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Radiobiological Hints from Clinical Studies

  • Silvia ScocciantiEmail author
  • Riccardo Santoni
  • Beatrice Detti
  • Gianluca Ingrosso
  • Daniela Greto
  • Giulio Francolini
Chapter
  • 612 Downloads
Part of the Current Clinical Pathology book series (CCPATH)

Abstract

An overview of the clinical series assessing the efficacy of the most important targeted agents when used together with radiotherapy against glioblastoma is herein provided.

Keywords

mTOR Inhibitor Tuberous Sclerosis Complex Methylated MGMT Promoter Recurrent Glioblastoma Integrin Antagonist 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. 1.
    Debus J, Abdollahi A. For the next trick: new discoveries in radiobiology applied to glioblastoma. Am Soc Clin Oncol Educ Book. 2014:e95–9. doi:  10.14694/EdBook_AM.2014.34.e95.Google Scholar
  2. 2.
    Gutin PH, Iwamoto FM, Beal K, Mohile NA, Karimi S, Hou BL, et al. Safety and efficacy of bevacizumab with hypofractionated stereotactic irradiation for recurrent malignant gliomas. Int J Radiat Oncol Biol Phys. 2009;75(1):156–63.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Cuneo KC, Vredenburgh JJ, Sampson JH, Reardon DA, Desjardins A, Peters KB, et al. Safety and efficacy of stereotactic radiosurgery and adjuvant bevacizumab in patients with recurrent malignant gliomas. Int J Radiat Oncol Biol Phys. 2012;82(5):2018–24.CrossRefPubMedGoogle Scholar
  4. 4.
    Shapiro LQ, Beal K, Goenka A, Karimi S, Iwamoto FM, Yamada Y, et al. Patterns of failure after concurrent bevacizumab and hypofractionated stereotactic radiation therapy for recurrent high-grade glioma. Int J Radiat Oncol Biol Phys. 2013;85(3):636–42.CrossRefPubMedGoogle Scholar
  5. 5.
    Niyazi M, Ganswindt U, Schwarz SB, Kreth FW, Tonn JC, Geisler J, et al. Irradiation and bevacizumab in high-grade glioma retreatment settings. Int J Radiat Oncol Biol Phys. 2012;82(1):67–76.CrossRefPubMedGoogle Scholar
  6. 6.
    Flieger M, Ganswindt U, Schwarz SB, Kreth FW, Tonn JC, la Fougère C, et al. Re-irradiation and bevacizumab in recurrent high-grade glioma: an effective treatment option. J Neurooncol. 2014;117(2):337–45.CrossRefPubMedGoogle Scholar
  7. 7.
    Hundsberger T, Brügge D, Putora PM, Weder P, Weber J, Plasswilm L. Re-irradiation with and without bevacizumab as salvage therapy for recurrent or progressive high-grade gliomas. J Neurooncol. 2013;112(1):133–9.CrossRefPubMedGoogle Scholar
  8. 8.
    Cabrera AR, Cuneo KC, Desjardins A, Sampson JH, McSherry F, Herndon 2nd JE, et al. Concurrent stereotactic radiosurgery and bevacizumab in recurrent malignant gliomas: a prospective trial. Int J Radiat Oncol Biol Phys. 2013;86(5):873–9.CrossRefPubMedGoogle Scholar
  9. 9.
    Gilbert MR, Dignam JJ, Armstrong TS, Wefel JS, Blumenthal DT, Vogelbaum MA. A randomized trial of bevacizumab for newly diagnosed glioblastoma. N Engl J Med. 2014;370(8):699–708.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Chinot OL, Wick W, Mason W, Henriksson R, Saran F, Nishikawa R. Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma. N Engl J Med. 2014;370(8):709–22.CrossRefPubMedGoogle Scholar
  11. 11.
