS  PubMed  PubMed Central  Google Scholar 

  2. 2.

    Cao Y. Future options of anti-angiogenic cancer therapy. Chin J Cancer 2016; 35(2): 21.

    PubMed  PubMed Central  Google Scholar 

  3. 3.

    Kuusk T, Albiges L, Escudier B, Grivas N, Haanen J, Powles T, Bex A. Antiangiogenic therapy combined with immune checkpoint blockade in renal cancer. Angiogenesis 2017; 20(2): 205–215.

    CAS  PubMed  Google Scholar 

  4. 4.

    Eisermann K, Fraizer G. The Androgen Receptor and VEGF: Mechanisms of Androgen-Regulated Angiogenesis in Prostate Cancer. Cancers (Basel) 2017; 9(4): 32.

    Google Scholar 

  5. 5.

    Hardee ME, Zagzag D. Mechanisms of glioma-associated neovascularization. Am J Pathol 2012; 181(4): 1126–1141.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Galldiks N, Langen KJ, Holy R, Pinkawa M, Stoffels G, Nolte KW, Kaiser HJ, Filss CP, Fink GR, Coenen HH, Eble MJ, Piroth MD. Assessment of treatment response in patients with glioblastoma using O-(2-18F-fluoroethyl)-L-tyrosine PET in comparison to MRI. J Nucl Med 2012; 53(7): 1048–1057.

    CAS  PubMed  Google Scholar 

  7. 7.

    Krcek R, Latzer P, Adamietz IA, Bühler H, Theiss C. Influence of vascular endothelial growth factor and radiation on gap junctional intercellular communication in glioblastoma multiforme cell lines. Neural Regen Res 2017; 12(11): 1816–1822.

    PubMed  PubMed Central  Google Scholar 

  8. 8.

    Fu P, He YS, Huang Q, Ding T, Cen YC, Zhao HY, Wei X. Bevacizumab treatment for newly diagnosed glioblastoma: Systematic review and meta-analysis of clinical trials. Mol Clin Oncol 2016; 4(5): 833–838.

    PubMed  PubMed Central  Google Scholar 

  9. 9.

    Jain RK. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 2005; 307(5706): 58–62.

    CAS  PubMed  Google Scholar 

  10. 10.

    Tobelem G. VEGF: a key therapeutic target for the treatment of cancer-insights into its role and pharmacological inhibition. Target Oncol 2007; 2(3): 153–164.

    Google Scholar 

  11. 11.

    Yanagisawa M, Yorozu K, Kurasawa M, Nakano K, Furugaki K, Yamashita Y, Mori K, Fujimoto- Ouchi K. Bevacizumab improves the delivery and efficacy of paclitaxel. Anticancer Drugs 2010; 21(7): 687–694.

    CAS  PubMed  Google Scholar 

  12. 12.

    Borgström P, Bourdon MA, Hillan KJ, Sriramarao P, Ferrara N. Neutralizing anti-vascular endothelial growth factor antibody completely inhibits angiogenesis and growth of human prostate carcinoma micro tumors in vivo. Prostate 1998; 35(1): 1–10.

    PubMed  Google Scholar 

  13. 13.

    Bagri A, Berry L, Gunter B, Singh M, Kasman I, Damico LA, Xiang H, Schmidt M, Fuh G, Hollister B, Rosen O, Plowman GD. Effects of anti-VEGF treatment duration on tumor growth, tumor regrowth, and treatment efficacy. Clin Cancer Res 2010; 16(15): 3887–3900.

    CAS  PubMed  Google Scholar 

  14. 14.

    Warren RS, Yuan H, Matli MR, Gillett NA, Ferrara N. Regulation by vascular endothelial growth factor of human colon cancer tumorigenesis in a mouse model of experimental liver metastasis. J Clin Invest 1995; 95(4): 1789–1797.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Mabuchi S, Terai Y, Morishige K, Tanabe-Kimura A, Sasaki H, Kanemura M, Tsunetoh S, Tanaka Y, Sakata M, Burger RA, Kimura T, Ohmichi M. Maintenance treatment with bevacizumab prolongs survival in an in vivo ovarian cancer model. Clin Cancer Res 2008; 14(23): 7781–7789.

    CAS  PubMed  Google Scholar 

  16. 16.

    Zhang J, Wang S, Liu H, Du X, Chen X, Guo Y, Zhang J, Fang J, Zhang W. Quantitative MRI assessment of glioma response to bevacizumab in a mouse model. Int J Clin Exp Med 2017; 10(10): 14232–14243.

    Google Scholar 

  17. 17.

    Friedman HS, Prados MD, Wen PY, Mikkelsen T, Schiff D, Abrey LE, Yung WK, Paleologos N, Nicholas MK, Jensen R, Vredenburgh J, Huang J, Zheng M, Cloughesy T. Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol 2009; 27(28): 4733–4740.

    CAS  PubMed  Google Scholar 

  18. 18.

