Virotherapy of ovarian cancer with polymer-cloaked adenovirus retargeted to the epidermal growth factor receptor
Joanne Morrison (1), Simon S Briggs (2), Nicola Green (3), Kerry Fisher (2), Vladimir Subr (4), Karel Ulbrich (4), Sean Kehoe (1) and Leonard W Seymour (2)
Molecular Therapy vol. 16 no. 2 Feb. 2008
Ovarian cancer is a leading cause of cancer death in the developed world. It is a disease that frequently shows no or few symptoms during the early stages and is often diagnosed only when it has become advanced. In the UK, 7000 women are diagnosed with ovarian cancer every year and only 30% of those women will survive for more than 5 years after diagnosis.
Whereas some cancers will spread throughout the body when they reach advanced stages, ovarian cancer cells tend to remain within the abdominal cavity. This makes ovarian cancer appropriate for treatments delivered directly into the abdominal cavity. Targeted therapies are being investigated increasingly for their efficacy in the treatment of numerous cancers in the hope that they will be associated with fewer of the side effects that are commonly associated with traditional anticancer treatments, such as chemotherapy.
In recent years, researchers have begun investigating modified viruses as vehicles for delivering gene therapy directly into cancer cells or using the virus itself as a means of achieving selective killing of cancer cells. Recent studies have raised concerns with the use of viruses for the treatment of ovarian cancer due to the risk of intra-abdominal adhesion formation. Adhesions form when inflammatory responses to a treatment – in this case the introduction of a modified virus – cause the infiltration and aggregation of immune cells so that tissues within the abdominal cavity become ‘sticky’ and adhere together. Intra-abdominal adhesions can have severe implications for sufferers, causing pain, infertility and even bowel obstruction in some patients.
In this study, the research team developed a modified virus that was coated with a special polymer and targeted to the epidermal growth factor receptor (EGFR) – a receptor that is present in much greater numbers on the surfaces of cancer cells than on non-malignant cells. Previous work had shown that polymer coating could reduce toxic side effects of virus given into the blood stream and it was hoped that the coating would prevent inflammatory responses, reducing the risk of side effects such as adhesion formation. . Virus particles cause cell death by entering host cells with the aid of cell surface receptors, replicating, and then rupturing – or lysing – the cells to enable the release of the new viral particles. The researchers hypothesized that targeting the coated virus to the EGFR would improve selectivity for cancer cells and would also provide a means of transporting the virus particles inside the cancer cells to enable them to achieve cell lysis.
The study was successful, showing that in mice, targeted, coated virus particles were capable of selecting, entering and killing ovarian cancer cells. Importantly, compared with untreated virus, the targeted, coated virus caused much less intra-abdominal adhesion formation and was associated with no side effects even at a relatively high virus doses.
This extremely promising study represents the first time it has been shown that modified virus particles can retain their virulence sufficiently to cross tumour cell membranes and kill the cells without harming non-malignant cells or causing significant side effects. These results highlight the considerable potential of this technology as a future targeted treatment for women with ovarian cancer.
1Nuffield Department of Obstetrics and Gynaecology, University of Oxford, John Radcliffe Hospital, Headington, Oxford, Oxfordshire, UK; 2Department of Clinical Pharmacology, University of Oxford, Radcliffe Infirmary, Oxford, Oxfordshire, UK; 3Hybrid Systems Ltd, Cherwell Innovation Centre, Heyford Park, Upper Heyford, Oxfordshire, UK; 4Institute of Macromolecular Chemistry, Academy of Sciences of the Czech Republic, Prague, Czech Republic
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