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Efficacy of systemic temozolomide-activated phage-targeted gene therapy in human glioblastoma

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Przystal et al_ EMBO Mol Med 2019-compressed.pdfAccepted version4.31 MBAdobe PDFView/Open
Title: Efficacy of systemic temozolomide-activated phage-targeted gene therapy in human glioblastoma
Authors: Przystal, J
Waramit, S
Pranjol, MZI
Yan, W
Chu, G
Chongchai, A
Samarth, G
Olaciregui, N
Tabatabai, G
Carcaboso, A
Aboagye, E
Suwan, K
Hajitou, A
Item Type: Journal Article
Abstract: Glioblastoma multiforme (GBM) is the most lethal primary intracranial malignant neoplasm in adults and most resistant to treatment. Integration of gene therapy and chemotherapy, chemovirotherapy, has the potential to improve treatment. We have introduced an intravenous bacteriophage (phage) vector for dual targeting of therapeutic genes to glioblastoma. It is a hybrid AAV/phage, AAVP, designed to deliver a recombinant adeno‐associated virus genome (rAAV) by the capsid of M13 phage. In this vector, dual tumor targeting is first achieved by phage capsid display of the RGD4C ligand that binds the αvβ3 integrin receptor. Second, genes are expressed from a tumor‐activated and temozolomide (TMZ)‐induced promoter of the glucose‐regulated protein, Grp78. Here, we investigated systemic combination therapy using TMZ and targeted suicide gene therapy by the RGD4C/AAVP‐Grp78. Firstly, in vitro we showed that TMZ increases endogenous Grp78 gene expression and boosts transgene expression from the RGD4C/AAVP‐Grp78 in human GBM cells. Next, RGD4C/AAVP‐Grp78 targets intracranial tumors in mice following intravenous administration. Finally, combination of TMZ and RGD4C/AAVP‐Grp78 targeted gene therapy exerts a synergistic effect to suppress growth of orthotopic glioblastoma.
Issue Date: 26-Feb-2019
Date of Acceptance: 4-Feb-2019
URI: http://hdl.handle.net/10044/1/67412
DOI: https://dx.doi.org/10.15252/emmm.201708492
ISSN: 1757-4676
Publisher: Wiley
Journal / Book Title: EMBO Molecular Medicine
Volume: 11
Issue: 2
Copyright Statement: ©2019 The Authors. Published under the terms of the CC BY4.0 license. This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Sponsor/Funder: Medical Research Council (MRC)
Cancer Research UK
Funder's Grant Number: G0701159
C2536/A16584
Keywords: 06 Biological Sciences
11 Medical And Health Sciences
Publication Status: Published
Online Publication Date: 2019-02-26
Appears in Collections:Division of Surgery
Division of Cancer
Department of Medicine



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