|dc.identifier.citation||Tookman, 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 London||en_US
|dc.description.abstract||Defects 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.sponsorship||Medical Research Council||en_US
|dc.publisher||Queen Mary University of London||en_US
|dc.rights||The 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.subject||DNA damage response||en_US
|dc.title||THE ROLE OF THE DNA DAMAGE AND REPAIR PATHWAYS IN THE EF F ICACY OF ONCOLYTIC ADENOVIRUS FOR OVARIAN CANCER||en_US