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Title: The dual influence of tumour hypoxia on the activity of a group B oncolytic adenovirus
Author: Ambuludi, Egon Jacobus
ISNI:       0000 0004 7971 5868
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2018
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Many oncolytic adenoviruses are in clinical development for the treatment of solid tumours and Enadenotucirev (EnAd), a chimeric group B adenovirus, is one leading candidate. Little is known about its activity in hypoxic regions, a feature present in virtually all solid carcinomas and well known to confer resistance to traditional therapies. Hypoxia may account for the long term persistence of adenovirus in tumours and incomplete tumour coverage, as intratumoral and even intravenous virus delivery may expose viruses to hypoxia due to perfusion changes in the tumour vasculature. We set out to define how hypoxia influences EnAd's oncolytic activity through an in-depth analysis of the viral infection in cancer cells, its dissemination to bystander cells in hypoxic conditions in vitro, and characterisation of virus dissemination in animal tumour models. Work in this thesis showed that hypoxia in vitro actually boosts expression of virus early and late gene products leading to increased production of infectious virus (2 to 12-fold). It also increases expression of virus-encoded biotherapeutic agents. The mechanism appears to involve hypoxia specific over-expression of the immediate-early gene E1A, and we provide evidence that a hypoxia responsive element within the promoter of this key viral gene could be induced in a HIF 2α dependent fashion. Nevertheless, in conditions involving cell-to-cell spread in vitro, this ability of hypoxic cancer cells to produce greater number of virus particles is masked, due to poor paracellular spread reflecting the presence, or absence, of a factor smaller than 5 kilodaltons, yet to be characterised. We also assessed the impact of hypoxia in vivo by combining EnAd with atovaquone, a mitochondrial Complex-III inhibitor that reduces the cellular oxygen consumption rate, thereby alleviating hypoxia in tumours. Oral atovaquone treatment, which does not increase virus production in vitro, led to an unprecedented increase of tumoural viral spread while significantly reducing the hypoxic fraction, suggesting that hypoxia could be a key therapeutic barrier. In conclusion, hypoxia boosts the oncolytic activity of adenoviruses, but can inhibit intercellular spread. The overall impact of hypoxia upon the success of oncolytic adenovirus therapy will likely rely on the balance of improved expression of virus-encoded therapeutics, anti-tumour effects of pro inflammatory (antiviral) signalling, and limited viral spread.
Supervisor: Seymour, Len Sponsor: Medical Research Council ; Cancer Research UK
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available