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Viral vector: potential therapeutic for glioblastoma multiforme



Glioblastoma multiforme is a highly malignant primary brain tumour found in adults and is highlighted as the most devastating among all the other grades of glioma. Well-established standard treatment methods, such as chemotherapy, radiation and surgery, have resulted in modest improvement in the survival of patients. Hence, the arduous search for novel treatments backed by advancements in molecular biology still persists. Glioblastoma has many distinctive characteristics, which makes it a potential candidate for gene therapy. Gene therapy involves the delivery of genetic material of therapeutic use into tumour cells, which produces a specific antitumour response. Moreover, viruses stimulate a vigorous cytotoxic effect, they are easily modifiable and the inherent property of horizontal transfer of genetic material makes them valuable tools for genetic engineering. In this review, we have enlisted the various viral vectors employed in gene therapy for glioblastoma.

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  1. 1.

    Jäkel S, Dimou L. Glial cells and their function in the adult brain: a journey through the history of their ablation. Front Cell Neurosci. 2017;11:1–17.

    Article  CAS  Google Scholar 

  2. 2.

    Louis DN, Perry A, Reifenberger G, von Deimling A, Figarella-Branger D, Cavenee WK et al. The 2016 World Health Organization classification of tumors of the central nervous system: a summary. Acta Neuropathol. 2016;131:803–20.

    PubMed  Article  Google Scholar 

  3. 3.

    Wu W, Lamborn KR, Buckner JC, Novotny PJ, Chang SM, O’Fallon JR, et al. Joint NCCTG and NABTC prognostic factors analysis for high-grade recurrent glioma. Neuro Oncol. 2010;12:164–72.

    CAS  PubMed  Article  Google Scholar 

  4. 4.

    Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, et al. The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol. 2007;114:97–109.

    PubMed  PubMed Central  Article  Google Scholar 

  5. 5.

    Wen PY, Reardon DA. Neuro-oncology in 2015: Progress in glioma diagnosis, classification and treatment. Nat Rev Neurol. 2016;12:69–70.

    CAS  PubMed  Article  Google Scholar 

  6. 6.

    Krakstad C, Chekenya M. Survival signalling and apoptosis resistance in glioblastomas: opportunities for targeted therapeutics. Mol Cancer. 2010;9:1–14.

    Article  CAS  Google Scholar 

  7. 7.

    Ostrom QT, Gittleman H, Farah P, Ondracek A, Chen Y, Wolinsky Y, et al. CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2006-2010. Neuro Oncol. 2013;15:ii1–56.

    PubMed  PubMed Central  Article  Google Scholar 

  8. 8.

    Tamimi AF, Juweid M. Epidemiology and outcome of glioblastoma. In: De Vleeschouwer S, editor. Glioblastoma [Internet]. Brisbane (AU): CodonPublications; 2017. Chapter 8. Available from:

    Google Scholar 

  9. 9.

    Bouwens TAM, Trouw LA, Veerhuis R, Dirven CMF, Lamfers MLM, Al-Khawaja H. Complement activation in glioblastoma multiforme pathophysiology: evidence from serum levels and presence of complement activation products in tumor tissue. J Neuroimmunol. 2015;278:271–6.

    CAS  PubMed  Article  Google Scholar 

  10. 10.

    Young JS, Chmura SJ, Wainwright DA, Yamini B, Peters KB, Lukas RV. Management of glioblastoma in elderly patients. J Neurol Sci. 2017;380:250–5.

    CAS  PubMed  Article  Google Scholar 

  11. 11.

    Heiland DH, Haaker G, Watzlawick R, Delev D, Masalha W, Franco P, et al. One decade of glioblastoma multiforme surgery in 342 elderly patients: what have we learned? J Neurooncol. 2018;140:385–91.

    PubMed  Article  Google Scholar 

  12. 12.

    Schmidinger M, Linzmayer L, Becherer A, Fazeny-Doerner B, Fakhrai N, Prayer D, et al. Psychometric- and quality-of-life assessment in long-term gliblastoma survivors. J Neurooncol. 2003;63:55–61.

    PubMed  Article  Google Scholar 

  13. 13.

    Kwiatkowska A, Nandhu M, Behera P, Chiocca E, Viapiano M. Strategies in gene therapy for glioblastoma. Cancers. 2013;5:1271–305.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  14. 14.

    Ohgaki H, Kleihues P. The definition of primary and secondary glioblastoma. Clin Cancer Res. 2013;19:764–72.

