Preclinical Models of Glioblastoma in Radiobiology: Evolving Protocols and Research Methods

  • Anita TandleEmail author
  • Uma Shankavaram
  • Cody Schlaff
  • Kevin Camphausen
  • Andra Krauze
Part of the Current Clinical Pathology book series (CCPATH)


Gliomas are the most common form of primary brain tumors with glioblastoma (GBM) being the most malignant. The standard therapy for newly diagnosed malignant gliomas involves maximal surgical resection, radiotherapy, and chemotherapy with a median survival of 9–14 months. The combination of RT with chemotherapeutic agents that sensitize tumor cells to the cytotoxic effects of RT has been studied in an attempt to enhance tumor control and minimize the radiation toxicity. Although such combination chemoradiation protocols have improved treatment outcomes in several human malignancies, they are still less than optimal, as the existing agents can cause undesirable toxicity. Therefore, a continuing endeavor in experimental and translational oncology research has been to identify more effective agents to augment the radiosensitivity of tumor cells. Recent efforts toward this goal have focused on molecularly targeted agents directed against certain components of intracellular signaling pathways involved in tumor growth and radioresistance.

The current chapter discusses the preclinical models in GBM radiobiology. This chapter reviews the developments that allowed basic scientists and radiation oncologists to maximize therapeutic benefits of radiation in treating GBM. The chapter also discusses past, present, and future preclinical methods in optimizing treatment for GBM.


Glioblastoma Preclinical models Radiotherapy Radiosensitization DNA damage response DNA damage repair γH2AX foci Mitotic catastrophe Clonogenic survival 


  1. 1.
    Berens ME, Giese A. “…those left behind.” Biology and oncology of invasive glioma cells. Neoplasia. 1999;1(3):208–19.PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Connell PP, Hellman S. Advances in radiotherapy and implications for the next century: a historical perspective. Cancer Res. 2009;69(2):383–92.PubMedCrossRefGoogle Scholar
  3. 3.
    Jeggo P, Lavin MF. Cellular radiosensitivity: how much better do we understand it? Int J Radiat Biol. 2009;85(12):1061–81.PubMedCrossRefGoogle Scholar
  4. 4.
    Bhide SA, Nutting CM. Recent advances in radiotherapy. BMC Med. 2010;8:25.PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Bischoff P, Altmeyer A, Dumont F. Radiosensitising agents for the radiotherapy of cancer: advances in traditional and hypoxia targeted radiosensitisers. Expert Opin Ther Pat. 2009;19(5):643–62.PubMedCrossRefGoogle Scholar
  6. 6.
    Verheij M, Vens C, van Triest B. Novel therapeutics in combination with radiotherapy to improve cancer treatment: rationale, mechanisms of action and clinical perspective. Drug Resist Updat. 2010;13(1-2):29–43.PubMedCrossRefGoogle Scholar
  7. 7.
    Begg AC, Stewart FA, Vens C. Strategies to improve radiotherapy with targeted drugs. Nat Rev Cancer. 2011;11(4):239–53.PubMedCrossRefGoogle Scholar
  8. 8.
    Withers HR. The four R’s of radiotherapy. In: Lett JT, Adler H, editors. Advances in radiation biology. New York: Academic Press; 1975. p. 5.Google Scholar
  9. 9.
    Steel GG, McMillan TJ, Peacock JH. The 5Rs of radiobiology. Int J Radiat Biol. 1989;56(6):1045–8.PubMedCrossRefGoogle Scholar
  10. 10.
    Deacon J, Peckham MJ, Steel GG. The radioresponsiveness of human tumours and the initial slope of the cell survival curve. Radiother Oncol. 1984;2(4):317–23.PubMedCrossRefGoogle Scholar
  11. 11.
    Bernier J, Hall EJ, Giaccia A. Radiation oncology: a century of achievements. Nat Rev Cancer. 2004;4(9):737–47.PubMedCrossRefGoogle Scholar
  12. 12.
