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Journal of Neuro-Oncology

, Volume 113, Issue 3, pp 345–352 | Cite as

Blood-based biomarkers for malignant gliomas

  • Matthias HoldhoffEmail author
  • Susannah G. Yovino
  • Osei Boadu
  • Stuart A. Grossman
Topic Review

Abstract

Malignant gliomas remain incurable and present unique challenges to clinicians, radiologists and clinical and translational investigators. One of the major problems in treatment of these tumors is our limited ability to reliably assess tumor response or progression. The most frequently used neuro-imaging studies (contrast-enhanced MRI and CT) rely on changes of blood–brain barrier (BBB) integrity, providing only an indirect assessment of tumor burden. In addition, the BBB can be altered by commonly used interventions including radiation, glucocorticoids and vascular endothelial growth factor inhibitors, further complicating the interpretation of scans. Newer radiologic techniques including PET and magnetic resonance spectroscopy are theoretically promising but thus far have not meaningfully changed the assessment of patients with malignant gliomas. A tumor-specific, blood-based biomarker would be of immediate use to clinicians and investigators if sufficiently sensitive and specific. This review discusses the potential utility of such a biomarker, the general classes of tumor-derived blood-based biomarkers and it summarizes the currently available data on circulating tumor cells, circulating nucleic acids and circulating proteins in patients with malignant gliomas. It is unclear which marker or marker class appears to be the most promising for these tumors. This article provides thoughts on how novel candidate blood-based markers could be discovered and tested in a more comprehensive way and why these efforts should be among the top priorities in neuro-oncologic research in the coming years.

Keywords

Malignant glioma Glioblastoma Circulating tumor DNA Circulating tumor cells Circulating biomarker Blood-based biomarker Pseudo-progression 

Notes

Acknowledgments

This work is supported by the Robert H. Gross Memorial Fund.

Conflict of interest

The authors have no financial conflict of interest to declare.