    Vredenburgh JJ, Desjardins A, Herndon JE 2nd, Dowell JM, Reardon DA, Quinn JA, Rich JN, Sathornsumetee S, Gururangan S, Wagner M, Bigner DD, Friedman AH, Friedman HS. Phase II trial of bevacizumab and irinotecan in recurrent malignant glioma. Clin Cancer Res 2007; 13(4): 1253–1259.

    CAS  PubMed  Google Scholar 

  19. 19.

    Jakobsen JN, Hasselbalch B, Stockhausen MT, Lassen U, Poulsen HS. Irinotecan and bevacizumab in recurrent glioblastoma multiforme. Expert Opin Pharmacother 2011; 12(5): 825–833.

    CAS  PubMed  Google Scholar 

  20. 20.

    Odia Y, Iwamoto FM, Moustakas A, Fraum TJ, Salgado CA, Li A, Kreisl TN, Sul J, Butman JA, Fine HA. A phase II trial of enzastaurin (LY317615) in combination with bevacizumab in adults with recurrent malignant gliomas. J Neurooncol 2016; 127(1): 127–135.

    CAS  PubMed  Google Scholar 

  21. 21.

    Heiland DH, Masalha W, Franco P, Machein MR, Weyerbrock A. Progression-free and overall survival in patients with recurrent Glioblastoma multiforme treated with last-line bevacizumab versus bevacizumab/lomustine. J Neurooncol 2016; 126(3): 567–575.

    CAS  PubMed  Google Scholar 

  22. 22.

    Al-Abd AM, Alamoudi AJ, Abdel-Naim AB, Neamatallah TA, Ashour OM. Anti-angiogenic agents for the treatment of solid tumors: Potential pathways, therapy and current strategies — A review. J Adv Res 2017; 8(6): 591–605.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Ozel O, Kurt M, Ozdemir O, Bayram J, Akdeniz H, Koca D. Complete response to bevacizumab plus irinotecan in patients with rapidly progressive GBM: Cases report and literature review. J Oncol Sci 2016; 2(2–3): 87–94.

    Google Scholar 

  24. 24.

    Huang RY, Neagu MR, Reardon DA, Wen PY. Pitfalls in the neuroimaging of glioblastoma in the era of antiangiogenic and immuno/targeted therapy — detecting illusive disease, defining response. Front Neurol 2015; 6: 33.

    PubMed  PubMed Central  Google Scholar 

  25. 25.

    Wen PY, Macdonald DR, Reardon DA, Cloughesy TF, Sorensen AG, Galanis E, Degroot J, Wick W, Gilbert MR, Lassman AB, Tsien C, Mikkelsen T, Wong ET, Chamberlain MC, Stupp R, Lamborn KR, Vogelbaum MA, van den Bent MJ, Chang SM. Updated response assessment criteria for high-grade gliomas: response assessment in neuro-oncology working group. J Clin Oncol 2010; 28(11): 1963–1972.

    PubMed  Google Scholar 

  26. 26.

    Norden AD, Drappatz J, Muzikansky A, David K, Gerard M, McNamara MB, Phan P, Ross A, Kesari S, Wen PY. An exploratory survival analysis of anti-angiogenic therapy for recurrent malignant glioma. J Neurooncol 2009; 92(2): 149–155.

    CAS  PubMed  Google Scholar 

  27. 27.

    Nedergaard MK, Michaelsen SR, Perryman L, Erler J, Poulsen HS, Stockhausen MT, Lassen U, Kjaer A. Comparison of (18)FFET and (18)F-FLT small animal PET for the assessment of anti-VEGF treatment response in an orthotopic model of glioblastoma. Nucl Med Biol 2016; 43(3): 198–205.

    CAS  PubMed  Google Scholar 

  28. 28.

    Hutterer M, Nowosielski M, Putzer D, Waitz D, Tinkhauser G, Kostron H, Muigg A, Virgolini IJ, Staffen W, Trinka E, Gotwald T, Jacobs AH, Stockhammer G. O-(2-18F-fluoroethyl)-L-tyrosine PET predicts failure of antiangiogenic treatment in patients with recurrent high-grade glioma. J Nucl Med 2011; 52(6): 856–864.

    CAS  PubMed  Google Scholar 

  29. 29.

    Schwarzenberg J, Czernin J, Cloughesy TF, Ellingson BM, Pope WB, Geist C, Dahlbom M, Silverman DH, Satyamurthy N, Phelps ME, Chen W. 3’-deoxy-3’-18F-fluorothymidine PET and MRI for early survival predictions in patients with recurrent malignant glioma treated with bevacizumab. J Nucl Med 2012; 53(1): 29–36.

    CAS  PubMed  Google Scholar 

  30. 30.

    Gulyás B, Halldin C. New PET radiopharmaceuticals beyond FDG for brain tumor imaging. Q J Nucl Med Mol Imaging 2012; 56(2): 173–190.