    Blazek ER, Foutch JL, Maki G. Daoy medulloblastoma cells that express CD133 are radioresistant relative to CD133- cells, and the CD133+ sector is enlarged by hypoxia. Int J Radiat Oncol Biol Phys. 2007;67(1):1–5.PubMedCrossRefGoogle Scholar
  13. 13.
    Holmquist-Mengelbier L, et al. Recruitment of HIF-1alpha and HIF-2alpha to common target genes is differentially regulated in neuroblastoma: HIF-2alpha promotes an aggressive phenotype. Cancer Cell. 2006;10(5):413–23.PubMedCrossRefGoogle Scholar
  14. 14.
    Bertout JA, et al. HIF2alpha inhibition promotes p53 pathway activity, tumor cell death, and radiation responses. Proc Natl Acad Sci U S A. 2009;106(34):14391–6.PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Holmquist L, Lofstedt T, Pahlman S. Effect of hypoxia on the tumor phenotype: the neuroblastoma and breast cancer models. Adv Exp Med Biol. 2006;587:179–93.PubMedCrossRefGoogle Scholar
  16. 16.
    Beaman GM, et al. Reliability of HSP70 (HSPA) expression as a prognostic marker in glioma. Mol Cell Biochem. 2014;393(1-2):301–7.PubMedCrossRefGoogle Scholar
  17. 17.
    Kinner A, et al. Gamma-H2AX in recognition and signaling of DNA double-strand breaks in the context of chromatin. Nucleic Acids Res. 2008;36(17):5678–94.PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Rogakou EP, et al. DNA double-stranded breaks induce histone H2AX phosphorylation on serine 139. J Biol Chem. 1998;273(10):5858–68.PubMedCrossRefGoogle Scholar
  19. 19.
    Rogakou EP, et al. Megabase chromatin domains involved in DNA double-strand breaks in vivo. J Cell Biol. 1999;146(5):905–16.PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Sedelnikova OA, et al. Quantitative detection of (125)IdU-induced DNA double-strand breaks with gamma-H2AX antibody. Radiat Res. 2002;158(4):486–92.PubMedCrossRefGoogle Scholar
  21. 21.
    Klokov D, et al. Phosphorylated histone H2AX in relation to cell survival in tumor cells and xenografts exposed to single and fractionated doses of X-rays. Radiother Oncol. 2006;80(2):223–9.PubMedCrossRefGoogle Scholar
  22. 22.
    Iwabuchi K, et al. Two cellular proteins that bind to wild-type but not mutant p53. Proc Natl Acad Sci U S A. 1994;91(13):6098–102.PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Schultz LB, et al. p53 binding protein 1 (53BP1) is an early participant in the cellular response to DNA double-strand breaks. J Cell Biol. 2000;151(7):1381–90.PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Anderson L, Henderson C, Adachi Y. Phosphorylation and rapid relocalization of 53BP1 to nuclear foci upon DNA damage. Mol Cell Biol. 2001;21(5):1719–29.PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Iwabuchi K, et al. 53BP1 contributes to survival of cells irradiated with X-ray during G1 without Ku70 or Artemis. Genes Cells. 2006;11(8):935–48.PubMedCrossRefGoogle Scholar
  26. 26.
    Ostling O, Johanson KJ. Microelectrophoretic study of radiation-induced DNA damages in individual mammalian cells. Biochem Biophys Res Commun. 1984;123(1):291–8.PubMedCrossRefGoogle Scholar
  27. 27.
    Singh NP, et al. A simple technique for quantitation of low levels of DNA damage in individual cells. Exp Cell Res. 1988;175(1):184–91.PubMedCrossRefGoogle Scholar
  28. 28.
    Azqueta A, Collins AR. The essential comet assay: a comprehensive guide to measuring DNA damage and repair. Arch Toxicol. 2013;87(6):949–68.PubMedCrossRefGoogle Scholar
  29. 29.
    Shaposhnikov S, et al. Detection of Alu sequences and mtDNA in comets using padlock probes. Mutagenesis. 2006;21(4):243–7.PubMedCrossRefGoogle Scholar
  30. 30.
    Dudas A, Chovanec M. DNA double-strand break repair by homologous recombination. Mutat Res. 2004;566(2):131–67.PubMedCrossRefGoogle Scholar
  31. 31.