    PubMed  Article  CAS  Google Scholar 

  15. 15.

    The Cancer Genome Atlas Research Network, Hayden E, Atlas CG, Institutes USN, Vogelstein B, Cancer I, et al. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature. 2008;455:1061.

  16. 16.

    Ohgaki H, Kleihues P. Genetic pathways to primary and secondary glioblastoma. Am J Pathol. 2007;170:1445–53.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  17. 17.

    Killela PJ, Reitman ZJ, Jiao Y, Bettegowda C, Agrawal N, Diaz LA, et al. TERT promoter mutations occur frequently in gliomas and a subset of tumors derived from cells with low rates of self-renewal. Proc Natl Acad Sci USA. 2013;110:6021–6.

    CAS  PubMed  Article  Google Scholar 

  18. 18.

    Ohgaki H, Dessen P, Jourde B, Horstmann S, Nishikawa T, Di Patre PL, et al. Genetic pathways to glioblastoma: a population-based study. Cancer Res. 2004;64:6892–9.

    CAS  PubMed  Article  Google Scholar 

  19. 19.

    Ohgaki H, Kleihues P. Genetic alterations and signaling pathways in the evolution of gliomas. Cancer Sci. 2009;100:2235–41.

  20. 20.

    Ozdemir-Kaynak E, Qutub AA, Yesil-Celiktas O. Advances in glioblastoma multiforme treatment: new models for nanoparticle therapy. Front Physiol. 2018;9:170.

  21. 21.

    Davis ME. GBM treatment overview. Clin J Oncol Nurs. 2016;20:1–14.

    Article  Google Scholar 

  22. 22.

    Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–74.

    CAS  Article  Google Scholar 

  23. 23.

    Polivka J Jr, Janku F. Molecular targets for cancer therapy in the PI3K/AKT/mTOR pathway. Pharmacol Ther. 2014;142:164–75.

    CAS  Article  Google Scholar 

  24. 24.

    Kane JR, Miska J, Young JS, Kanojia D, Kim JW, Lesniak MS. Sui generis: gene therapy and delivery systems for the treatment of glioblastoma. Neuro Oncol. 2015;17:ii24–36.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  25. 25.

    Dixit K, Kumthekar P. Gene delivery in neuro-oncology. Curr Oncol Rep. 2017;19:69.

  26. 26.

    Murphy AM, Rabkin SD. Current status of gene therapy for brain tumors. Transl Res. 2013;161:339–54.

    CAS  PubMed  Article  Google Scholar 

  27. 27.

    Cross D, Burmester JK. Gene therapy for cancer treatment: past, present and future. Clin Med Res. 2006;4:218–27.

    CAS  Article  Google Scholar 

  28. 28.

    M Costa P. Viral and non-viral gene therapy for glioblastoma: new insights into the treatment of malignant brain tumors. J Genet Syndr Gene Ther. 2013;4:1–9.

  29. 29.

    Ram Z, Culver KW, Oshiro EM, Viola JJ, Devroom HL, Otto E, et al. Therapy of malignant brain tumors by intratumoral implantation of retroviral vector-producing cells. Nat Med. 1997;3:1354.

    CAS  PubMed  Article  Google Scholar 

  30. 30.

    Culver KW, Ram Z, Wallbridge S, Ishii H, Oldfield EH, Blaese RM. In vivo gene transfer with retroviral vector-producer cells for treatment of experimental brain tumors. Science. 1992;256:1550–2.

    CAS  PubMed  Article  Google Scholar 

  31. 31.

    Ostertag D, Amundson KK, Espinoza FL, Martin B, Buckley T, Da Silva APG, et al. Brain tumor eradication and prolonged survival from intratumoral conversion of 5-fluorocytosine to 5-fluorouracil using a nonlytic retroviral replicating vector. Neuro Oncol. 2012;14:145–59.

    CAS  PubMed  Article  Google Scholar 

  32. 32.

    Naldini L, Blömer U, Gallay P, Ory D, Mulligan R, Gage FH, et al. In vivo gene delivery and stable transduction of nondividing cells by a lentiviral vector. Science. 1996;272:263–7.

    CAS  PubMed  Article  Google Scholar 

  33. 33.

    Bukrinsky MI, Haffar OK. HIV-1 nuclear import: in search of a leader. Front Biosci. 1997;2:d578–87.

    CAS  PubMed  Article  Google Scholar 

  34. 34.