    di Tomaso E, Snuderl M, Kamoun WS, Duda DG, Auluck PK. Fazlollahi glioblastoma recurrence after cediranib therapy in patients: lack of “rebound” revascularization as mode of escape. Cancer Res. 2011;71(1):19–28.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Kioi M, Vogel H, Schultz G, Hoffman RM, Harsh GR, Brown JM. Inhibition of vasculogenesis, but not angiogenesis, prevents the recurrence of glioblastoma after irradiation in mice. J Clin Invest. 2010;120(3):694–705.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Kozin SV, Kamoun WS, Huang Y, Dawson MR, Jain RK, Duda DG. Recruitment of myeloid but not endothelial precursor cells facilitates tumor regrowth after local irradiation. Cancer Res. 2010;70(14):5679–85.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Lu-Emerson C, Snuderl M, Kirkpatrick ND, Goveia J, Davidson C, Huang Y, et al. Increase in tumor-associated macrophages after antiangiogenic therapy is associated with poor survival among patients with recurrent glioblastoma. Neuro Oncol. 2013;15(8):1079–87.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Lund-Johansen M, Bjerkvig R, Humphrey PA, Bigner SH, Bigner DD, Laerum OD. Effect of epidermal growth factor on glioma cell growth, migration, and invasion in vitro. Cancer Res. 1990;50(18):6039–44.PubMedGoogle Scholar
  16. 16.
    Shinojima N, Tada K, Shiraishi S, Kamiryo T, Kochi M, Nakamura H, et al. Prognostic value of epidermal growth factor receptor in patients with glioblastoma multiforme. Cancer Res. 2003;63(20):6962–70.PubMedGoogle Scholar
  17. 17.
    Watanabe K, Tachibana O, Sata K, Yonekawa Y, Kleihues P, Ohgaki H. Overexpression of the EGF receptor and p53 mutations are mutually exclusive in the evolution of primary and secondary glioblastomas. Brain Pathol. 1996;6(3):217–23.CrossRefPubMedGoogle Scholar
  18. 18.
    Barker FG, Simmons ML, Chang SM, Prados MD, Larson DA, Sneed PK, et al. EGFR overexpression and radiation response in glioblastoma multiforme. Int J Radiat Oncol Biol Phys. 2001;51(2):410–8.CrossRefPubMedGoogle Scholar
  19. 19.
    Chakravarti A, Chakladar A, Delaney MA, Latham DE, Loeffler JS. The epidermal growth factor receptor pathway mediates resistance to sequential administration of radiation and chemotherapy in primary human glioblastoma cells in a RAS-dependent manner. Cancer Res. 2002;62(15):4307–15.PubMedGoogle Scholar
  20. 20.
    Halatsch ME, Gehrke EE, Vougioukas VI, Bötefür IC, A-Borhani F, Efferth T. Inverse correlation of epidermal growth factor receptor messenger RNA induction and suppression of anchorage-independent growth by OSI-774, an epidermal growth factor receptor tyrosine kinase inhibitor, in glioblastoma multiforme cell lines. J Neurosurg. 2004;100(3):523–33.CrossRefPubMedGoogle Scholar
  21. 21.
    Prados MD, Lamborn KR, Chang S, Burton E, Butowski N, Malec M. Phase 1 study of erlotinib HCl alone and combined with temozolomide in patients with stable or recurrent malignant glioma. Neuro Oncol. 2006;8(1):67–78.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Vogelbaum MA, Peereboom D, Stevens G, Barnett GH, Brewer C. Response rate to single agent therapy with the EGFR tyrosine kinase inhibitor erlotinib in recurrent glioblastoma multiforme: results of a phase II study. Proceedings of the ninth meeting of the society for neuro-oncology 2004;384.Google Scholar
  23. 23.
    Prados MD, Chang SM, Butowski N, DeBoer R, Parvataneni R, Carliner H, et al. Phase II study of erlotinib plus temozolomide during and after radiation therapy in patients with newly diagnosed glioblastoma multiforme or gliosarcoma. J Clin Oncol. 2009;27(4):579–84.CrossRefPubMedGoogle Scholar
  24. 24.