    PubMed  Google Scholar 

  31. 31.

    Isselbacher KJ. Sugar and amino acid transport by cells in culture-differences between normal and malignant cells. N Engl J Med 1972; 286(17): 929–933.

    CAS  PubMed  Google Scholar 

  32. 32.

    BUSCH H, DAVIS JR, HONIG GR, ANDERSON DC, NAIR PV, NYHAN WL. The uptake of a variety of amino acids into nuclear proteins of tumors and other tissues. Cancer Res 1959; 19(10): 1030–1039.

    CAS  PubMed  Google Scholar 

  33. 33.

    Holzgreve A, Brendel M, Gu S, Carlsen J, Mille E, Böning G, Mastrella G, Unterrainer M, Gildehaus FJ, Rominger A, Bartenstein P, Kälin RE, Glass R, Albert NL. Monitoring of Tumor Growth with [(18)F]-FET PET in a Mouse Model of Glioblastoma: SUV Measurements and Volumetric Approaches. Front Neurosci 2016; 10: 260.

    PubMed  PubMed Central  Google Scholar 

  34. 34.

    Ramasawmy R, Johnson SP, Roberts TA, Stuckey DJ, David AL, Pedley RB, Lythgoe MF, Siow B, Walker-Samuel S. Monitoring the Growth of an Orthotopic Tumour Xenograft Model: Multi-Modal Imaging Assessment with Benchtop MRI (1T), High-Field MRI (9.4T), Ultrasound and Bioluminescence. PLoS One 2016; 11(5): e0156162.

    PubMed  PubMed Central  Google Scholar 

  35. 35.

    Jarzabek MA, Sweeney KJ, Evans RL, Jacobs AH, Stupp R, O’Brien D, Berger MS, Prehn JH, Byrne AT. Molecular imaging in the development of a novel treatment paradigm for glioblastoma (GBM): an integrated multidisciplinary commentary. Drug Discov Today 2013; 18(21–22): 1052–1066.

    PubMed  Google Scholar 

  36. 36.

    Nedergaard MK, Michaelsen SR, Urup T, Broholm H, El Ali H, Poulsen HS, Stockhausen MT, Kjaer A, Lassen U. 18F-FET microPET and microMRI for anti-VEGF and anti-PlGF response assessment in an orthotopic murine model of human glioblastoma. PLoS One 2015; 10(2): e0115315.

    PubMed  PubMed Central  Google Scholar 

  37. 37.

    Christoph S, Schlegel J, Alvarez-Calderon F, Kim YM, Brandao LN, DeRyckere D, Graham DK. Bioluminescence imaging of leukemia cell lines in vitro and in mouse xenografts: effects of monoclonal and polyclonal cell populations on intensity and kinetics of photon emission. J Hematol Oncol 2013; 6(1): 10.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Khalil AA, Jameson MJ, Broaddus WC, Lin PS, Dever SM, Golding SE, Rosenberg E, Valerie K, Chung TD. The Influence of Hypoxia and pH on Bioluminescence Imaging of Luciferase-Transfected Tumor Cells and Xenografts. Int J Mol Imaging 2013; 2013: 287697.

    PubMed  PubMed Central  Google Scholar 

  39. 39.

    O’Farrell AC, Shnyder SD, Marston G, Coletta PL, Gill JH. Noninvasive molecular imaging for preclinical cancer therapeutic development. Br J Pharmacol 2013; 169(4): 719–735.

    PubMed  PubMed Central  Google Scholar 

  40. 40.

    Galldiks N, Law I, Pope WB, Arbizu J, Langen KJ. The use of amino acid PET and conventional MRI for monitoring of brain tumor therapy. Neuroimage Clin 2016; 13: 386–394.

    PubMed  PubMed Central  Google Scholar 

  41. 41.

    Jalali S, Chung C, Foltz W, Burrell K, Singh S, Hill R, Zadeh G. MRI biomarkers identify the differential response of glioblastoma multiforme to anti-angiogenic therapy. Neuro Oncol 2014; 16(6): 868–879.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Götz I, Grosu A-L, Spehl TS. Role of PET Imaging in Patients with High-Grade Gliomas Undergoing Anti- Angiogenic Therapy with Bevacizumab-Review of the Literature and Case Report. Eur Assoc NeuroOncology Mag 2014; 4(3):102–108.

    Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to Hye Kyung Chung.

Rights and permissions

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://doi.org/creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Kim, O., Park, J.W., Lee, E.S. et al. [18F]FET PET is a useful tool for treatment evaluation and prognosis prediction of anti-angiogenic drug in an orthotopic glioblastoma mouse model. Lab Anim Res 34, 248–256 (2018). https://doi.org/10.5625/lar.2018.34.4.248

Download citation

Keywords

  • [18F]FET PET
  • glioblastoma
  • bevacizumab
  • anti-angiogenic drug
  • orthotopic model