    Chang CJ, Hsu CC, Yung MC, Chen KY, Tzao C, Wu WF, et al. Enhanced radiosensitivity and radiation-induced apoptosis in glioma CD133-positive cells by knockdown of SirT1 expression. Biochem Biophys Res Commun. 2009;380:236–42.

    CAS  PubMed  Article  Google Scholar 

  35. 35.

    Cui Q, Yang S, Ye P, Tian E, Sun G, Zhou J, et al. Downregulation of TLX induces TET3 expression and inhibits glioblastoma stem cell self-renewal and tumorigenesis. Nat Commun. 2016;7:10637.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  36. 36.

    Sánchez-Hernández L, Hernández-Soto J, Vergara P, González RO, Segovia J. Additive effects of the combined expression of soluble forms of GAS1 and PTEN inhibiting glioblastoma growth. Gene Ther. 2018;25:439–49.

    PubMed  Article  CAS  Google Scholar 

  37. 37.

    Castro MG, Candolfi M, Wilson TJ, Calinescu A, Paran C, Kamran N, et al. Adenoviral vector-mediated gene therapy for gliomas: coming of age. Expert Opin Biol Ther. 2014;14:1241–57.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  38. 38.

    van Putten EH, Dirven CM, van den Bent MJ, Lamfers ML. Sitimagene ceradenovec: a gene-based drug for the treatment of operable high-grade glioma. Future Oncol. 2010;6:1691–710.

    CAS  PubMed  Article  Google Scholar 

  39. 39.

    Kurozumi K, Tamiya T, Ono Y, Otsuka S, Kambara H, Adachi Y, et al. Apoptosis induction with 5-fluorocytosine/cytosine deaminase gene therapy for human malignant glioma cells mediated by adenovirus. J Neurooncol. 2004;66:117–27.

    PubMed  Article  Google Scholar 

  40. 40.

    Candolfi M, Xiong W, Yagiz K, Liu C, Muhammad AKMG, Puntel M, et al. Gene therapy-mediated delivery of targeted cytotoxins for glioma therapeutics. Proc Natl Acad Sci. 2010;107:20021–6.

    CAS  PubMed  Article  Google Scholar 

  41. 41.

    Salem A, Farrokhi C, Lowenstein PR, Puntel M, Curtin JF, Bondale NS, et al. A novel bicistronic high-capacity gutless adenovirus vector that drives constitutive expression of herpes simplex virus type 1 thymidine kinase and tet-inducible expression of Flt3L for glioma therapeutics. J Virol. 2010;84:6007–17.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  42. 42.

    Ishida J, Kumon H, Oka T, Kurozumi K, Shimazu Y, Watanabe M, et al. Integrin antagonist augments the therapeutic effect of adenovirus-mediated REIC/Dkk-3 gene therapy for malignant glioma. Gene Ther. 2014;22:146–54.

    PubMed  Google Scholar 

  43. 43.

    Lakka SS, Rajan M, Gondi C, Yanamandra N, Chandrasekar N, Jasti SL, et al. Adenovirus-mediated expression of antisense MMP-9 in glioma cells inhibits tumor growth and invasion. Oncogene. 2002;21:8011.

    CAS  PubMed  Article  Google Scholar 

  44. 44.

    Kaliberov SA, Kaliberova LN, Yan H, Kapoor V, Hallahan DE. Retargeted adenoviruses for radiation-guided gene delivery. Cancer Gene Ther. 2016;23:303–14.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  45. 45.

    Atchison RW, Casto BC, Hammon WM. Adenovirus-associated defective virus particles. Science. 1965;149:754–6.

    CAS  PubMed  Article  Google Scholar 

  46. 46.

    Hoggan MD, Blacklow NR, Rowe WP. Studies of small DNA viruses found in various adenovirus preparations: physical, biological, andimmunological characteristics. Proc Natl Acad Sci USA. 1966;55:1467.

    CAS  Article  Google Scholar 

  47. 47.

    Rutledge EA, Halbert CL, Russell DW. Infectious clones and vectors derived from adeno-associated virus (AAV) serotypes other than AAV type 2. J Virol. 1998;72:309–19.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  48. 48.

    Gao G, Vandenberghe LH, Alvira MR, Lu Y, Calcedo R, Zhou X, et al. Clades of adeno-associated viruses are widely disseminated in human tissues. J Virol. 2004;78:6381–8.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  49. 49.

    Wu Z, Asokan A, Samulski RJ. Adeno-associated virus serotypes: vector toolkit for human gene therapy. Mol Ther. 2006;14:316–27.

