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Introduction and Background

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Radiobiology of Glioblastoma

Part of the book series: Current Clinical Pathology ((CCPATH))

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Abstract

Glioblastoma (GB) accounts for 54 % of primary brain tumors, with an incidence of about five new cases for every 100,000 per year, and after aggressive multimodal treatments, prognosis remains poor, with a 5-year Overall Survival (OS) rate barely reaching 5 %, as extensively documented in this book Maximum achievable safe surgical resection, and limited-volume radiotherapy with concurrent and sequential chemotherapy based on the alkylating agent Temozolomide, achieve 40, 15, and 7–8 % OS rates, respectively at 1-, 2-, and 3-years. These present standards of treatment mostly stem from studies dating back to the seventies of the last century, and progressively evolving through subsequent clinical trials. Radioresistance of GB is one challenge for Radiation Biology, that has emerged from the clinical setting, and important questions raised by clinical experiences are addressed by basic laboratory research. However, Radiation Biology is a scarcely known discipline outside of the inner circle of the radiological science scholars, and we are convinced that a comprehensive and updated coverage of this subject is warranted, that is, the aim of this book. The researchers and the practitioners studying GB in the domains of radiation and medical oncology, pathology, biology, and physics may profit from reciprocal scientific contributions collected in a lineup fitting the present state-of-the-art.

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References

  1. Stupp R, Tonn JC, Brada M, et al. On behalf of the ESMO Guidelines Working Group: high-grade malignant glioma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2010;21:190–3.

    Article  Google Scholar 

  2. Salazar OM, Rubin P, Donald JF, Feldstein ML. High-dose radiation therapy in the treatment of glioblastoma multiforme. Int J Radiat Oncol Biol Phys. 1976;1:717–27.

    Article  CAS  PubMed  Google Scholar 

  3. Walker MD, Strike TA, Sheline GE. Analysis of dose-effect relationship in the radiotherapy of malignant gliomas. Int J Radiat Oncol Biol Phys. 1979;5:1715–31.

    Article  Google Scholar 

  4. Curran Jr WJ, Scott CB, Horton J, et al. Recursive partitioning analysis of prognostic factors in three Radiation Therapy Oncology Group malignant glioma trials. J Natl Cancer Inst. 1993;85:704–10.

    Article  PubMed  Google Scholar 

  5. Pedicini P, Fiorentino A, Simeon V, et al. Clinical radiobiology of glioblastoma multiforme: estimation of tumor control probability from various radiotherapy fractionation schemes. Strahlenther Onkol. 2014;190:925–32.

    Article  PubMed  Google Scholar 

  6. Brennan C, Verhaak RGW, McKenna A, et al. The somatic genomic landscape of glioblastoma. Cell. 2013;155:462–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Patel MA, Kim JE, Ruzevick J, et al. The future of glioblastoma therapy: synergism of standard of care and immunotherapy. Cancers. 2014;6:1953–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Prados MD, Byron SA, Tran NL, et al. Towards precision medicine in glioblastoma: the promise and the challenges. Neuro Oncol. 2015;17:1051–63. doi:10.1093/neuronc/nov031:1-10.

    Article  PubMed  Google Scholar 

  9. Bastien JL, McNeill KA, Fine HA. Molecular characterization of glioblastoma, target therapy, and clinical results to date. Cancer. 2014;121:502–10.

    Article  PubMed  Google Scholar 

  10. Baumann M, Bodis S, Dikomey E, et al. Molecular radiation biology/oncology at its best: cutting edge research presented at the 13th international Wofsberg meeting on molecular radiation biology/oncology. Radiother Oncol. 2013;108:357–61.

    Article  PubMed  Google Scholar 

  11. Verhaak RGW, Hoadley KA, Purdom E, et al. An integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR and NF1. Cancer Cell. 2010;17(1):98. doi:10.1016/J.ccr2009.12.020.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Cohen-Jonathan Moyal E. Du laboratoire vers la clinique: expérience du glioblastoma pur moduler la radiosensibilité tumorale. Cancer Radiother. 2012;16:25–8.

    Article  CAS  PubMed  Google Scholar 

  13. Toulany M, Rodemann HP. Potential of Akt mediated repair in radioresistance of solid tumors overexpressing erbB-PI3K-Akt pathway. Transl Cancer Res. 2013;2:190–202.

