Abstract
Animal models have proven invaluable for progress toward greater understanding of the etiology, pathogenesis, and genetics of a wide range of human diseases. The development of relevant brain tumor animal models is a critical resource for building our understanding of cancers that arise within the brain and for the development of novel therapies. The central role of these models is particularly apparent for gliomas, which are common and devastating primary brain tumors. Effective models accurately demonstrate pathological features and behavior that are analogous to the human disease. Models aim to develop tumors with high penetrance and low latency, features that are ideal for preclinical therapeutic development. Lentiviral vector-induced models fulfill these requirements while giving investigators excellent control over the genetic profile of resulting tumors. This flexibility is especially relevant in the context of recent advances in the understanding of the genetic lesions found in human grade IV glioma, glioblastoma multiforme (GBM). Further, these endogenous tumor models would be ideal for the testing of novel gene therapy strategies which could potentially be implemented in Phase 1 clinical trials for these devastating human brain cancers.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Similar content being viewed by others
References
Grossman SA, Ye X, Piantadosi S et al (2010) Survival of patients with newly diagnosed glioblastoma treated with radiation and temozolomide in research studies in the United States. Clin Cancer Res 16:2443–2449
Verhaak RG, Hoadley KA, Purdom E et al (2010) Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell 17:98–110
Candolfi M, Curtin JF, Nichols WS et al (2007) Intracranial glioblastoma models in preclinical neuro-oncology: neuropathological characterization and tumor progression. J Neurooncol 85:133–148
Chow LM, Baker SJ (2012) Capturing the molecular and biological diversity of high-grade astrocytoma in genetically engineered mouse models. Oncotarget 3:67–77
Turcan S, Rohle D, Goenka A et al (2012) IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype. Nature 483:479–483
Parsons DW, Jones S, Zhang X et al (2008) An integrated genomic analysis of human glioblastoma multiforme. Science 321:1807–1812
Ducray F, Marie Y, Sanson M (2009) IDH1 and IDH2 mutations in gliomas. N Engl J Med 360:2248–2249, author reply 2249
Assanah M, Lochhead R, Ogden A et al (2006) Glial progenitors in adult white matter are driven to form malignant gliomas by platelet-derived growth factor-expressing retroviruses. J Neurosci 26:6781–6790
Dai C, Celestino JC, Okada Y et al (2001) PDGF autocrine stimulation dedifferentiates cultured astrocytes and induces oligodendrogliomas and oligoastrocytomas from neural progenitors and astrocytes in vivo. Genes Dev 15:1913–1925
Dai C, Lyustikman Y, Shih A et al (2005) The characteristics of astrocytomas and oligodendrogliomas are caused by two distinct and interchangeable signaling formats. Neoplasia 7:397–406
de Vries NA, Bruggeman SW, Hulsman D et al (2010) Rapid and robust transgenic high-grade glioma mouse models for therapy intervention studies. Clin Cancer Res 16:3431–3441
Hambardzumyan D, Amankulor NM, Helmy KY (2009) Modeling adult gliomas using RCAS/t-va technology. Transl Oncol 2:89–95
Holland EC, Celestino J, Dai C et al (2000) Combined activation of Ras and Akt in neural progenitors induces glioblastoma formation in mice. Nat Genet 25:55–57
Lei L, Sonabend AM, Guarnieri P et al (2011) Glioblastoma models reveal the connection between adult glial progenitors and the proneural phenotype. PLoS One 6:e20041
Marumoto T, Tashiro A, Friedmann-Morvinski D et al (2009) Development of a novel mouse glioma model using lentiviral vectors. Nat Med 15:110–116
Uhrbom L, Dai C, Celestino JC et al (2002) Ink4a-Arf loss cooperates with KRas activation in astrocytes and neural progenitors to generate glioblastomas of various morphologies depending on activated Akt. Cancer Res 62:5551–5558
Wiesner SM, Decker SA, Larson JD et al (2009) De novo induction of genetically engineered brain tumors in mice using plasmid DNA. Cancer Res 69:431–439
Lynes JWM, Koschmann C, Baker G et al (2014) Lentiviral induced high-grade gliomas in rats: the effects of PDGFB, HRAS-G12V, AKT and IDH1-R132H. Neurotherapeutics 11(3):623–635
Rankin SL, Zhu G, Baker SJ (2012) Review: insights gained from modelling high-grade glioma in the mouse. Neuropathol Appl Neurobiol 38:254–270
