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Title: Preclinical modelling of hepatocellular carcinoma and novel strategies for therapeutic intervention
Author: Willoughby, Catherine Elizabeth
ISNI:       0000 0004 7971 2800
Awarding Body: Newcastle University
Current Institution: University of Newcastle upon Tyne
Date of Award: 2018
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Hepatocellular carcinoma (HCC) is the most common form of liver cancer and the third-highest cause of cancer mortality worldwide. Existing treatments for HCC are limited, conferring a 5-year survival rate of just 5%. This thesis centred on evaluating two novel therapeutic approaches for HCC in cell lines and appropriate preclinical models. DNA-dependent protein kinase (DNA-PK) is a key component in DNA double-strand break repair via non-homologous end-joining. Elevated DNA-PK expression and activity in HCC are strongly correlated with increased tumour grade, resistance to DNAdamaging therapies and poor survival. Selective inhibition of DNA-PK in combination with DNA-damaging agents was explored as a potential therapeutic strategy in HCC using NDD0004 - a novel, orally-bioavailable inhibitor of DNA-PK catalytic activity. NDD0004 dose-dependently inhibited activation of DNA-PK in HCC cell lines in vitro. NDD0004 sensitised HCC cell lines to doxorubicin and ionising radiation in proliferation and survival assays by around 5-fold, and significantly increased DNA damage following treatment. In vivo efficacy was evaluated using a novel model of localised doxorubicin therapy, involving intratumoural injection of doxorubicin-loaded polymer beads into established human HCC xenografts in CD1 nude mice. Twice-daily oral treatment with 30 mg/kg NDD0004 significantly augmented the anti-tumour activity of doxorubicinloaded beads and increased tumour γH2AX staining. The transcription factor CCAAT/enhancer-binding protein alpha (C/EBPα) is involved in normal hepatocyte functioning and response to injury, and is frequently downregulated in HCC. Small activating RNA (saRNA)-mediated upregulation of C/EBPα was examined as a novel therapeutic approach, and found to inhibit HepG2 proliferation in vitro. The in vivo efficacy of C/EBPα-saRNA is currently under evaluation in a 48-week dietary model of non-alcoholic fatty liver disease-induced HCC. Collectively, these data strongly support the concept of combining a DNA-PK inhibitor with localised DNA-damaging therapies, and suggest that saRNA-mediated upregulation of C/EBPα may be beneficial in the treatment of HCC.
Supervisor: Not available Sponsor: Cancer Research UK
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available