    CAS  Google Scholar 

  14. Hatampaa KJ, Burma S, Zhao D, Habib AA. Epidermal growth factor receptor in glioma: signal transduction, neuropathology, imaging, and radioresistance. Neoplasia. 2010;12:675–84.

    Article  Google Scholar 

  15. Mukheriee B, McEllin B, Camacho CV, et al. EGFRvIII and DNA double strand break repair: a molecular mechanism for radioresistance in glioblastoma. Cancer Res. 2009;69:4252–9.

    Article  Google Scholar 

  16. Mellinghoff IK, Wang MY, Vivanco I, et al. Molecular determinants of the response of glioblastoma to EGFR kinase inhibitors. N Engl J Med. 2005;353:2012–24.

    Article  CAS  PubMed  Google Scholar 

  17. Krakstad C, Chekenya M. Survival signaling and apoptosis resistance in glioblastomas: opportunities for target therapies. Mol Cancer. 2010;9:135. http://www.molecular-cancer.com/content/9/1/135

  18. Taylor TE, Furnari FB, Cavanee WK. Targeting EGFR for treatment of glioblastoma: molecular basis to overcome resistance. Curr Cancer Drug Targets. 2012;12:197–209.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Wong R. Apoptosis in cancer: from pathogenesis to treatment. J Exp Clin Cancer Res. 2011;30:87. doi:10.1186/1756-9966-30-87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Balcer-Kubiczek EK. Apoptosis in radiation therapy: a double edged sword. Exp Oncol. 2012;34:277–85.

    CAS  PubMed  Google Scholar 

  21. Ma H, Rao L, Wang HL, Mao ZW, et al. Transcriptome analysis of glioma cells for the dynamic response to irradiation and dual regulation of apoptosis genes: a new insight into radiotherapy for glioblastoma. Cell Death Dis. 2013;4, e895. doi:10.1038/cddis.2013.412.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Mirzayans R, Andrais B, Scott A, et al. Ionizing radiation-induced responses in human cells with differing TP53 status. Int J Mol Sci. 2013;14:22409–35.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Galluzzi L, Vitale I, Abrams JM, et al. Molecular definitions of cell death subroutines: recommendations of the Nomenclature Committee on Cell Death 2012. Cell Death Differ. 2012;19:107–20.

    Article  CAS  PubMed  Google Scholar 

  24. Miracco C, Palumbo S, Pirtoli L, Comincini S. Autophagy in human brain cancer: therapeutic implications. In: Hayat MA, editor. Autophagy: cancer, other pathologies, inflammation, immunity, infection, and aging, vol. 5. San Diego: Elsevier/Academic Press; 2015. p. 105–20.

    Google Scholar 

  25. Kang R, Zeh HJ, Lotze MT, Tang D. The beclin1 network regulates autophagy and apoptosis. Cell Death Differ. 2011;18:571–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Wei Y, Zou Z, Becker N, et al. XEGFR-mediated beclin1 phosphorylation in autophagy suppression, tumor progression, and tumor chemoresistance. Cell. 2013;154:1269–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Palumbo S, Tini P, Toscano M, et al. Combined EGFR and autophagy modulation impairs cell migration and enhances radiosensitivity in human glioblastoma cells. J Cell Physiol. 2014;229:1863–73.

    Article  CAS  PubMed  Google Scholar 

  28. Tini P, Belmonte G, Toscano M et al. Combined epidermal growth factor receptor and beclin1 autophagic protein expression analysis identifies different clinical presentations, responses to chemo- and radiotherapy, and prognosis in glioblastoma. BioMed Res Int. 2015; ID 208076. http://dx.doi.org/10.1159/2015/208076

  29. Schonberg DL, Lubelski D, Miller TE, Rich JN. Brain tumor stem cells: molecular characteristics and their impact on therapy. Mol Aspects Med. 2014;39:82–101.

    Article  CAS  PubMed  Google Scholar 

  30. Carrasco-Garcia E, Sampron N, Aldaz P, et al. Therapeutic strategies targeting glioblastoma stem cells. Recent Pat Anticancer Drug Discov. 2013;8:216–27.