References

  1. 1.
    Macdonald DR, Cascino TL, Schold SC Jr, Cairncross JG (1990) Response criteria for phase II studies of supratentorial malignant glioma. J Clin Oncol 8:1277–1280PubMedGoogle Scholar
  2. 2.
    Wen PY, Macdonald DR, Reardon DA, Cloughesy TF, Sorensen AG, Galanis E, Degroot J, Wick W, Gilbert MR, Lassman AB et al (2010) Updated response assessment criteria for high-grade gliomas: response assessment in neuro-oncology working group. J Clin Oncol 28:1963–1972. doi: 10.1200/JCO.2009.26.3541 PubMedCrossRefGoogle Scholar
  3. 3.
    Burger PC (1983) Pathologic anatomy and CT correlations in the glioblastoma multiforme. Appl Neurophysiol 46:180–187PubMedGoogle Scholar
  4. 4.
    Brandsma D, Stalpers L, Taal W, Sminia P, van den Bent MJ (2008) Clinical features, mechanisms, and management of pseudoprogression in malignant gliomas. Lancet Oncol 9:453–461. doi: 10.1016/S1470-2045(08)70125-6 PubMedCrossRefGoogle Scholar
  5. 5.
    Armstrong AJ, Eisenberger MA, Halabi S, Oudard S, Nanus DM, Petrylak DP, Sartor AO, Scher HI (2012) Biomarkers in the management and treatment of men with metastatic castration-resistant prostate cancer. Eur Urol 61:549–559. doi: 10.1016/j.eururo.2011.11.009 PubMedCrossRefGoogle Scholar
  6. 6.
    Zheng PP, Hop WC, Luider TM, Sillevis Smitt PA, Kros JM (2007) Increased levels of circulating endothelial progenitor cells and circulating endothelial nitric oxide synthase in patients with gliomas. Ann Neurol 62:40–48. doi: 10.1002/ana.21151 PubMedCrossRefGoogle Scholar
  7. 7.
    Alexiou GA, Vartholomatos G, Karamoutsios A, Batistatou A, Kyritsis AP, Voulgaris S (2012) Circulating progenitor cells: a comparison of patients with glioblastoma or meningioma. Acta Neurol Belg. doi: 10.1007/s13760-012-0097-y PubMedGoogle Scholar
  8. 8.
    Smith DR, Hardman JM, Earle KM (1969) Metastasizing neuroectodermal tumors of the central nervous system. J Neurosurg 31:50–58. doi: 10.3171/jns.1969.31.1.0050 PubMedCrossRefGoogle Scholar
  9. 9.
    Smith DR, Hardman JM, Earle KM (1969) Contiguous glioblastoma multiforme and fibrosarcoma with extracranial metastasis. Cancer 24:270–276PubMedCrossRefGoogle Scholar
  10. 10.
    Pasquier B, Pasquier D, N’Golet A, Panh MH, Couderc P (1980) Extraneural metastases of astrocytomas and glioblastomas: clinicopathological study of two cases and review of literature. Cancer 45:112–125PubMedCrossRefGoogle Scholar
  11. 11.
    Lun M, Lok E, Gautam S, Wu E, Wong ET (2011) The natural history of extracranial metastasis from glioblastoma multiforme. J Neurooncol. doi: 10.1007/s11060-011-0575-8 PubMedGoogle Scholar
  12. 12.
    Beauchesne P (2012) Letter to the editor: the natural history of extra-cranial metastasis from glioblastoma multiform. J Neurooncol. doi: 10.1007/s11060-011-0575-8. J Neurooncol 109:593–4; author reply 595. doi: 10.1007/s11060-012-0921-5
  13. 13.
    Armanios MY, Grossman SA, Yang SC, White B, Perry A, Burger PC, Orens JB (2004) Transmission of glioblastoma multiforme following bilateral lung transplantation from an affected donor: case study and review of the literature. Neuro Oncol 6:259–263. doi: 10.1215/S1152851703000474 PubMedCrossRefGoogle Scholar
  14. 14.
    Healey PJ, Davis CL (1998) Transmission of tumours by transplantation. Lancet 352:2–3. doi: 10.1016/S0140-6736(98)22027-7 PubMedCrossRefGoogle Scholar
  15. 15.
    Diehl F, Schmidt K, Choti MA, Romans K, Goodman S, Li M, Thornton K, Agrawal N, Sokoll L, Szabo SA et al (2008) Circulating mutant DNA to assess tumor dynamics. Nat Med 14:985–990. doi: 10.1038/nm.1789 PubMedCrossRefGoogle Scholar
  16. 16.
    Angenendt P, Juhl DH, Diehl F (2010) Detection of phosphoinositide-3-kinase, catalytic, and alpha polypeptide (PIK3CA) mutations in matched tissue and plasma samples from patients with metastatic breast cancer. J Clin Oncol 28:10502Google Scholar
  17. 17.
    Diehl F, Li M, He Y, Kinzler KW, Vogelstein B, Dressman D (2006) BEAMing: single-molecule PCR on microparticles in water-in-oil emulsions. Nat Methods 3:551–559. doi: 10.1038/nmeth898 PubMedCrossRefGoogle Scholar
