| dc.description.abstract | Oncolytic vaccinia virus has great potential in the treatment of cancer and two engineered
strains have entered clinical trials. As the advent for oncolytic vaccinia virus as an approved
therapy beckons, it is critical to consider some of the barriers that may hinder this progress.
These include suboptimal delivery of the virus to tumour sites, incomplete destruction of the
tumour mass, and a lack of full understanding of the way in which oncolytic vaccinia kills its
target cells. This thesis attempts to address these issues, with a particular focus on ovarian
cancer.
As ovarian cancer is generally restricted to the peritoneal cavity, intraperitoneal delivery may
be preferable over intravenous delivery. Here, it is shown that Lister-dTK, an engineered
vaccinia strain, is able to selectively replicate in ovarian tumours, including metastases to the
liver following intraperitoneal delivery. To determine whether Lister-dTK could potentially
be used in combination with current therapies for ovarian cancer, the effect of cisplatin and
Lister-dTK together was assessed in vitro but showed no improvement in overall cell death.
In an attempt to further improve the anti-tumour efficacy of Lister-dTK, the extracellular
matrix protein (ECM) decorin was expressed from the virus. Decorin interacts with various
signalling pathways and is proposed to enhance virus spread. However, abrogation of EGFR
and TGFβ signalling could not be demonstrated in vitro, nor could improved virus spread. In
an intraperitoneal model of ovarian cancer, Lister-mDCN did not demonstrate enhanced
efficacy over a control virus.
To determine the mechanisms of ovarian cancer cell death induced by Lister-dTK, the roles of
apoptosis, autophagy and necrosis were investigated. Whilst some features of both apoptosis
and autophagy were observed, inhibition of these pathways did not attenuate Lister-dTK. It is
proposed that necrosis is the primary cause of cell death but that this process may occur in a
regulated manner. | en_US |