    Peereboom DM, Shepard DR, Ahluwalia MS, Brewer CJ, Agarwal N, Stevens GH, et al. Phase II trial of erlotinib with temozolomide and radiation in patients with newly diagnosed glioblastoma multiforme. J Neurooncol. 2010;98(1):93–9.CrossRefPubMedGoogle Scholar
  25. 25.
    Chakravarti A, Wang M, Robins HI, Lautenschlaeger T, Curran WJ, Brachman DG, 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.CrossRefPubMedGoogle Scholar
  26. 26.
    Belda-Iniesta C, Carpeño Jde C, Saenz EC, Gutiérrez M, Perona R, Barón MG. Long term responses with cetuximab therapy in glioblastoma multiforme. Cancer Biol Ther. 2006;5(8):912–4.CrossRefPubMedGoogle Scholar
  27. 27.
    Neyns B, Sadones J, Joosens E, Bouttens F, Verbeke L, Baurain JF, et al. Stratified phase II trial of cetuximab in patients with recurrent high-grade glioma. Ann Oncol. 2009;20(9):1596–603.CrossRefPubMedGoogle Scholar
  28. 28.
    Combs SE, Schulz-Ertner D, Hartmann C, Welzel T, Timke C, Herfarth KK, et al. Erbitux (Cetuximab) plus temozolomide as radiochemotherapy for primary glioblastoma (GERT): interim results of a phase I/II study. Int J Radiat Oncol Biol Phys. 2008;72(1S):S10–1.CrossRefGoogle Scholar
  29. 29.
    Wang Y, Pan L, Sheng XF, Chen S, Dai JZ. Nimotuzumab, a humanized monoclonal antibody specific for the EGFR, in combination with temozolomide and radiation therapy for newly diagnosed glioblastoma multiforme: first results in Chinese patients. Asia Pac J Clin Oncol. 2014. doi: 10.1111/ajco.12166.Google Scholar
  30. 30.
    Solomon MT, Miranda N, Jorrín E, Chon I, Marinello JJ, Alert J, et al. Nimotuzumab in combination with radiotherapy in high grade glioma patients: a single institution experience. Cancer Biol Ther. 2014;15(5):504–9.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Westphal M, Bach F. Final results of a randomized phase III trial of nimotuzumab for the treatment of newly diagnosed glioblastoma in addition to standard radiation and chemotherapy with temozolomide versus standard radiation and temoziolamide. J Clin Oncol 30, 2012, suppl abstr 2033,Google Scholar
  32. 32.
    Jänne PA, Gurubhagavatula S, Yeap BY, Lucca J, Ostler P, Skarin AT, et al. Outcomes of patients with advanced non-small cell lung cancer treated with gefitinib (ZD1839, “iressa”) on an expanded access study. Lung Cancer. 2004;44(2):221–30.CrossRefPubMedGoogle Scholar
  33. 33.
    Cappuzzo F, Hirsch FR, Rossi E, Bartolini S, Ceresoli GL, Bemis L, et al. Epidermal growth factor receptor gene and protein and gefitinib sensitivity in non-small-cell lung cancer. J Natl Cancer Inst. 2005;97(9):643–55.CrossRefPubMedGoogle Scholar
  34. 34.
    Han SW, Kim TY, Jeon YK, Hwang PG, Im SA, Lee KH, et al. Optimization of patient selection for gefitinib in non-small cell lung cancer by combined analysis of epidermal growth factor receptor mutation, K-ras mutation, and Akt phosphorylation. Clin Cancer Res. 2006;12(8):2538–44.CrossRefPubMedGoogle Scholar
  35. 35.
    Rich JN, Reardon DA, Peery T, Dowell JM, Quinn JA, Penne KL, et al. Phase II trial of gefitinib in recurrent glioblastoma. J Clin Oncol. 2004;22(1):133–42.CrossRefPubMedGoogle Scholar
  36. 36.