    Vasileva A, Linden RM, Jessberger R. Homologous recombination is required for AAV-mediated gene targeting. Nucleic Acids Res. 2006;34(11):3345–60.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Yun S, Lie ACC, Porter AC. Discriminatory suppression of homologous recombination by p53. Nucleic Acids Res. 2004;32(22):6479–89.PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Lieber MR. The mechanism of human nonhomologous DNA end joining. J Biol Chem. 2008;283(1):1–5.PubMedCrossRefGoogle Scholar
  34. 34.
    Labhart P. Nonhomologous DNA end joining in cell-free systems. Eur J Biochem. 1999;265(3):849–61.PubMedCrossRefGoogle Scholar
  35. 35.
    North P, Ganesh A, Thacker J. The rejoining of double-strand breaks in DNA by human cell extracts. Nucleic Acids Res. 1990;18(21):6205–10.PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Falck J, Coates J, Jackson SP. Conserved modes of recruitment of ATM, ATR and DNA-PKcs to sites of DNA damage. Nature. 2005;434(7033):605–11.PubMedCrossRefGoogle Scholar
  37. 37.
    Matsuoka S, et al. ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage. Science. 2007;316(5828):1160–6.PubMedCrossRefGoogle Scholar
  38. 38.
    Yang J, et al. ATM, ATR and DNA-PK: initiators of the cellular genotoxic stress responses. Carcinogenesis. 2003;24(10):1571–80.PubMedCrossRefGoogle Scholar
  39. 39.
    Kastan MB, Bartek J. Cell-cycle checkpoints and cancer. Nature. 2004;432(7015):316–23.PubMedCrossRefGoogle Scholar
  40. 40.
    Brown JM, Wouters BG. Apoptosis, p53, and tumor cell sensitivity to anticancer agents. Cancer Res. 1999;59(7):1391–9.PubMedGoogle Scholar
  41. 41.
    Broker LE, Kruyt FA, Giaccone G. Cell death independent of caspases: a review. Clin Cancer Res. 2005;11(9):3155–62.PubMedCrossRefGoogle Scholar
  42. 42.
    Vakifahmetoglu H, Olsson M, Zhivotovsky B. Death through a tragedy: mitotic catastrophe. Cell Death Differ. 2008;15(7):1153–62.PubMedCrossRefGoogle Scholar
  43. 43.
    Surova O, Zhivotovsky B. Various modes of cell death induced by DNA damage. Oncogene. 2013;32(33):3789–97.PubMedCrossRefGoogle Scholar
  44. 44.
    Rello-Varona S, et al. An automated fluorescence videomicroscopy assay for the detection of mitotic catastrophe. Cell Death Dis. 2010;1, e25.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Biederbick A, Kern HF, Elsasser HP. Monodansylcadaverine (MDC) is a specific in vivo marker for autophagic vacuoles. Eur J Cell Biol. 1995;66(1):3–14.PubMedGoogle Scholar
  46. 46.
    Mizushima N. Methods for monitoring autophagy. Int J Biochem Cell Biol. 2004;36(12):2491–502.PubMedCrossRefGoogle Scholar
  47. 47.
    Roninson IB. Tumor cell senescence in cancer treatment. Cancer Res. 2003;63(11):2705–15.PubMedGoogle Scholar
  48. 48.
    Guo L, Xie B, Mao Z. Autophagy in premature senescent cells is activated via AMPK pathway. Int J Mol Sci. 2012;13(3):3563–82.PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Puck TT, Marcus PI, Cieciura SJ. Clonal growth of mammalian cells in vitro; growth characteristics of colonies from single HeLa cells with and without a feeder layer. J Exp Med. 1956;103(2):273–83.PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Weisenthal LM, Lippman ME. Clonogenic and nonclonogenic in vitro chemosensitivity assays. Cancer Treat Rep. 1985;69(6):615–32.PubMedGoogle Scholar
  51. 51.
    Hoffman RM. In vitro sensitivity assays in cancer: a review, analysis, and prognosis. J Clin Lab Anal. 1991;5(2):133–43.PubMedCrossRefGoogle Scholar
  52. 52.
