Efficacy of systemic temozolomide‐activated phage‐targeted gene therapy in human glioblastoma
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)...
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| Format: | Article |
| Language: | English |
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Springer Nature
2019-02-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.201708492 |
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| author | Justyna Magdalena Przystal Sajee Waramit Md Zahidul Islam Pranjol Wenqing Yan Grace Chu Aitthiphon Chongchai Gargi Samarth Nagore Gene Olaciregui Ghazaleh Tabatabai Angel Montero Carcaboso Eric Ofori Aboagye Keittisak Suwan Amin Hajitou |
| author_facet | Justyna Magdalena Przystal Sajee Waramit Md Zahidul Islam Pranjol Wenqing Yan Grace Chu Aitthiphon Chongchai Gargi Samarth Nagore Gene Olaciregui Ghazaleh Tabatabai Angel Montero Carcaboso Eric Ofori Aboagye Keittisak Suwan Amin Hajitou |
| author_sort | Justyna Magdalena Przystal |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-60117942bc3047b89c4b5b2a9b7d4cca |
| institution | Kabale University |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2019-02-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-60117942bc3047b89c4b5b2a9b7d4cca2025-08-20T03:46:19ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842019-02-0111412110.15252/emmm.201708492Efficacy of systemic temozolomide‐activated phage‐targeted gene therapy in human glioblastomaJustyna Magdalena Przystal0Sajee Waramit1Md Zahidul Islam Pranjol2Wenqing Yan3Grace Chu4Aitthiphon Chongchai5Gargi Samarth6Nagore Gene Olaciregui7Ghazaleh Tabatabai8Angel Montero Carcaboso9Eric Ofori Aboagye10Keittisak Suwan11Amin Hajitou12Phage Therapy Group, Division of Brain Sciences, Department of Medicine, Imperial College LondonPhage Therapy Group, Division of Brain Sciences, Department of Medicine, Imperial College LondonPhage Therapy Group, Division of Brain Sciences, Department of Medicine, Imperial College LondonPhage Therapy Group, Division of Brain Sciences, Department of Medicine, Imperial College LondonPhage Therapy Group, Division of Brain Sciences, Department of Medicine, Imperial College LondonThailand Excellence Centre for Tissue Engineering and Stem Cells, Department of Biochemistry, Faculty of Medicine, Chiang Mai UniversityPhage Therapy Group, Division of Brain Sciences, Department of Medicine, Imperial College LondonInstitute de Recerca Sant Joan de DeuInterdisciplinary Division of Neuro‐Oncology, Hertie Institute for Clinical Brain Research, Center for CNS Tumors, Comprehensive Cancer Center, University Hospital Tübingen, Eberhard Karls UniversityInstitute de Recerca Sant Joan de DeuComprehensive Cancer Imaging Centre, Imperial College London, Faculty of MedicinePhage Therapy Group, Division of Brain Sciences, Department of Medicine, Imperial College LondonPhage Therapy Group, Division of Brain Sciences, Department of Medicine, Imperial College LondonAbstract 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.https://doi.org/10.15252/emmm.201708492bacteriophageglioblastomaGrp78targetingtemozolomide |
| spellingShingle | Justyna Magdalena Przystal Sajee Waramit Md Zahidul Islam Pranjol Wenqing Yan Grace Chu Aitthiphon Chongchai Gargi Samarth Nagore Gene Olaciregui Ghazaleh Tabatabai Angel Montero Carcaboso Eric Ofori Aboagye Keittisak Suwan Amin Hajitou Efficacy of systemic temozolomide‐activated phage‐targeted gene therapy in human glioblastoma EMBO Molecular Medicine bacteriophage glioblastoma Grp78 targeting temozolomide |
| title | Efficacy of systemic temozolomide‐activated phage‐targeted gene therapy in human glioblastoma |
| title_full | Efficacy of systemic temozolomide‐activated phage‐targeted gene therapy in human glioblastoma |
| title_fullStr | Efficacy of systemic temozolomide‐activated phage‐targeted gene therapy in human glioblastoma |
| title_full_unstemmed | Efficacy of systemic temozolomide‐activated phage‐targeted gene therapy in human glioblastoma |
| title_short | Efficacy of systemic temozolomide‐activated phage‐targeted gene therapy in human glioblastoma |
| title_sort | efficacy of systemic temozolomide activated phage targeted gene therapy in human glioblastoma |
| topic | bacteriophage glioblastoma Grp78 targeting temozolomide |
| url | https://doi.org/10.15252/emmm.201708492 |
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