  18. 18.
    Leary RJ, Kinde I, Diehl F, Schmidt K, Clouser C, Duncan C, Antipova A, Lee C, McKernan K, De La Vega FM, et al (2010) Development of personalized tumor biomarkers using massively parallel sequencing. Sci Transl Med 2:20ra14. doi: 10.1126/scitranslmed.3000702
  19. 19.
    Boisselier B, Perez-Larraya JG, Rossetto M, Labussiere M, Ciccarino P, Marie Y, Delattre JY, Sanson M (2012) Detection of IDH1 mutation in the plasma of patients with glioma. Neurology 79:1693–1698. doi: 10.1212/WNL.0b013e31826e9b0a PubMedCrossRefGoogle Scholar
  20. 20.
    Balana C, Ramirez JL, Taron M, Roussos Y, Ariza A, Ballester R, Sarries C, Mendez P, Sanchez JJ, Rosell R (2003) O6-methyl-guanine-DNA methyltransferase methylation in serum and tumor DNA predicts response to 1,3-bis(2-chloroethyl)-1-nitrosourea but not to temozolamide plus cisplatin in glioblastoma multiforme. Clin Cancer Res 9:1461–1468PubMedGoogle Scholar
  21. 21.
    Weaver KD, Grossman SA, Herman JG (2006) Methylated tumor-specific DNA as a plasma biomarker in patients with glioma. Cancer Invest 24:35–40. doi: 10.1080/07357900500449546 PubMedCrossRefGoogle Scholar
  22. 22.
    Wakabayashi T, Natsume A, Hatano H, Fujii M, Shimato S, Ito M, Ohno M, Ito S, Ogura M, Yoshida J (2009) P16 promoter methylation in the serum as a basis for the molecular diagnosis of gliomas. Neurosurgery 64:455–461. doi: 10.1227/01.NEU.0000340683.19920.E3 (discussion 461-2)PubMedCrossRefGoogle Scholar
  23. 23.
    Lavon I, Refael M, Zelikovitch B, Shalom E, Siegal T (2010) Serum DNA can define tumor-specific genetic and epigenetic markers in gliomas of various grades. Neuro Oncol 12:173–180. doi: 10.1093/neuonc/nop041 PubMedCrossRefGoogle Scholar
  24. 24.
    Roth P, Wischhusen J, Happold C, Chandran PA, Hofer S, Eisele G, Weller M, Keller A (2011) A specific miRNA signature in the peripheral blood of glioblastoma patients. J Neurochem 118:449–457. doi: 10.1111/j.1471-4159.2011.07307.x PubMedCrossRefGoogle Scholar
  25. 25.
    Ilhan-Mutlu A, Wagner L, Wohrer A, Jungwirth S, Marosi C, Fischer P, Preusser M (2012) Blood alterations preceding clinical manifestation of glioblastoma. Cancer Invest 30:625–629. doi: 10.3109/07357907.2012.725443 PubMedCrossRefGoogle Scholar
  26. 26.
    Skog J, Wurdinger T, van Rijn S, Meijer DH, Gainche L, Sena-Esteves M, Curry WT Jr, Carter BS, Krichevsky AM, Breakefield XO (2008) Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers. Nat Cell Biol 10:1470–1476. doi: 10.1038/ncb1800 PubMedCrossRefGoogle Scholar
  27. 27.
    Noerholm M, Balaj L, Limperg T, Salehi A, Zhu LD, Hochberg FH, Breakefield XO, Carter BS, Skog J (2012) RNA expression patterns in serum microvesicles from patients with glioblastoma multiforme and controls. BMC Cancer 12:22-2407-12-22. doi: 10.1186/1471-2407-12-22 Google Scholar
  28. 28.
    Jung CS, Foerch C, Schanzer A, Heck A, Plate KH, Seifert V, Steinmetz H, Raabe A, Sitzer M (2007) Serum GFAP is a diagnostic marker for glioblastoma multiforme. Brain 130:3336–3341. doi: 10.1093/brain/awm263 PubMedCrossRefGoogle Scholar
  29. 29.
    Brommeland T, Rosengren L, Fridlund S, Hennig R, Isaksen V (2007) Serum levels of glial fibrillary acidic protein correlate to tumour volume of high-grade gliomas. Acta Neurol Scand 116:380–384. doi: 10.1111/j.1600-0404.2007.00889.x PubMedCrossRefGoogle Scholar
  30. 30.
    Husain H, Savage W, Grossman SA, Ye X, Burger PC, Everett A, Bettegowda C, Diaz LA Jr, Blair C, Romans KE et al (2012) Pre- and post-operative plasma glial fibrillary acidic protein levels in patients with newly diagnosed gliomas. J Neurooncol 109:123–127. doi: 10.1007/s11060-012-0874-8 PubMedCrossRefGoogle Scholar
  31. 31.
    Kesari S, Schiff D, Henson JW, Muzikansky A, Gigas DC, Doherty L, Batchelor TT, Longtine JA, Ligon KL, Weaver S et al (2008) Phase II study of temozolomide, thalidomide, and celecoxib for newly diagnosed glioblastoma in adults. Neuro Oncol 10:300–308. doi: 10.1215/15228517-2008-005 PubMedCrossRefGoogle Scholar
  32. 32.
