Targeting pre-clinical imaging & therapy to the angiogenic blood vessels & tumour cells of glioma

Pre-clinical therapy using novel bacteriophage nanoparticles and ADI-PEG20 to target angiogenic blood vessels and tumour cells of primary human glioma established in the brain of mice

1-year research technician project from March 2012-March 2013 (completed)

Extension: 2-year PhD studentship from June 2013-May 2015 (completed)

Extension to May 2016 (completed)

Investigators: Dr Amin Hajitou, Dr Nel Syed , Justyna Pryzstal, (PhD student)

Lay summary: Malignant glioma is the most frequent primary brain tumour in adults and is one of the most lethal malignancies. The effects of current therapies are limited and novel therapeutic approaches are urgently needed. The blood-brain barrier (BBB) is a major obstacle in accessing and treating malignant brain tumours through systemic delivery. In solid tumours, the vasculature is an attractive target for therapy because vascular cells are accessible through the systemic circulation and express several surface markers that are absent or barely detectable in normal blood vessels. Also it is estimated that up of 100 tumour cells are sustained by a single endothelial cell of the tumour vasculature, thus blood vessel destruction has the potential to increase efficacy of anti-cancer therapies against human glioma. Finally the vascular cells in solid tumours are less likely to acquire resistance to therapy. Therefore targeted disruption of the vasculature of glioma would overcome, at least in part, the challenging BBB. However, targeted systemic therapy of cancer has faced a major problem, namely the lack of an efficient and safe systemic carrier to deliver therapeutic drugs to the tumour blood vessels without harming the normal and healthy tissues.

Bacteriophage (phage) – the viruses that infect bacteria only – have been used for therapy of bacterial infections in human. Bacteriophages do not infect animal cells and have been safely administered to both adults and children against human pathogens over many years. Importantly, they can be engineered to target a specific receptor in tumours without harming normal healthy tissues. We have reported a targeted bacteriophage particle that targets a specific cell surface receptor that is highly expressed on the abnormal new blood vessels that form within tumours but absent in normal vasculature. After intravenous administration, the targeted bacteriophage specifically and efficiently delivered therapeutic genes to the blood vessels of subcutaneous tumours in mice, rats and dogs while sparing normal organs. We propose to use bacteriophage in order to target the disruption of the blood vessels of human glioma established in the brain of mice.

Arginine is one of the non-essential amino acids for humans. Normal cells synthesize arginine from citrulline in two steps using the urea cycle enzymes ASS1 and argininosuccinate lyase (ASL). Some human cancers, however, do not express sufficient levels of ASS1 and/or ASL and thus require an exogenous arginine supply. These tumours might therefore be sensitive to ADT. We wish to explore if ADT using an enzyme that degrades arginine (ADI-PEG20) can kill brain tumours established in mice. These two approaches may represent novel treatment strategies for human glial tumours.