Naldini L, Blomer U, Gallay P et al (1996) In vivo gene delivery and stable transduction of nondividing cells by a lentiviral vector. Science 272:263–267
Park F (2007) Lentiviral vectors: are they the future of animal transgenesis? Physiol Genomics 31:159–173
Immonen A, Vapalahti M, Tyynela K et al (2004) AdvHSV-tk gene therapy with intravenous ganciclovir improves survival in human malignant glioma: a randomised, controlled study. Mol Ther 10:967–972
Maatta AM, Samaranayake H, Pikkarainen J et al (2009) Adenovirus mediated herpes simplex virus-thymidine kinase/ganciclovir gene therapy for resectable malignant glioma. Curr Gene Ther 9:356–367
Chiocca EA, Aguilar LK, Bell SD et al (2011) Phase IB study of gene-mediated cytotoxic immunotherapy adjuvant to up-front surgery and intensive timing radiation for malignant glioma. J Clin Oncol 29:3611–3619
Paxinos G, Watson C (1998) The rat atlas in stereotaxic coordinates. Elsevier Science & Technology Books. 256 p
Barcia C, Gerdes C, Xiong WD et al (2006) Immunological thresholds in neurological gene therapy: highly efficient elimination of transduced cells might be related to the specific formation of immunological synapses between T cells and virus-infected brain cells. Neuron Glia Biol 2:309–322
Thomas CE, Birkett D, Anozie I et al (2001) Acute direct adenoviral vector cytotoxicity and chronic, but not acute, inflammatory responses correlate with decreased vector-mediated transgene expression in the brain. Mol Ther 3:36–46
Thomas CE, Schiedner G, Kochanek S et al (2001) Preexisting antiadenoviral immunity is not a barrier to efficient and stable transduction of the brain, mediated by novel high-capacity adenovirus vectors. Hum Gene Ther 12:839–846
Barcia C, Thomas CE, Curtin JF et al (2006) In vivo mature immunological synapses forming SMACs mediate clearance of virally infected astrocytes from the brain. J Exp Med 203:2095–2107
Dewey RA, Morrissey G, Cowsill CM et al (1999) Chronic brain inflammation and persistent herpes simplex virus 1 thymidine kinase expression in survivors of syngeneic glioma treated by adenovirus-mediated gene therapy: implications for clinical trials. Nat Med 5:1256–1263
Puntel M, Kroeger KM, Sanderson NS et al (2010) Gene tranfer into at brain using adenoviral vectors Curr Protoc Neurosci. 50:4.24:4.24:1–4.24.49
Acknowledgments
This work was supported by National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS) Grants 1UO1-NS052465, UO1-NS052465-S1, 1R21-NSO54143, 1RO1-NS057711, 1RO1-NS074387, MICHR Pilot R14 U040007, and BioInterfaces Institute, University of Michigan U042841 to M.G.C.; NIH/NINDS Grants 1RO1-NS054193, 1RO1-NS061107, 1RO1-NS082311, R21-NS084275, and M-Cube U036756 University of Michigan to P.R.L.; the Department of Neurosurgery, University of Michigan School of Medicine; the Michigan Institute for Clinical and Health Research, NIH UL1-TR000433; University of Michigan Cancer Biology Training Grant, NIH/NCI (National Cancer Institute) T32-CA009676; University of Michigan Training in Clinical and Basic Neuroscience, NIH/NINDS T32-NS007222; and the University of Michigan Medical Scientist Training Program, NIH/NIGMS (National Institute of General Medicine Sciences) T32-GM007863, and the National Institutes of Health through the University of Michigan’s Cancer Center Support Grant P30-CA046592. C.K. is supported by an NIH T32 training grant under Dr. James Ferrara (2-T32-HL-007622-26-A1). M.C. receives financial support from the National Council for Science and Technology (PIP 114-201101-00353, CONICET, Argentina). M.A.M.A. is supported by a doctoral fellowship from CONICET (Argentina). We are grateful to Dr. Karin Murasko for her academic leadership and D. Tomford and S. Napolitan for their superb administrative support.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2015 Springer Science+Business Media New York
About this protocol
Cite this protocol
Lynes, J. et al. (2015). Gene Therapy Approaches Using Reproducible and Fully Penetrant Lentivirus-Mediated Endogenous Glioma Models. In: Bo, X., Verhaagen, J. (eds) Gene Delivery and Therapy for Neurological Disorders. Neuromethods, vol 98. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-2306-9_14
Download citation
DOI: https://doi.org/10.1007/978-1-4939-2306-9_14
Published:
Publisher Name: Humana Press, New York, NY
Print ISBN: 978-1-4939-2305-2
Online ISBN: 978-1-4939-2306-9
eBook Packages: Springer Protocols