    Groves MD, Puduvalli VK, Chang SM, Conrad CA, Gilbert MR, Tremont-Lukats IW, Liu TJ, Peterson P, Schiff D, Cloughesy TF et al (2007) A North American brain tumor consortium (NABTC 99–04) phase II trial of temozolomide plus thalidomide for recurrent glioblastoma multiforme. J Neurooncol 81:271–277. doi: 10.1007/s11060-006-9225-y PubMedCrossRefGoogle Scholar
  33. 33.
    Quaranta M, Divella R, Daniele A, Di Tardo S, Venneri MT, Lolli I, Troccoli G (2007) Epidermal growth factor receptor serum levels and prognostic value in malignant gliomas. Tumori 93:275–280PubMedGoogle Scholar
  34. 34.
    Batchelor TT, Sorensen AG, di Tomaso E, Zhang WT, Duda DG, Cohen KS, Kozak KR, Cahill DP, Chen PJ, Zhu M et al (2007) AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell 11:83–95. doi: 10.1016/j.ccr.2006.11.021 PubMedCrossRefGoogle Scholar
  35. 35.
    Batchelor TT, Duda DG, di Tomaso E, Ancukiewicz M, Plotkin SR, Gerstner E, Eichler AF, Drappatz J, Hochberg FH, Benner T et al (2010) Phase II study of cediranib, an oral pan-vascular endothelial growth factor receptor tyrosine kinase inhibitor, in patients with recurrent glioblastoma. J Clin Oncol 28:2817–2823. doi: 10.1200/JCO.2009.26.3988 PubMedCrossRefGoogle Scholar
  36. 36.
    Fine HA, Figg WD, Jaeckle K, Wen PY, Kyritsis AP, Loeffler JS, Levin VA, Black PM, Kaplan R, Pluda JM et al (2000) Phase II trial of the antiangiogenic agent thalidomide in patients with recurrent high-grade gliomas. J Clin Oncol 18:708–715PubMedGoogle Scholar
  37. 37.
    Hulshof MC, Sminia P, Barten-Van Rijbroek AD, Gonzalez Gonzalez D (2001) Prognostic value of plasma transforming growth factor-beta in patients with glioblastoma multiforme. Oncol Rep 8:1107–1110PubMedGoogle Scholar
  38. 38.
    de Groot JF, Piao Y, Tran H, Gilbert M, Wu HK, Liu J, Bekele BN, Cloughesy T, Mehta M, Robins HI et al (2011) Myeloid Biomarkers Associated with Glioblastoma Response to Anti-VEGF Therapy with Aflibercept. Clin Cancer Res 17:4872–4881. doi: 10.1158/1078-0432.CCR-11-0271 PubMedCrossRefGoogle Scholar
  39. 39.
    Hormigo A, Gu B, Karimi S, Riedel E, Panageas KS, Edgar MA, Tanwar MK, Rao JS, Fleisher M, DeAngelis LM et al (2006) YKL-40 and matrix metalloproteinase-9 as potential serum biomarkers for patients with high-grade gliomas. Clin Cancer Res 12:5698–5704. doi: 10.1158/1078-0432.CCR-06-0181 PubMedCrossRefGoogle Scholar
  40. 40.
    Iwamoto FM, Hottinger AF, Karimi S, Riedel E, Dantis J, Jahdi M, Panageas KS, Lassman AB, Abrey LE, Fleisher M et al (2011) Longitudinal prospective study of matrix metalloproteinase-9 as a serum marker in gliomas. J Neurooncol. doi: 10.1007/s11060-011-0628-z Google Scholar
  41. 41.
    Ilhan-Mutlu A, Wagner L, Widhalm G, Wohrer A, Bartsch S, Czech T, Heinzl H, Leutmezer F, Prayer D, Marosi C et al (2012) Exploratory investigation of eight circulating plasma markers in brain tumor patients. Neurosurg Rev. doi: 10.1007/s10143-012-0401-6 PubMedGoogle Scholar
  42. 42.
    Blakeley JO, Olson J, Grossman SA, He X, Weingart J, Supko JG, New Approaches to Brain Tumor Therapy (NABTT) Consortium (2009) Effect of blood brain barrier permeability in recurrent high grade gliomas on the intratumoral pharmacokinetics of methotrexate: a microdialysis study. J Neurooncol 91:51–58. doi: 10.1007/s11060-008-9678-2 PubMedCrossRefGoogle Scholar
  43. 43.
    Blakeley J, Portnow J (2010) Microdialysis for assessing intratumoral drug disposition in brain cancers: a tool for rational drug development. Expert Opin Drug Metab Toxicol 6:1477–1491. doi: 10.1517/17425255.2010.523420 PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Matthias Holdhoff
    • 1
    Email author
  • Susannah G. Yovino
    • 1
    • 2
  • Osei Boadu
    • 1
  • Stuart A. Grossman
    • 1
  1. 1.Brain Cancer Program, Department of OncologySidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of MedicineBaltimoreUSA
  2. 2.Department of Radiation Oncology and Molecular Radiation SciencesSidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of MedicineBaltimoreUSA

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