    Article  CAS  PubMed  Google Scholar 

  31. Altaner C. Glioblastoma and stem cells. Neoplasma. 2008;55:369–74.

    CAS  PubMed  Google Scholar 

  32. Bao S, Wu Q, McLendon RE, Hao Y, et al. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature. 2006;444:756–60.

    Article  CAS  PubMed  Google Scholar 

  33. Bao S, Wu Q, Sathornsumetee S, Hao Y, et al. Stem cell-like glioma cells promote tumor angiogenesis through vascular endothelial growth factor. Cancer Res. 2006;66:7843–8.

    Article  CAS  PubMed  Google Scholar 

  34. Wang J, Ma Y, Cooper MK. Cancer stem cells in glioma: challenges and opportunities. Transl Cancer Res. 2013;2:429–41.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Wang R, Chadalavada K, Wilshire J, et al. Glioblastoma stem-like cells give rise to tumour endothelium. Nature. 2010;468:829–33.

    Article  CAS  PubMed  Google Scholar 

  36. Ricci-Vitiani L, Pallini R, Biffoni M, et al. Tumour vascularization via endothelial differentiation of glioblastoma stem-like cells. Nature. 2010;468:824–8.

    Article  CAS  PubMed  Google Scholar 

  37. Cheng L, Huang Z, Zhou W, et al. Glioblastoma stem cells generate vascular pericytes to support vessel function and tumor growth. Cell. 2013;153:139–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Kioi M, Vogel H, Schultz G, et al. Inhibition of vasculogenesis, but not angiogenesis, prevents the recurrence of glioblastoma after irradiation in mice. J Clin Invest. 2010;120:694–705.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Horsman MR, Overgaard J. The oxygen effect and tumor microenvironment. In: Steel G, editor. Basic clinical radiobiology. London: Arnold; 2002. p. 158–68.

    Google Scholar 

  40. Persano L, Rampazzo E, Della Puppa A, Pistollato F, et al. The three-layer concentric model of glioblastoma: cancer stem cells, microenvironmental regulation, and therapeutic implications. Scientific World Journal. 2011;11:1829–41.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Shiao SL, Ganesan AP, Rugo HS, Coussens LM. Immune microenvironments in solid tumors: new targets for therapy. Genes Dev. 2011;25:2559–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Hanahan D, Coussens LM. Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell. 2012;21:309–402.

    Article  CAS  PubMed  Google Scholar 

  43. Yang L, Lin C, Wang L, Guo H, et al. Hypoxia and hypoxia-inducible factors in glioblastoma multiforme progression and therapeutic implications. Exp Cell Res. 2012;318:2417–26.

    Article  CAS  PubMed  Google Scholar 

  44. Sandberg CJ, Altschuler G, Jeong J, et al. Comparison of glioma stem cells to neural stem cells from the adult human brain identifies dysregulated Wnt-signaling and a fingerprint associated with clinical outcome. Exp Cell Res. 2013;319:2230–43.

    Article  CAS  PubMed  Google Scholar 

  45. Rossi M, Magnoni L, Miracco C, et al. β-catenin and Gli1 are prognostic markers in glioblastoma. Cancer Biol Ther. 2011;11:1–9.

    Article  Google Scholar 

  46. Bütof R, Dubrowska A, Baumann N. Clinical perspectives of cancer stem cell research in radiation oncology. Radiother Oncol. 2013;108:388–96.

    Article  PubMed  Google Scholar 

  47. Chaudry MA, Omaruddin RA. Different DNA methylation alterations in radiation-sensitive and -resistant cells. DNA Cell Biol. 2012;31:657–63.

    Google Scholar 

  48. Kim J-G, Park M-T, Heo K, et al. Epigenetics meets radiation biology as a new approach in cancer treatment. Int J Mol Sci. 2013;14:45059–73.

    Google Scholar 

  49. Dawson MA, Kouzarides T. Cancer epigenetics: from mechanism to therapy. Cell. 2012;150:12–27.

    Article  CAS  PubMed  Google Scholar 

  50. Hegi ME, Diserens AC, Gorlia T, et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med. 2005;352:997–1003.

    Article  CAS  PubMed  Google Scholar 

  51. Olson R, Brastianos PK, Palma DA. Prognostic and predictive value of epigenetic silencing of MGMT in patients with high grade gliomas: a systematic review and meta-analysis. J Neuroncolol. 2011;105:325–35.