    CAS  PubMed  Article  Google Scholar 

  50. 50.

    GuhaSarkar D, Neiswender J, Su Q, Gao G, Sena-Esteves M. Intracranial AAV-IFN-β gene therapy eliminates invasive xenograft glioblastoma and improves survival in orthotopic syngeneic murine model. Mol Oncol. 2017;11:180–93.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  51. 51.

    Zhang C, Yao T, Zheng Y, Li Z, Zhang Q, Zhang L, et al. Development of next generation adeno-associated viral vectors capable of selective tropism and efficient gene delivery. Biomaterials. 2016;80:134–45.

    PubMed  Article  CAS  Google Scholar 

  52. 52.

    Ma HI, Hueng DY, Shui HA, Han JM, Wang CH, Lai YH, et al. Intratumoral decorin gene delivery by AAV vector inhibits brain glioblastomas and prolongs survival of animals by inducing cell differentiation. Int J Mol Sci. 2014;15:4393–414.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  53. 53.

    Ständer M, Naumann U, Dumitrescu L, Heneka M, Löschmann P, Gulbins E, et al. Decorin gene transfer-mediated suppression of TGF-β synthesis abrogates experimental malignant glioma growth in vivo. Gene Ther. 1998;5:1187–94.

    PubMed  Article  Google Scholar 

  54. 54.

    Meijer DH, Maguire CA, Leroy SG, Sena-Esteves M. Controlling brain tumor growth by intraventricular administration of an AAV vector encoding IFN-Β. Cancer Gene Ther. 2009;16:664–71.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  55. 55.

    Burges HD, Croizier G, Huber J. A review of safety tests on baculoviruses. Entomophaga. 1980;25:329–39.

    Article  Google Scholar 

  56. 56.

    Wang CY, Li F, Yang Y, Guo HY, Wu CX, Wang S. Recombinant baculovirus containing the diphtheria toxin A gene for malignant glioma therapy. Cancer Res. 2006;66:5798–806.

    CAS  PubMed  Article  Google Scholar 

  57. 57.

    Wu C, Lin J, Hong M, Choudhury Y, Balani P, Leung D, et al. Combinatorial control of suicide gene expression by tissue-specific promoter and microrna regulation for cancer therapy. Mol Ther. 2009;17:2058–66.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  58. 58.

    Balani P, Boulaire J, Zhao Y, Zeng J, Lin J, Wang S. High mobility group box2 promoter-controlled suicide gene expression enables targeted glioblastoma treatment. Mol Ther. 2009;17:1003–11.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  59. 59.

    Guo H, Choudhury Y, Yang J, Chen C, Tay FC, Lim TM, et al. Antiglioma effects of combined use of a baculovirual vector expressing wild-type p53 and sodium butyrate. J Gene Med. 2011;13:26–36.

    CAS  PubMed  Article  Google Scholar 

  60. 60.

    Chao CN, Yang YH, Wu MS, Chou MC, Fang CY, Lin MC, et al. Gene therapy for human glioblastoma using neurotropic JC virus-like particles as a gene delivery vector. Sci Rep. 2018;8:1–11.

    Article  CAS  Google Scholar 

  61. 61.

    Foreman PM, Friedman GK, Cassady KA, Markert JM. Oncolytic virotherapy for the treatment of malignant glioma. Neurotherapeutics. 2017;14:333–44.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  62. 62.

    Liu TC, Kirn D. Gene therapy progress and prospects cancer: oncolytic viruses. Gene Ther. 2008;15:877–84.

    CAS  PubMed  Article  Google Scholar 

  63. 63.

    Dautzenberg IJC, Van Den Hengel SK, De Vrij J, Ravesloot L, Cramer SJ, Hong SS, et al. Baculovirus-assisted reovirus infection in monolayer and spheroid cultures of glioma cells. Sci Rep. 2017;7:17654.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  64. 64.

    Rommelaere J, Geletneky K, Angelova AL, Daeffler L, Dinsart C, Kiprianova I, et al. Oncolytic parvoviruses as cancer therapeutics. Cytokine Growth Factor Rev. 2010;21:185–95.

    CAS  Article  Google Scholar 

  65. 65.

    Geletneky K, Kiprianova I, Ayache A, Koch R, Herrero Y Calle M, et al. Regression of advanced rat and human gliomas by local or systemic treatment with oncolytic parvovirus H-1 in rat models. Neuro Oncol. 2010;12:804–14.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  66. 66.

