Open AccessEfficacy of systemic temozolomide‐activated phage‐targeted gene therapy in human glioblastoma
Author(s) -
Przystal Justyna Magdalena,
Waramit Sajee,
Pranjol Md Zahidul Islam,
Yan Wenqing,
Chu Grace,
Chongchai Aitthiphon,
Samarth Gargi,
Olaciregui Nagore Gene,
Tabatabai Ghazaleh,
Carcaboso Angel Montero,
Aboagye Eric Ofori,
Suwan Keittisak,
Hajitou Amin
Publication year - 2019
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.201708492
Subject(s) - library science , medicine , excellence , temozolomide , oncology , glioblastoma , political science , cancer research , law , computer science
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 α v β 3 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.