Targeted AAVP-based therapy in a mouse model of human glioblastoma: a comparison of cytotoxic versus suicide gene delivery strategies.
Animals
Antineoplastic Agents
/ administration & dosage
Bacteriophages
/ genetics
Brain Neoplasms
/ blood supply
Cell Line, Tumor
Dependovirus
/ genetics
Drug Delivery Systems
/ methods
Endothelium, Vascular
/ drug effects
Female
Ganciclovir
/ administration & dosage
Gene Transfer Techniques
Genes, Transgenic, Suicide
/ genetics
Genetic Vectors
/ administration & dosage
Glioblastoma
/ blood supply
Humans
Mice
Molecular Imaging
/ methods
Molecular Targeted Therapy
/ methods
Simplexvirus
/ genetics
Thymidine Kinase
/ genetics
Tumor Necrosis Factor-alpha
/ genetics
Viral Proteins
/ genetics
Xenograft Model Antitumor Assays
Journal
Cancer gene therapy
ISSN: 1476-5500
Titre abrégé: Cancer Gene Ther
Pays: England
ID NLM: 9432230
Informations de publication
Date de publication:
05 2020
05 2020
Historique:
received:
19
12
2018
accepted:
27
04
2019
revised:
09
04
2019
pubmed:
28
5
2019
medline:
11
5
2021
entrez:
28
5
2019
Statut:
ppublish
Résumé
Glioblastoma persists as a uniformly deadly diagnosis for patients and effective therapeutic options are gravely needed. Recently, targeted gene therapy approaches are reemerging as attractive experimental clinical agents. Our ligand-directed hybrid virus of adeno-associated virus and phage (AAVP) is a targeted gene delivery vector that has been used in several formulations displaying targeting ligand peptides to deliver clinically applicable transgenes. Here we compared different constructs side-by-side in a tumor model, an orthotopic model of xenograft human glioblastoma cells stereotactically implanted in immunodeficient mice. We have used divergent therapeutic strategies for two AAVP constructs, both displaying a double-cyclic RGD4C motif ligand specific for alpha V integrins expressed in tumor vascular endothelium, but carrying different genes of interest for the treatment of intracranial xenografted tumors. One construct delivered tumor necrosis factor (TNF), a purely cytotoxic gene for antitumor activity (RGD4C-AAVP-TNF); in the other construct, we delivered Herpes simplex virus thymidine kinase (HSVtk) for in tandem molecular-genetic imaging and targeted therapy (RGD4C-AAVP-HSVtk) utilizing ganciclovir (GCV) for a suicide gene therapy. Both AAVP constructs demonstrated antitumor activity, with damage to the tumor-associated neovasculature and induction of cell death evident after treatment. In addition, the ability to monitor transgene expression with a radiolabeled HSVtk substrate pre and post GCV treatment demonstrated the theranostic potential of RGD4C-AAVP-HSVtk. We conclude that targeted AAVP constructs delivering either cytotoxic TNF or theranostic HSVtk followed by suicide gene therapy with GCV have comparable preclinical efficacy, at least in this standard experimental model. The results presented here provide a blueprint for future studies of targeted gene delivery against human glioblastomas and other brain tumors.
Identifiants
pubmed: 31130731
doi: 10.1038/s41417-019-0101-2
pii: 10.1038/s41417-019-0101-2
pmc: PMC6879804
mid: NIHMS1528126
doi:
Substances chimiques
Antineoplastic Agents
0
TNF protein, human
0
Tumor Necrosis Factor-alpha
0
Viral Proteins
0
Thymidine Kinase
EC 2.7.1.21
Ganciclovir
P9G3CKZ4P5
Types de publication
Comparative Study
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
301-310Subventions
Organisme : NCI NIH HHS
ID : R01 CA122568
Pays : United States
Références
Wen PY, Kesari S. Malignant gliomas in adults. N Engl J Med. 2008;359:492–507.
doi: 10.1056/NEJMra0708126
Jessen NA, Munk AS, Lundgaard I, Nedergaard M. The glymphatic system: a beginner’s guide. Neurochem Res. 2015;40:2583–99.
doi: 10.1007/s11064-015-1581-6
Batich KA, Sampson JH. Standard of care and future pharmacological treatment options for malignant glioma: an urgent need for screening and identification of novel tumor-specific antigens. Expert Opin Pharmacother. 2014;15:2047–61.