    Parker JN, Bauer DF, Cody JJ, Markert JM. Oncolytic viral therapy of malignant glioma. Neurotherapeutics. 2009;6:558–69.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  67. 67.

    Phuong LK, Allen C, Peng KW, Giannini C, Greiner S, TenEyck CJ, et al. Use of a vaccine strain of measles virus genetically engineered to produce carcinoembryonic antigen as a novel therapeutic agent against glioblastoma multiforme. Cancer Res. 2003;63:2462–9.

    CAS  PubMed  Google Scholar 

  68. 68.

    Allen C, Paraskevakou G, Liu C, Iankov ID, Msaouel P, Zollman P, et al. Oncolytic measles virus strains in the treatment of gliomas. Expert Opin Biol Ther. 2008;8:213–20.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  69. 69.

    McKenzie BA, Zemp FJ, Pisklakova A, Narendran A, McFadden G, Lun X, et al. In vitro screen of a small molecule inhibitor drug library identifies multiple compounds that synergize with oncolytic myxoma virus against human brain tumor-initiating cells. Neuro Oncol. 2015;17:1086–94.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  70. 70.

    Li K, Hu C, Xing F, Gao M, Liang J, Xiao X, et al. Deficiency of the IRE1α-autophagy axis enhances the antitumor effects of the oncolytic virus M1. J Virol. 2017;92:e01331–17. pii

    Google Scholar 

  71. 71.

    Kay MA, Glorioso JC, Naldini L. Viral vectors for gene therapy: the art of turning infectious agents into vehicles of therapeutics. Nat Med. 2001;7:33–40.

    CAS  PubMed  Article  Google Scholar 

  72. 72.

    Zhang W, Cao S, Martin JL, Mueller JD, Mansky LM. Morphology and ultrastructure of retrovirus particles. AIMS Biophys. 2015;2:343.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  73. 73.

    Caffery B, Lee J, Alexander-Bryant A. Vectors for glioblastoma gene therapy: viral & non-viral delivery strategies. Nanomaterials. 2019;9:105.

    PubMed Central  Article  CAS  Google Scholar 

  74. 74.

    Denard J, Rundwasser S, Laroudie N, Gonnet F, Naldini L, Radrizzani M, et al. Quantitative proteomic analysis of lentiviral vectors using 2-DE. Proteomics. 2009;9:3666–76.

    CAS  PubMed  Article  Google Scholar 

  75. 75.

    Tolmachov O, Tolmachova T, Al-Allaf FA. Designing lentiviral gene vectors. InViral gene therapy. London, United Kingdom: Intech Open Limited; 2012.

    Google Scholar 

  76. 76.

    Rux JJ, Burnett RM. Adenovirus structure. Hum Gene Ther. 2004;15:1167–76.

    CAS  PubMed  Article  Google Scholar 

  77. 77.

    Stephen SL, Montini E, Sivanandam VG, Al-Dhalimy M, Kestler HA, Finegold M, et al. Chromosomal integration of adenoviral vector DNA in vivo. J Virol. 2010;84:9987–94.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  78. 78.

    Wirth T, Samaranayake H, Pikkarainen J, Määttä AM, Ylä-Herttuala S. Clinical trials for glioblastoma multiforme using adenoviral vectors. Curr Opin Mol Ther. 2009;11:485–92.

  79. 79.

    Daya S, Berns KI. Gene therapy using adeno-associated virus vectors. Clin Microbiol Rev. 2008;21:583–93.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  80. 80.

    Gao Y, Ng SSM, Chau DHW, Yao H, Yang C, Man K, et al. Development of recombinant adeno-associated virus and adenovirus cocktail system for efficient hTERTC27 polypeptide-mediated cancer gene therapy. Cancer Gene Ther. 2008;15:723–32.

    CAS  PubMed  Article  Google Scholar 

  81. 81.

    Merrihew RV, Clay WC, Condreay JP, Witherspoon SM, Dallas WS, Kost TA. Chromosomal integration of transduced recombinant baculovirus DNA in mammalian cells. J Virol. 2002;75:903–9.

    Article  Google Scholar 

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This work is supported by an extramural funding from the Department of Biotechnology, Government of India (Sanction no: BT/PR19625/MED/30/1703/2016) awarded to DS.

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Manikandan, C., Kaushik, A. & Sen, D. Viral vector: potential therapeutic for glioblastoma multiforme. Cancer Gene Ther 27, 270–279 (2020).

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