    Article  Google Scholar 

  52. Van Vlodrop IJ, Niessen HE, Derks S, et al. Analysis of promoter CpG island hypermethylation in cancer: location, location, location! Clin Cancer Res. 2011;17:4225–31.

    Article  PubMed  Google Scholar 

  53. Van Nifterik KA, Van den Berg J, Slotman BJ, et al. Valproic acid sensitizes human glioma cells for temozolomide and γ-radiation. J NeuroOncol. 2012;107:61–7.

    Article  CAS  PubMed  Google Scholar 

  54. Chen CH, Chang YJ, Ku MS, et al. Enhancement of temozolomide-induced apoptosis by valproic acid in human glioma cell lines through redox regulation. J Mol Med (Berl). 2011;89:303–15.

    Article  CAS  Google Scholar 

  55. Weller M, Gorlia T, Cairncross JG, et al. Prolonged survival with valproic acid use in the EORTC/NCIC temozolomide trial for glioblastoma. Neurology. 2011;77:1156–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Hara T, Omura-Minamisawa M, Kang Y, et al. Flavopiridol potentiates the cytotoxic effects of radiation in radioresistant tumor cells in which p53 is mutated or Bcl-2 is overexpressed. Int J Radiat Oncol Biol Phys. 2008;71:1485–95.

    Article  CAS  PubMed  Google Scholar 

  57. Chen G, Zhu W, Shi D, et al. MicroRNA-181a sensitizes human malignant glioma U87MG cells to radiation by targeting Bcl-2. Oncol Rep. 2010;23:997–1003.

    CAS  PubMed  Google Scholar 

  58. Li Y, Zhao S, Zhen Y, Li Q, et al. A miR-21 inhibitor enhances apoptosis and reduces G(2)-M accumulation induced by ionizing radiation in human glioblastoma U251 cells. Brain Tumor Pathol. 2011;28:209–14.

    Article  PubMed  Google Scholar 

  59. Chao TF, Xiong HH, Liu W, et al. MiR-21 mediates the radiation resistance of glioblastoma cells by regulating PDCD4 and hMSH2. J Huazhong Univ SciTechnol Med Sci. 2013;33:525–9.

    Article  CAS  Google Scholar 

  60. Carlsson SK, Brothers SP, Wahlestedt C. Emerging treatment strategies for glioblastoma multiforme. EMBO Mol Med. 2014;6:1359–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Thomas AA, Ernstoff MS, Fadul CE. Immunotherapy for the treatment of glioblastoma. Cancer J. 2012;18:59–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Wilson TA, Karajannis MA, Harter DH. Glioblastoma multiforme: state of the art and future therapeutics. Surg Neurol Int. 2014;5:64. doi:10.4103/2152-7806.132138.

    Article  PubMed  PubMed Central  Google Scholar 

  63. Veliz I, Loo Y, Castillo O, et al. Advances and challenges in the molecular biology and treatment of glioblastoma—is there any hope for the future. Ann Transl Med. 2015;3(1):7. doi:10.3978/j.issn.2305-5839-2014.10.06.

    PubMed  PubMed Central  Google Scholar 

  64. Weeke E. The development of lymphopenia in uremic patients undergoing extracorporeal irradiation of the blood with portable beta units. Radiat Res. 1973;56:554–9.

    Article  CAS  PubMed  Google Scholar 

  65. Belcaid Z, Phallen JA, Zeng J, et al. Focal radiation therapy combined with 4-1BB activation and CTLa-4 blockade yields long-term survival and a protective antigen-specific memory response in a murine glioma model. PLos One. 2014;9:e101764. doi:10.1371/journal.pone.0101764.

    Google Scholar 

  66. Zitvogel L, Kroemer G. Targeting PD-1/PD-L1 interactions for cancer immunotherapy. Oncoimmunology. 2012;1:1223–5.

    Article  PubMed  PubMed Central  Google Scholar 

  67. Shindo Y, Yoshimura K, Kuramasu A, et al. Combination immunotherapy with 4-1BB activation and PD-1 blockade enhances antitumor efficacy in a mouse model of subcutaneous tumor. Anticancer Res. 2015;35:129–36.