doi: 10.1517/14656566.2014.947266
Kim JW, Chang AL, Kane JR, Young JS, Qiao J, Lesniak MS. Gene therapy and virotherapy of gliomas. Prog Neurol Surg. 2018;32:112–23.
doi: 10.1159/000469685
Twumasi-Boateng K, Pettigrew JL, Kwok YYE, Bell JC, Nelson BH. Oncolytic viruses as engineering platforms for combination immunotherapy. Nat Rev Cancer. 2018;18:419–32.
doi: 10.1038/s41568-018-0009-4
Hajitou A, Trepel M, Lilley CE, Soghomonyan S, Alauddin MM, Marini FC 3rd, et al. A hybrid vector for ligand-directed tumor targeting and molecular imaging. Cell. 2006;125:385–98.
doi: 10.1016/j.cell.2006.02.042
Tandle A, Hanna E, Lorang D, Hajitou A, Moya CA, Pasqualini R, et al. Tumor vasculature-targeted delivery of tumor necrosis factor-alpha. Cancer. 2009;115:128–39.
doi: 10.1002/cncr.24001
Yuan Z, Syrkin G, Adem A, Geha R, Pastoriza J, Vrikshajanani C, et al. Blockade of inhibitors of apoptosis (IAPs) in combination with tumor-targeted delivery of tumor necrosis factor-alpha leads to synergistic antitumor activity. Cancer Gene Ther. 2013;20:46–56.
doi: 10.1038/cgt.2012.83
Smith TL, Yuan Z, Cardó-Vila M, Sanchez Claros C, Adem A, Cui MH, et al. AAVP displaying octreotide for ligand-directed therapeutic transgene delivery in neuroendocrine tumors of the pancreas. Proc Natl Acad Sci USA. 2016;113:2466–71.
doi: 10.1073/pnas.1525709113
Paoloni MC, Tandle A, Mazcko C, Hanna E, Kachala S, Leblanc A, et al. Launching a novel preclinical infrastructure: comparative oncology trials consortium directed therapeutic targeting of TNFalpha to cancer vasculature. PLoS ONE. 2009;4:e4972.
doi: 10.1371/journal.pone.0004972
Wang X, Lin Y. Tumor necrosis factor and cancer, buddies or foes? Acta Pharm Sin. 2008;29:1275–88.
doi: 10.1111/j.1745-7254.2008.00889.x
Dobroff AS, D’Angelo S, Eckhardt BL, Ferrara F, Staquicini DI, Cardó-Vila M, et al. Towards a transcriptome-based theranostic platform for unfavorable breast cancer phenotypes. Proc Natl Acad Sci USA. 2016;113:12780–5.
doi: 10.1073/pnas.1615288113
Ferrara F, Staquicini DI, Driessen WH, D’Angelo S, Dobroff AS, Barry M, et al. Targeted molecular-genetic imaging and ligand-directed therapy in aggressive variant prostate cancer. Proc Natl Acad Sci USA. 2016;113:12786–91.
doi: 10.1073/pnas.1615400113
Hajitou A, Lev DC, Hannay JA, Korchin B, Staquicini FI, Soghomonyan S, et al. A preclinical model for predicting drug response in soft-tissue sarcoma with targeted AAVP molecular imaging. Proc Natl Acad Sci USA. 2008;105:4471–6.
doi: 10.1073/pnas.0712184105
Staquicini FI, Ozawa MG, Moya CA, Driessen WH, Barbu EM, Nishimori H, et al. Systemic combinatorial peptide selection yields a non-canonical iron-mimicry mechanism for targeting tumors in a mouse model of human glioblastoma. J Clin Investig. 2011;121:161–73.
doi: 10.1172/JCI44798
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;49:380–9. discussion 90
pubmed: 11504114
Paolillo M, Serra M, Schinelli S. Integrins in glioblastoma: still an attractive target? Pharmacol Res. 2016;113(Pt A):55–61.
doi: 10.1016/j.phrs.2016.08.004
Wu Y, Zhang X, Xiong Z, Cheng Z, Fisher DR, Liu S, et al. microPET imaging of glioma integrin {alpha}v{beta}3 expression using (64)Cu-labeled tetrameric RGD peptide. J Nucl Med. 2005;46:1707–18.
pubmed: 16204722
Christianson DR, Ozawa MG, Pasqualini R, Arap W. Techniques to decipher molecular diversity by phage display. Methods Mol Biol. 2007;357:385–406.
pubmed: 17172704
Hajitou A, Rangel R, Trepel M, Soghomonyan S, Gelovani JG, Alauddin MM, et al. Design and construction of targeted AAVP vectors for mammalian cell transduction. Nat Protoc. 2007;2:523–31.