    Boucher Y, et al. Interstitial hypertension in superficial metastatic melanomas in humans. Cancer Res. 1991;51(24):6691–4.PubMedGoogle Scholar
  53. 53.
    Olive PL. Radiation-induced reoxygenation in the SCCVII murine tumour: evidence for a decrease in oxygen consumption and an increase in tumour perfusion. Radiother Oncol. 1994;32(1):37–46.PubMedCrossRefGoogle Scholar
  54. 54.
    Crokart N, et al. Early reoxygenation in tumors after irradiation: determining factors and consequences for radiotherapy regimens using daily multiple fractions. Int J Radiat Oncol Biol Phys. 2005;63(3):901–10.PubMedCrossRefGoogle Scholar
  55. 55.
    Diepart C, et al. Comparison of methods for measuring oxygen consumption in tumor cells in vitro. Anal Biochem. 2010;396(2):250–6.PubMedCrossRefGoogle Scholar
  56. 56.
    James PE, et al. The effects of endotoxin on oxygen consumption of various cell types in vitro: an EPR oximetry study. Free Radic Biol Med. 1995;18(4):641–7.PubMedCrossRefGoogle Scholar
  57. 57.
    von Heimburg D, et al. Oxygen consumption in undifferentiated versus differentiated adipogenic mesenchymal precursor cells. Respir Physiol Neurobiol. 2005;146(2-3):107–16.CrossRefGoogle Scholar
  58. 58.
    de Jong M, Essers J, van Weerden WM. Imaging preclinical tumour models: improving translational power. Nat Rev Cancer. 2014;14(7):481–93.PubMedCrossRefGoogle Scholar
  59. 59.
    Camphausen K, et al. Influence of in vivo growth on human glioma cell line gene expression: convergent profiles under orthotopic conditions. Proc Natl Acad Sci U S A. 2005;102(23):8287–92.PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Jacobs VL, et al. Current review of in vivo GBM rodent models: emphasis on the CNS-1 tumour model. ASN Neuro. 2011;3(3), e00063.PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Wilding JL, Bodmer WF. Cancer cell lines for drug discovery and development. Cancer Res. 2014;74(9):2377–84.PubMedCrossRefGoogle Scholar
  62. 62.
    Shankavaram UT, et al. Molecular profiling indicates orthotopic xenograft of glioma cell lines simulate a subclass of human glioblastoma. J Cell Mol Med. 2012;16(3):545–54.PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Galli R, et al. Isolation and characterization of tumorigenic, stem-like neural precursors from human glioblastoma. Cancer Res. 2004;64(19):7011–21.PubMedCrossRefGoogle Scholar
  64. 64.
    Singh SK, et al. Identification of a cancer stem cell in human brain tumors. Cancer Res. 2003;63(18):5821–8.PubMedGoogle Scholar
  65. 65.
    Bao S, et al. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature. 2006;444(7120):756–60.PubMedCrossRefGoogle Scholar
  66. 66.
    Bao S, et al. Targeting cancer stem cells through L1CAM suppresses glioma growth. Cancer Res. 2008;68(15):6043–8.PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Bao S, et al. Stem cell-like glioma cells promote tumor angiogenesis through vascular endothelial growth factor. Cancer Res. 2006;66(16):7843–8.PubMedCrossRefGoogle Scholar
  68. 68.
    Huang Z, et al. Cancer stem cells in glioblastoma—molecular signaling and therapeutic targeting. Protein Cell. 2010;1(7):638–55.PubMedCrossRefGoogle Scholar
  69. 69.
    Jamal M, et al. The brain microenvironment preferentially enhances the radioresistance of CD133(+) glioblastoma stem-like cells. Neoplasia. 2012;14(2):150–8.PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Stratton MR, Campbell PJ, Futreal PA. The cancer genome. Nature. 2009;458(7239):719–24.PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Vogelstein B, Kinzler KW. Cancer genes and the pathways they control. Nat Med. 2004;10(8):789–99.PubMedCrossRefGoogle Scholar
  72. 72.