    Franceschi E, Cavallo G, Lonardi S, Magrini E, Tosoni A, Grosso D, et al. Gefitinib in patients with progressive high-grade gliomas: a multicentre phase II study by Gruppo Italiano Cooperativo di Neuro-Oncologia (GICNO). Br J Cancer. 2007;96(7):1047–51.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Gallego O, Cuatrecasas M, Benavides M, Segura PP, Berrocal A, Erill N, et al. Efficacy of erlotinib in patients with relapsed gliobastoma multiforme who expressed EGFRVIII and PTEN determined by immunohistochemistry. J Neurooncol. 2014;116(2):413–9.CrossRefPubMedGoogle Scholar
  38. 38.
    van den Bent MJ, Brandes AA, Rampling R, Kouwenhoven MC, Kros JM, Carpentier AF, et al. Randomized phase II trial of erlotinib versus temozolomide or carmustine in recurrent glioblastoma: EORTC brain tumor group study 26034. J Clin Oncol. 2009;27(8):1268–74.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Stupack DG, Puente XS, Boutsaboualoy S, Storgard CM, Cheresh DA. Apoptosis of adherent cells by recruitment of caspase-8 to unligated integrins. J Cell Biol. 2001;155(3):459–70.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Ruegg C, Mariotti A. Vascular integrins: pleiotropic adhesion and signaling molecules in vascular homeostasis and angiogenesis. Cell Mol Life Sci. 2003;60(6):1135–57.PubMedGoogle Scholar
  41. 41.
    Avraamides CJ, Garmy-Susini B, Varner JA. Integrins in angiogenesis and lymphangiogenesis. Nat Rev Cancer. 2008;8(8):604–17.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Alghisi GC, Ruegg C. Vascular integrins in tumor angiogenesis: mediators and therapeutic targets. Endothelium. 2006;13(2):113–35.CrossRefPubMedGoogle Scholar
  43. 43.
    Schnell O, Krebs B, Wagner E, Romagna A, Beer AJ, Grau SJ, et al. Expression of integrin alphavbeta3 in gliomas correlates with tumor grade and is not restricted to tumor vasculature. Brain Pathol. 2008;18(3):378–86.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Taga T, Suzuki A, Gonzalez-Gomez I, Gilles FH, Stins M, Shimada H, et al. Alpha vintegrin antagonist emd 121974 induces apoptosis in brain tumor cells growing on vitronectin and tenascin. Int J Cancer. 2002;98(5):690–7.CrossRefPubMedGoogle Scholar
  45. 45.
    Bello L, Francolini M, Marthyn P, Zhang J, Carroll RS, Nikas DC, et al. Alpha(v) beta3 and alpha(v)beta5 integrin expression in glioma periphery. Neurosurgery. 2001;49(2):380–9.PubMedGoogle Scholar
  46. 46.
    Ruegg C, Alghisi GC. Vascular integrins: therapeutic and imaging targets of tumor angiogenesis. Recent Results Cancer Res. 2010;180:83–101.CrossRefPubMedGoogle Scholar
  47. 47.
    Wild-Bode C, Weller M, Rimner A, Dichgans J, Wick W. Sublethal irradiation promotes migration and invasiveness of glioma cells: implications for radiotherapy of human glioblastoma. Cancer Res. 2001;61(6):2744–50.PubMedGoogle Scholar
  48. 48.
    Mikkelsen T, Brodie C, Finniss S, Berens ME, Rennert JL, Nelson K, et al. Radiation sensitization of glioblastoma by cilengitide has unanticipated schedule-dependency. Int J Cancer. 2009;124(11):2719–27.CrossRefPubMedGoogle Scholar
  49. 49.
    Abdollahi A, Griggs DW, Zieher H, Roth A, Lipson KE, Saffrich R, et al. Inhibition of alpha(v) beta3 integrin survival signaling enhances antiangiogenic and antitumor effects of radiotherapy. Clin Cancer Res. 2005;11:6270–9.CrossRefPubMedGoogle Scholar
  50. 50.
