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Development of a Functional Assay to Test for Homologous Recombination

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Development of a Functional Assay to Test for Homologous Recombination Use of the androgen signalling pathway to identify ovarian cancer patients suitable for hormonal therapy Thesis submitted for the degree of Doctor of Philosophy Northern Institute for Cancer Research Angelika Kaufmann Clinical Research Fellow Northern Gynaecological Cancer Centre, Queen Elizabeth Hospital, Gateshead Supervisors Professor Richard J Edmondson Professor of Gynaecological Oncology, Faculty Institute for Cancer Sciences, University of Manchester Professor Craig N Robson Professor of Molecular Urology, NICR, Newcastle University Luke Gaughan University Lecturer, NICR, Newcastle University March 2020 Statement of originality The work presented in this thesis is original except where acknowledged in the references and was carried out between February 2012 until January 2015 at the at the Northern Institute for Cancer Research, Newcastle University and the Northern Gynaecological Oncology Centre, Gateshead. It has not been, or will not be, submitted for any other qualification at any other university. i ii Abstract Background Despite confirmed AR expression in epithelial ovarian cancer (EOC), clinical response to anti- androgen treatment is poor. Stratification of susceptible individuals with a specific biomarker, such as the previously described Rab35, might enable more effective treatment strategies. Abiraterone, a steroid synthesis inhibitor, might be of therapeutic benefit in specific EOC subgroups. Methods Primary cell cultures (PCO) generated from ascites were used as a representative model for the heterogeneity of EOC. PCOs were examined for AR and Rab35 expression at mRNA and protein level and were stimulated with androgens to evaluate subsequent Rab35 expression. CYP17 expression was measured in ovarian cancer cell lines and PCOs and the effect of abiraterone on proliferation was assessed in two ovarian cancer cell lines. Results The AR expression was widely different when examined with qRT-PCR, Western blotting and immunohistochemistry. No correlations were found between the modalities for either AR or Rab35 expression. In contrast, AR and Rab35 expression showed a positive correlation at the protein and mRNA level. However, androgen treatment of PCOs showed >50% increase in Rab35 mRNA expression in only 40% of PCOs. CYP17 expression was confirmed in all examined cell cultures and PCOs at both, the protein and mRNA level. Abiraterone treatment of the ovarian cancer cell lines led to significant inhibitory effects on proliferation. On protein level however, abiraterone exposure resulted in increased expression of AR and CYP17. Conclusion Although AR expression was confirmed in POCs, it remains unclear which technique would be most suitable to stratify for androgen expressing tumours. iii Rab35 in PCOs appeared to be androgen-related and hence may not be a suitable biomarker in EOC for AR. The inhibitory effect of abiraterone on proliferation that was observed in ovarian cultures is suggestive of a dual action of the compound. Response to abiraterone exposure in PCOs might help to determine potential treatment effects. iv Acknowledgements I would like to thank my supervisors Prof Richard Edmondson and Prof Craig Robson for their guidance, support and trouble-shooting during this project and Luke Gaughan and Peter Donoghue for enduring my many questions. The immense help, teaching, advice and support from all the members from the Solid Tumour Target Discovery Group and my “ovarian partners in crime” Rachel O’Donnell and Aiste McCormick has greatly influenced this project. I am grateful for the funding received from and the lessons learnt at the Northern Gynaecology Oncology Centre (NGOC) during my time in Newcastle and Gateshead. But most of all, I would like to thank the women donating ascites to enable this project in the hope to selflessly help other ovarian cancer sufferers. Meeting these women and their families has touched me deeply. Family and friends near and afar: for your love and support before, throughout and after this journey- thank you. v vi Table of Contents Statement of originality ............................................................................................................. i Abstract ....................................................................................................................................iii Acknowledgements ................................................................................................................... v Table of Contents .................................................................................................................... vii List of Abbreviations ............................................................................................................... xi List of Figures ........................................................................................................................ xiv List of Tables ........................................................................................................................xviii 1 Introduction ...................................................................................................................... 1 1.1 Ovarian cancer ............................................................................................................. 1 1.1.1 Epidemiology of ovarian cancer ........................................................................... 1 1.2 Classification of ovarian cancer ................................................................................... 3 1.2.1 Historical classification of ovarian cancer ............................................................ 3 1.2.2 New classification of epithelial ovarian cancer .................................................... 3 1.3 Aetiology of ovarian cancer ......................................................................................... 4 1.4 Risk factors for ovarian cancer .................................................................................... 7 1.4.1 Hormonal factors .................................................................................................. 8 1.5 Protective factors for ovarian cancer ......................................................................... 10 1.6 Screening in ovarian cancer ....................................................................................... 11 1.7 Treatment in ovarian cancer ....................................................................................... 13 1.7.1 Treatment in primary disease ............................................................................. 13 1.7.2 Treatment of recurrent disease ........................................................................... 14 1.7.3 Targeted therapy ................................................................................................. 14 1.8 Androgens and ovarian cancer ................................................................................... 19 1.8.1 Androgens in the healthy female ........................................................................ 19 1.8.2 Androgen receptor (AR) ..................................................................................... 21 1.8.3 Androgen receptor signalling in ovarian cancer ................................................. 22 1.8.4 Androgen Receptor expression in ovarian cancer .............................................. 25 1.8.5 Androgen receptor expression in ovarian cancer cell lines ................................ 26 1.8.6 Androgen receptor expression data in primary cell cultures .............................. 26 1.8.7 Epidemiologic evidence ..................................................................................... 27 1.8.8 Anti-Androgen therapy in ovarian cancer .......................................................... 28 1.9 GTPases ..................................................................................................................... 31 1.9.1 Rab subfamily ..................................................................................................... 32 1.10 Cytochrome P450 17α (CYP17) ............................................................................ 35 1.10.1 Congenital 17-hydroxylase/ 17,20 deficiency .................................................... 36 1.10.2 CYP17 and ovarian cancer ................................................................................. 36 1.10.3 Abiraterone (CB7598) ........................................................................................ 37 2 Materials and Methods................................................................................................... 42 2.1 General Laboratory Practice ...................................................................................... 42 vii 2.2 Tissue culture ............................................................................................................ 42 2.2.1 Cell lines ............................................................................................................ 42 2.2.2 Cell culture maintenance .................................................................................... 43 2.2.3 Primary cultures (PCO) ...................................................................................... 44 2.2.4 Cell culture storage ............................................................................................ 44 2.2.5 Thawing of cell cultures ..................................................................................... 45 2.3 Immunofluorescence ................................................................................................
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