    Weir B, Zhao X, Meyerson M. Somatic alterations in the human cancer genome. Cancer Cell. 2004;6(5):433–8.PubMedCrossRefGoogle Scholar
  73. 73.
    Cancer Genome Atlas Research Network. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature. 2008;455(7216):1061–8.CrossRefGoogle Scholar
  74. 74.
    Verhaak RG, et al. Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell. 2010;17(1):98–110.PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Bredel M, et al. NFKBIA deletion in glioblastomas. N Engl J Med. 2011;364(7):627–37.PubMedCrossRefGoogle Scholar
  76. 76.
    Parsons DW, et al. An integrated genomic analysis of human glioblastoma multiforme. Science. 2008;321(5897):1807–12.PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    Nicholas MK, et al. Molecular heterogeneity in glioblastoma: therapeutic opportunities and challenges. Semin Oncol. 2011;38(2):243–53.PubMedCrossRefGoogle Scholar
  78. 78.
    Noushmehr H, et al. Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma. Cancer Cell. 2010;17(5):510–22.PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Tran AN, et al. Increased sensitivity to radiochemotherapy in IDH1 mutant glioblastoma as demonstrated by serial quantitative MR volumetry. Neuro Oncol. 2014;16(3):414–20.PubMedCrossRefGoogle Scholar
  80. 80.
    Griffin JL, Shockcor JP. Metabolic profiles of cancer cells. Nat Rev Cancer. 2004;4(7):551–61.PubMedCrossRefGoogle Scholar
  81. 81.
    Spratlin JL, Serkova NJ, Eckhardt SG. Clinical applications of metabolomics in oncology: a review. Clin Cancer Res. 2009;15(2):431–40.PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Houillier C, et al. IDH1 or IDH2 mutations predict longer survival and response to temozolomide in low-grade gliomas. Neurology. 2010;75(17):1560–6.PubMedCrossRefGoogle Scholar
  83. 83.
    Baldewpersad Tewarie NM, et al. NADP+-dependent IDH1 R132 mutation and its relevance for glioma patient survival. Med Hypotheses. 2013;80(6):728–31.PubMedCrossRefGoogle Scholar
  84. 84.
    Lyons SK. Advances in imaging mouse tumour models in vivo. J Pathol. 2005;205(2):194–205.PubMedCrossRefGoogle Scholar
  85. 85.
    Puaux AL, et al. A comparison of imaging techniques to monitor tumor growth and cancer progression in living animals. Int J Mol Imag. 2011;2011:321538.Google Scholar
  86. 86.
    Patterson AP, Booth SA, Saba R. The emerging use of in vivo optical imaging in the study of neurodegenerative diseases. Biomed Res Int. 2014;2014:401306.PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Monici M. Cell and tissue autofluorescence research and diagnostic applications. Biotechnol Annu Rev. 2005;11:227–56.PubMedCrossRefGoogle Scholar
  88. 88.
    McNally JB, et al. Task-based imaging of colon cancer in the Apc(Min/+) mouse model. Appl Opt. 2006;45(13):3049–62.PubMedCrossRefGoogle Scholar
  89. 89.
    Aswendt M, et al. Boosting bioluminescence neuroimaging: an optimized protocol for brain studies. PLoS One. 2013;8(2), e55662.PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Jarzabek MA, et al. In vivo bioluminescence imaging validation of a human biopsy-derived orthotopic mouse model of glioblastoma multiforme. Mol Imaging. 2013;12(3):161–72.PubMedGoogle Scholar
  91. 91.
    Hingtgen S, et al. Real-time multi-modality imaging of glioblastoma tumor resection and recurrence. J Neurooncol. 2013;111(2):153–61.PubMedCrossRefGoogle Scholar
  92. 92.
    Sonabend AM, et al. Murine cell line model of proneural glioma for evaluation of anti-tumor therapies. J Neurooncol. 2013;112(3):375–82.PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Chakravarti A, et al. RTOG 0211: a phase 1/2 study of radiation therapy with concurrent gefitinib for newly diagnosed glioblastoma patients. Int J Radiat Oncol Biol Phys. 2013;85(5):1206–11.PubMedCrossRefGoogle Scholar
  94. 94.
