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Title: PARP inhibition in novel oropharyngeal cancer cell lines
Author: Pirotte, Evelyne
ISNI:       0000 0004 7228 9579
Awarding Body: Cardiff University
Current Institution: Cardiff University
Date of Award: 2017
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In recent decades many developed countries have seen unprecedented increases in incidence of Human Papillomavirus (HPV) associated oropharyngeal squamous cell carcinoma (OPSCC). HPV-positive OPSCC represents a new disease entity and preclinical assessment of novel therapies is hampered by a lack of relevant in vitro models. It is well-established that HPV-positive OPSCC patients generally survive longer than HPV-negative patients, and this may be partly attributable to defective repair of DNA double-strand-breaks in HPV-positive tumours. This study aimed to develop novel cell line models of HPV-OPSCC and use them, and previously validated lines, to test the hypothesis that defective DNA repair in HPV-positive cells could be exploited by synthetic lethal therapy using the Poly (ADP-ribose) polymerase (PARP) inhibitor Olaparib. Two novel HPV-positive OPSCC cell lines were derived and characterised. mRNA sequencing confirmed expression of the HPV oncogenes and HPV integration state, but did not show consistent differences in transcript levels of genes involved in DNA repair between HPV-positive and negative lines. The effects of Olaparib were assessed in a panel of eight cell lines, including effects on colony formation, cell cycle distribution, DNA double-strand-break persistence and p53 activity. All lines were sensitive to high doses of Olaparib (10 μM), however at doses between 0.5-1 μM, the surviving fractions differed significantly between lines. Two HPV-positive lines were sensitive to Olaparib (Surviving Fraction (SF) < 40%), and two were resistant (SF > 80%). Neither HPV-status, nor basal levels of PARP correlated with Olaparib sensitivity. The data were not consistent with the original hypothesis, but did suggest that monotherapy with PARP inhibitors might be useful in some OPSCC patients. The study also included an investigation into the natural history of HPV in the oropharynx. This demonstrated that HPV infection is a rare event in non-malignant tonsil tissue (prevalence of 0%: 95% confidence interval (CI) 0-0.58%).
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available