    Xiong JP, Stehle T, Zhang R, Joachimiak A, Frech M, Goodman SL, et al. Crystal structure of the extracellular segment of integrin alphaVbeta3 in complex with an arg-gly-asp ligand. Science. 2002;296(5565):151–5.CrossRefPubMedGoogle Scholar
  51. 51.
    Goodman SL, Hölzemann G, Sulyok GA, Kessler H. Nanomolar small molecule inhibitors for alphaV(beta)6, alphaV (beta)5, and alphaV(beta)3 integrins. J Med Chem. 2002;45(5):1045–51.CrossRefPubMedGoogle Scholar
  52. 52.
    Nisato RE, Tille JC, Jonczyk A, Goodman SL, Pepper MS. AlphaV beta 3 and alphav beta 5 integrin antagonists inhibit angiogenesis in vitro. Angiogenesis. 2003;6(2):105–19.CrossRefPubMedGoogle Scholar
  53. 53.
    Nabors B, Mikkelsen T, Rosenfeld S, Hochberg F, Shastry Akella N, Fisher J, et al. A phase I and correlative biology study of cilengitide in patients with recurrent malignant glioma. J Clin Oncol. 2007;25(13):1651–7.CrossRefPubMedGoogle Scholar
  54. 54.
    MacDonald TJ, Stewart CF, Kocak M, Goldman S, Ellenbogen RG, Phillips P, et al. Phase I clinical trial of cilengitide in children with refractory brain tumors: pediatric brain tumor consortium study pbtc-012. J Clin Oncol. 2008;26(6):919–24.CrossRefPubMedGoogle Scholar
  55. 55.
    Reardon DA, Fink KL, Mikkelsen T, Cloughesy TF, O’Neill A, Plotkin S, et al. Randomized phase II study of cilengitide, an integrin-targeting arginine-glycine-aspartic acid peptide, in recurrent glioblastoma multiforme. J Clin Oncol. 2008;26(34):5610–7.CrossRefPubMedGoogle Scholar
  56. 56.
    Fink N, Mikkelsen T, Nabors LB, Ravin P, Plotkin SR, Schiff D, et al. Long-term effects of cilengitide, a novel integrin inhibitor, in recurrent glioblastoma: a randomized phase II study. J Clin Oncol 2010;28(suppl; abstr, 2010).Google Scholar
  57. 57.
    Gilbert MR, Kuhn J, Lamborn KR, Lieberman F, Wen PY, Mehta M, et al. Cilengitide in patients with recurrent glioblastoma: the results of NABTC 03-02, a phase II trial with measures of treatment delivery. J Neurooncol. 2012;106(1):147–53.CrossRefPubMedGoogle Scholar
  58. 58.
    Nabors L, NABTT 0306: A randomized phase II trial of EMD 121974 in conjunction with concomitant and adjuvant temozolomide with radiation therapy in patients with newly diagnosed glioblastoma multiforme (GBM). Proc Am Soc Clin Oncol, J Clin Oncol 2009.Google Scholar
  59. 59.
    Stupp R, Hegi ME, Neyns B, Goldbrunner R, Schlegel U, Clement PM, et al. Phase I/IIa study of cilengitide and temozolomide with concomitant radiotherapy followed by cilengitide and temozolomide maintenance therapy in patients with newly diagnosed glioblastoma. J Clin Oncol. 2010;28(16):2712–8.CrossRefPubMedGoogle Scholar
  60. 60.
    Stupp R, Hegi ME, Gorlia T, Erridge SC, Perry J, Hong YK, et al. Cilengitide combined with standard treatment for patients with newly diagnosed glioblastoma with methylated MGMT promoter (CENTRIC EORTC 26071-22072 study): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2014;15(10):1100–8.CrossRefPubMedGoogle Scholar
  61. 61.