    CAS  PubMed  Google Scholar 

  68. Sampson JH, Archer GE, Mitchell DA, et al. An epidermal growth factor receptor variant III-targeted vaccine is safe and immunogenic in patients with glioblastoma multiforme. Mol Cancer Ther. 2009;8:2773–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Sampson JH, Heimberger AB, Archer GE, Aldape KD, Friedman AH, Friedman HS, et al. Immunologic escape after prolonged progression-free survival with epidermal growth factor receptor variant III peptide vaccination in patients with newly diagnosed glioblastoma. J Clin Oncol. 2010;28:4722–9.

    Article  PubMed  PubMed Central  Google Scholar 

  70. Schuster J, Lai RK, Recht LD, et al. A phase II, multicenter trial of rindopepimut (CDX-110) in newly diagnosed glioblastoma: the ACT III study. Neuro Oncol. 2015;17:854–61.

    Article  PubMed  PubMed Central  Google Scholar 

  71. Rosenschöld PMA, Engelholm S, Ohlhues L, et al. Photon and proton therapy planning comparison for malignant glioma based on CT, FDG-PET, DTI-MRI and fiber tracking. Acta Oncol. 2011;50:777–83.

    Article  Google Scholar 

  72. Garcia-Barros M, Paris F, Cordon-Cardo C, et al. Tumor response to radiotherapy regulated by endothelial cell apoptosis. Science. 2003;300:1155–9.

    Article  CAS  PubMed  Google Scholar 

  73. Yamada Y, Bilsky MH, Lovelock DM, et al. High-dose, single-fraction image-guided intensity-modulated radiotherapy for metastatic spinal lesions. Int J Radiat Oncol Biol Phys. 2008;71:484–90.

    Article  PubMed  Google Scholar 

  74. Kondo T. Radiation-induced cell-death and its mechanisms. Rad Emergency Med. 2013;2:1–14.

    Google Scholar 

  75. Finkelstein SE, Timmermann R, McBride WH, et al. The confluence of stereotactic ablative radiotherapy and tumor immunology. Clin Dev Immunol. 2011;2011:439752. doi:10.1155/2011/439752.

    Article  PubMed  PubMed Central  Google Scholar 

  76. Srikrishna G, Freeze HH. Endogenous damage-associated molecular pattern molecules at the crossroads of inflammation and cancer. Neoplasia. 2009;11:615–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Durante M, Reppingen N, Held KD. Immunologically augmented cancer treatment using modern radiotherapy. Trends Mol Med. 2013;19:565–82.

    Article  CAS  PubMed  Google Scholar 

  78. Park B, Yee C, Lee K-M. The effect of radiation on the immune response to cancers. Int J Mol Sci. 2014;15:927–43.

    Article  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Tuscany Tumor Institute, Florence, Italy

    Luigi Pirtoli

  2. Unit of Radiation Oncology, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy

    Luigi Pirtoli

  3. Department of Radiological, Oncological, and Anatomo-Pathological Sciences, University of Rome “La Sapienza”, Rome, Italy

    Giovanni Luca Gravina

  4. Sbarro Institute for Cancer Research and Molecular Medicine and Center for Biotechnology, Temple University, Philadelphia, PA, USA

    Antonio Giordano

  5. Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy

    Antonio Giordano

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  1. Luigi Pirtoli
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  2. Giovanni Luca Gravina
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  3. Antonio Giordano
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Correspondence to Luigi Pirtoli .

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Editors and Affiliations

  1. University of Siena, Sec. of Radiation Oncology,Dept. of Med., Siena, Italy

    Luigi Pirtoli

  2. Dept. of Applied Clinical & Biotech Sci., University of L’Aquila, L’Aquila, Italy

    Giovanni Luca Gravina

  3. Department of Biology, Temple University, Philadelphia, Pennsylvania, USA

    Antonio Giordano

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Pirtoli, L., Gravina, G.L., Giordano, A. (2016). Introduction and Background. In: Pirtoli, L., Gravina, G., Giordano, A. (eds) Radiobiology of Glioblastoma. Current Clinical Pathology. Humana Press, Cham. https://doi.org/10.1007/978-3-319-28305-0_1

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