doi: 10.1038/nprot.2007.51
Lal S, Lacroix M, Tofilon P, Fuller GN, Sawaya R, Lang FF. An implantable guide-screw system for brain tumor studies in small animals. J Neurosurg. 2000;92:326–33.
doi: 10.3171/jns.2000.92.2.0326
Soghomonyan S, Hajitou A, Rangel R, Trepel M, Pasqualini R, Arap W, et al. Molecular PET imaging of HSV1-tk reporter gene expression using [18F]FEAU. Nat Protoc. 2007;2:416–23.
doi: 10.1038/nprot.2007.49
Uhlen M, Fagerberg L, Hallstrom BM, Lindskog C, Oksvold P, Mardinoglu A, et al. Proteomics. Tissue-based map of the human proteome. Science. 2015;347:1260419.
doi: 10.1126/science.1260419
Przystal JM, Umukoro E, Stoneham CA, Yata T, O’Neill K, Syed N, et al. Proteasome inhibition in cancer is associated with enhanced tumor targeting by the adeno-associated virus/phage. Mol Oncol. 2013;7:55–66.
doi: 10.1016/j.molonc.2012.08.001
Przystal JM, Waramit S, Pranjol MZI, Yan W, Chu G, Chongchai A, et al. Efficacy of systemic temozolomide-activated phage-targeted gene therapy in human glioblastoma. EMBO Mol Med. 2019;11:e8492.
Caffery B, Lee JS, Alexander-Bryant AA. Vectors for glioblastoma gene therapy: viral & non-viral delivery strategies. Nanomaterials. 2019;9.
Kim SS, Rait A, Kim E, Pirollo KF, Chang EH. A tumor-targeting p53 nanodelivery system limits chemoresistance to temozolomide prolonging survival in a mouse model of glioblastoma multiforme. Nanomedicine. 2015;11:301–11.
doi: 10.1016/j.nano.2014.09.005
Tobias A, Ahmed A, Moon KS, Lesniak MS. The art of gene therapy for glioma: a review of the challenging road to the bedside. J Neurol Neurosurg Psychiatry. 2013;84:213–22.
doi: 10.1136/jnnp-2012-302946
Gilbert MR, Dignam JJ, Armstrong TS, Wefel JS, Blumenthal DT, Vogelbaum MA, et al. A randomized trial of bevacizumab for newly diagnosed glioblastoma. N Engl J Med. 2014;370:699–708.
doi: 10.1056/NEJMoa1308573
Ozawa MG, Zurita AJ, Dias-Neto E, Nunes DN, Sidman RL, Gelovani JG, et al. Beyond receptor expression levels: the relevance of target accessibility in ligand-directed pharmacodelivery systems. Trends Cardiovasc Med. 2008;18:126–32.
doi: 10.1016/j.tcm.2008.03.001
Pasqualini R, Koivunen E, Ruoslahti E. Alpha v integrins as receptors for tumor targeting by circulating ligands. Nat Biotechnol. 1997;15:542–6.
doi: 10.1038/nbt0697-542
Lombardi G, Pambuku A, Bellu L, Farina M, Della Puppa A, Denaro L, et al. Effectiveness of antiangiogenic drugs in glioblastoma patients: a systematic review and meta-analysis of randomized clinical trials. Crit Rev Oncol Hematol. 2017;111:94–102.
doi: 10.1016/j.critrevonc.2017.01.018
Jacobs A, Voges J, Reszka R, Lercher M, Gossmann A, Kracht L, et al. Positron-emission tomography of vector-mediated gene expression in gene therapy for gliomas. Lancet. 2001;358:727–9.
doi: 10.1016/S0140-6736(01)05904-9
Lang FF, Conrad C, Gomez-Manzano C, Yung WKA, Sawaya R, Weinberg JS, et al. Phase I study of DNX-2401 (Delta-24-RGD) oncolytic adenovirus: replication and immunotherapeutic effects in recurrent malignant glioma. J Clin Oncol. 2018;36:1419–27.
doi: 10.1200/JCO.2017.75.8219
Petersen SL, Wang L, Yalcin-Chin A, Li L, Peyton M, Minna J, et al. Autocrine TNFalpha signaling renders human cancer cells susceptible to Smac-mimetic-induced apoptosis. Cancer Cell. 2007;12:445–56.
doi: 10.1016/j.ccr.2007.08.029