    Kreisl TN, et al. A phase I/II trial of vandetanib for patients with recurrent malignant glioma. Neuro Oncol. 2012;14(12):1519–26.PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Raizer JJ, et al. A phase II trial of erlotinib in patients with recurrent malignant gliomas and nonprogressive glioblastoma multiforme postradiation therapy. Neuro Oncol. 2010;12(1):95–103.PubMedCrossRefGoogle Scholar
  96. 96.
    Guha A, et al. Proliferation of human malignant astrocytomas is dependent on Ras activation. Oncogene. 1997;15(23):2755–65.PubMedCrossRefGoogle Scholar
  97. 97.
    Glass TL, Liu TJ, Yung WK. Inhibition of cell growth in human glioblastoma cell lines by farnesyltransferase inhibitor SCH66336. Neuro Oncol. 2000;2(3):151–8.PubMedPubMedCentralGoogle Scholar
  98. 98.
    Feldkamp MM, et al. Normoxic and hypoxic regulation of vascular endothelial growth factor (VEGF) by astrocytoma cells is mediated by Ras. Int J Cancer. 1999;81(1):118–24.PubMedCrossRefGoogle Scholar
  99. 99.
    Kang KB, et al. Gefitinib radiosensitizes stem-like glioma cells: inhibition of epidermal growth factor receptor-Akt-DNA-PK signaling, accompanied by inhibition of DNA double-strand break repair. Int J Radiat Oncol Biol Phys. 2012;83(1):e43–52.PubMedCrossRefGoogle Scholar
  100. 100.
    Stupp R, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352(10):987–96.PubMedCrossRefGoogle Scholar
  101. 101.
    Mellinghoff IK, et al. Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors. N Engl J Med. 2005;353(19):2012–24.PubMedCrossRefGoogle Scholar
  102. 102.
    Galanis E, et al. Phase II trial of temsirolimus (CCI-779) in recurrent glioblastoma multiforme: a North Central Cancer Treatment Group Study. J Clin Oncol. 2005;23(23):5294–304.PubMedCrossRefGoogle Scholar
  103. 103.
    Chang SM. Does temsirolimus have a role in recurrent glioblastoma multiforme? Nat Clin Pract Oncol. 2006;3(2):70–1.PubMedCrossRefGoogle Scholar
  104. 104.
    Clarke JL, et al. A single-institution phase II trial of radiation, temozolomide, erlotinib, and bevacizumab for initial treatment of glioblastoma. Neuro Oncol. 2014;16(7):984–90.PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Bonavia R, et al. Heterogeneity maintenance in glioblastoma: a social network. Cancer Res. 2011;71(12):4055–60.PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Singh S, Dirks PB. Brain tumor stem cells: identification and concepts. Neurosurg Clin N Am. 2007;18(1):31–8. viii.PubMedCrossRefGoogle Scholar
  107. 107.
    Brescia P, et al. CD133 is essential for glioblastoma stem cell maintenance. Stem Cells. 2013;31(5):857–69.PubMedCrossRefGoogle Scholar
  108. 108.
    Rockne R, et al. Predicting the efficacy of radiotherapy in individual glioblastoma patients in vivo: a mathematical modeling approach. Phys Med Biol. 2010;55(12):3271–85.PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Jansen M, Yip S, Louis DN. Molecular pathology in adult gliomas: diagnostic, prognostic, and predictive markers. Lancet Neurol. 2010;9(7):717–26.PubMedPubMedCentralCrossRefGoogle Scholar
  110. 110.
    Horbinski C, et al. Diagnostic use of IDH1/2 mutation analysis in routine clinical testing of formalin-fixed, paraffin-embedded glioma tissues. J Neuropathol Exp Neurol. 2009;68(12):1319–25.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  • Anita Tandle
    • 1
    Email author
  • Uma Shankavaram
    • 1
  • Cody Schlaff
    • 1
  • Kevin Camphausen
    • 1
  • Andra Krauze
    • 1
  1. 1.Radiation Oncology BranchNational Cancer Institute, National Institutes of HealthBethesdaUSA

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