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dc.contributor.authorTookman, Laura
dc.date.accessioned2017-06-29T11:55:02Z
dc.date.available2017-06-29T11:55:02Z
dc.date.issued2016-12-12
dc.date.submitted2017-06-29T12:33:45.735Z
dc.identifier.citationTookman, L. 2016. THE ROLE OF THE DNA DAMAGE AND REPAIR PATHWAYS IN THE EF F ICACY OF ONCOLYTIC ADENOVIRUS FOR OVARIAN CANCER. Queen Mary University of Londonen_US
dc.identifier.urihttp://qmro.qmul.ac.uk/xmlui/handle/123456789/24648
dc.descriptionPhDen_US
dc.description.abstractDefects within the DNA damage response (DDR) pathways are common in human malignancies. This is especially true in high-grade serous ovarian cancer (HGSOC) where defects within the Homologous Recombination (HR) pathway may be present in up to 50% of tumours. Oncolytic adenovirus is a potential novel therapy for human malignancies. These viruses infect malignant cells and multiply selectively within them causing cell death and release of mature virions. Here, I have investigated the role of the DDR in determining the efficacy of the E1A-CR2 deleted adenovirus type 5 (Ad5) vector, dl922-947, in ovarian cancer. I show that infection with dl922-947 stimulates a robust DDR within the host cell, which the virus manipulates in order to ensure optimal viral replication. In a panel of HGSOC cell lines, the extent of overreplication of genomic DNA and the degree of genomic damage following infection with dl922-947 was shown to correlate closely with viral efficacy. Functional HR, however, promoted viral DNA replication and augmented overall anti-cancer efficacy. Mechanistically, both BRCA2 and RAD51 localised to viral replication centres within the infected cell nucleus. RAD51 co-localisation was also demonstrated in cells with defective HR and occurred independently of BRCA2. In addition, a direct interaction was identified between RAD51 and adenovirus E2 DNA binding protein. Using functional assays of HR competence, I show that Ad5 infection does not alter cellular ability to repair DNA double-strand break damage via HR. These data suggest that oncolytic adenoviral therapy may be most clinically relevant in tumours with intact HR function. Using a high-throughput siRNA DNA repair screen, potential novel targets have been identified that can increase the efficacy of dl922-947 (for example: NONO) and also result in increased resistance (RPA). These results highlight the complex interplay between adenovirus and host cell. Further understanding of these pathways is vital to increase efficacy, develop biomarkers and improve patient selection into clinical trials for these therapies.en_US
dc.description.sponsorshipMedical Research Councilen_US
dc.language.isoenen_US
dc.publisherQueen Mary University of Londonen_US
dc.rightsThe copyright of this thesis rests with the author and no quotation from it or information derived from it may be published without the prior written consent of the author
dc.subjectOncologyen_US
dc.subjectOvarian canceren_US
dc.subjectDNA damage responseen_US
dc.subjectOncolytic adenovirusen_US
dc.titleTHE ROLE OF THE DNA DAMAGE AND REPAIR PATHWAYS IN THE EF F ICACY OF ONCOLYTIC ADENOVIRUS FOR OVARIAN CANCERen_US
dc.typeThesisen_US


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    Theses Awarded by Queen Mary University of London

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