    Chinot O. Cilengitide in glioblastoma: when did it fail? Lancet Oncol. 2014;15(10):1044–5.CrossRefPubMedGoogle Scholar
  62. 62.
    Reynolds AR, Hart IR, Watson AR, Welti JC, Silva RG, Robinson SD, et al. Stimulation of tumour growth and angiogenesis by low concentrations of RGD-mimetic integrin inhibitors. Nat Med. 2009;15:392–400.CrossRefPubMedGoogle Scholar
  63. 63.
    Nabors LB, Mikkelsen T, Hegi ME, Batchelor T, Lesser G, Peereboom D, et al. A safety run-in and randomized phase 2 study of cilengitide combined with chemoradiation for newly diagnosed glioblastoma (NABTT 0306). Cancer. 2012;118:5601–7.CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Okada H, Mak TW. Pathways of apoptotic and non-apoptotic death in tumour cells. Nat Rev Cancer. 2004;4:592–603.CrossRefPubMedGoogle Scholar
  65. 65.
    McCubrey JA, Steelman LS, Abrams SL, Lee JT, Chang F, Bertrand FE, et al. Roles of the RAF/MEK/ERK and PI3K/PTEN/AKT pathways in malignant transformation and drug resistance. Adv Enzyme Regul. 2006;46:249–79.CrossRefPubMedGoogle Scholar
  66. 66.
    Hay N, Sonenberg N. Upstream and downstream of mTOR. Genes Dev. 2004;18:1926–45.CrossRefPubMedGoogle Scholar
  67. 67.
    Cancer Genome Atlas Research Network. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature. 2008;455:1061–8.CrossRefGoogle Scholar
  68. 68.
    Eshleman JS, Carlson BL, Mladek AC, Kastner BD, Shide KL, Sarkaria JN. Inhibition of the mammalian target of rapamycin sensitizes U87 xenografts to fractionated radiation therapy. Cancer Res. 2002;62(24):7291–7.PubMedGoogle Scholar
  69. 69.
    Anandharaj A, Cinghu S, Park WY. Rapamycin-mediated mTOR inhibition attenuates surviving and sensitizes glioblastoma cells to radiation therapy. Acta Biochim Biophys Sin (Shangai). 2011;43(4):292–300.CrossRefGoogle Scholar
  70. 70.
    Kim KW, Mutter RW, Cao C, Albert JM, Freeman M, Hallahan DE, et al. Autophagy for cancer therapy through inhibition of pro-apoptotic proteins and mammalian target of rapamycin signaling. J Biol Chem. 2006;281(48):36883–90.CrossRefPubMedGoogle Scholar
  71. 71.
    Shinohara ET, Cao C, Niermann K, Mu Y, Zeng F, Hallahan DE, et al. Enhanced radiation damage of tumor vasculature by mTOR inhibitors. Oncogene. 2005;24(35):5414–22.CrossRefPubMedGoogle Scholar
  72. 72.
    Seghal SN, Baker H, Vézina C. Rapamycin (AY-22,989), a new antifungal antibiotic. II. Fermentation, isolation and characterization. J Antibiot. 1975;28:727–32.CrossRefGoogle Scholar
  73. 73.
    Faivre S, Kroemer G, Raymond E. Current development of mTOR inhibitors as anticancer agents. Nat Rev Drug Discov. 2006;5:671–88.CrossRefPubMedGoogle Scholar
  74. 74.
    Sarkaria JN, Galanis E, Wu W, Dietz AB, Kaufmann TJ, Gustafson MP, et al. Combination of temsirolimus (CCI-779) with chemoradiation in newly diagnosed glioblastoma multiforme (NCCTG trial N027D) is associated with increased infectious risk. Clin Cancer Res. 2010;16(22):5573–80.CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Sarkaria JN, Galanis E, Wu W, Peller PJ, Giannini C, Brown PD, et al. North Central Treatment Group phase I trial N057K of everolimus (RAD001) and temozolomide in combination with radiation therapy in patients with newly diagnosed glioblastoma multiforme. Int J Radiat Oncol Biol Phys. 2011;81(2):468–75.CrossRefPubMedGoogle Scholar
  76. 76.
    Chang SM, Wen P, Cloughesy T, Greenberg H, Schiff D, Conrad C, et al. Phase II study of CCI-779 in patients with recurrent glioblastoma multiforme. Invest New Drugs. 2005;23:357–61.CrossRefPubMedGoogle Scholar
  77. 77.
    Galanis E, Buckner JC, Maurer MJ, Kreisberg JI, Ballman K, Boni J, 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.CrossRefPubMedGoogle Scholar
  78. 78.
    Reardon DA, Vredenburgh JJ, Desjardins A, Peters K, Gururangan S, Sampson JH, et al. Effect of CYP3A-inducing antiepileptics on sorafenib exposure: results of a phase II study of sorafenib plus daily temozolomide in adults with recurrent glioblastoma. J Neurooncol. 2011;101:57–66.CrossRefPubMedGoogle Scholar
  79. 79.
    Kreisl TN, Lassman AB, Mischel PS, Rosen N, Scher HI, Teruya-Feldstein J, et al. A pilot study of everolimus and gefitinib in the treatment of recurrent glioblastoma (GBM). J Neurooncol. 2009;92:99–105.CrossRefPubMedGoogle Scholar
  80. 80.
    Martelli AM, Chiarini E, Evangelisti C, Cappellini A, Buontempo F, Bressanin D, et al. Two hits are better than one: targeting both phosphatidylinositol 3-kinase and mammalian target of rapamycin as a therapeutic strategy for acute leukemia treatment. Oncotarget. 2012;3:371–94.CrossRefPubMedPubMedCentralGoogle Scholar
  81. 81.
    Jackson SP, Bartek J. The DNA-damage response in human biology and disease. Nature. 2009;462:1071–8.CrossRefGoogle Scholar
  82. 82.
    Shiloh Y, Ziv Y. The ATM protein kinase: regulating the cellular response to genotoxic stress, and more. Nat Rev Mol Cell Biol. 2013;14:197–210.CrossRefGoogle Scholar
  83. 83.
    Wang C, Lees-Miller SP. Detection and repair of ionizing radiation-induced DNA double strand breaks: new developments in nonhomologous end joining. Int J Radiat Oncol Biol Phys. 2013;86:440–9.CrossRefPubMedPubMedCentralGoogle Scholar
  84. 84.
    Mukherjee B, Tomimatsu N, Amancherla K, Camacho CV, Pichamoorthy N, Burma S. The dual PI3K/mTOR inhibitor NVP-BEZ235 is a potent inhibitor of ATM- and DNA-PKcs-mediated DNA damage responses. Neoplasia. 2012;14:34–43.CrossRefPubMedPubMedCentralGoogle Scholar
  85. 85.
    Rodrigo C, del Alcazar G, Hardebeck MC, Mukherjee B, Tomimatsu N, Gao X, et al. Inhibition of DNA double-strand break repair by the dual PI3K/mTOR inhibitor NVP-BEZ235 as a strategy for radiosensitization of glioblastoma. Clin Cancer Res. 2013;20(5):1235–48.Google Scholar
  86. 86.
    Clarke JL, Molinaro AM, Phillips JJ, Butowski NA, Chang SM, Perry A, 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.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  • Silvia Scoccianti
    • 1
    Email author
  • Riccardo Santoni
    • 2
  • Beatrice Detti
    • 1
  • Gianluca Ingrosso
    • 2
  • Daniela Greto
    • 1
  • Giulio Francolini
    • 1
  1. 1.Radiation Oncology UnitAzienda Ospedaliero—Universitaria CareggiFlorenceItaly
  2. 2.Radiation Oncology UnitUniversity of Rome “Tor Vergata”RomeItaly

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