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Novel Biomarkers in the Management of HPV-Positive & -Negative Oropharyngeal Carcinoma January 2016

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Novel Biomarkers in the Management of HPV-Positive & -Negative Oropharyngeal Carcinoma January 2016 THE UNIVERSITY OF SHEFFIELD Novel Biomarkers in the Management of HPV-Positive & -Negative Oropharyngeal Carcinoma Thesis submitted to the University of Sheffield for the degree of Doctor of Philosophy Robert Bolt Department of Oral & Maxillofacial Pathology January 2016 Abstract Human Papillomavirus (HPV)-related oropharyngeal carcinoma is considered to be in the early stages of an epidemic1-12. A marked rise in the incidence of this sexually-transmissible cancer has captured the public interest, and much debate exists over both the prophylactic and therapeutic strategies currently employed to manage this healthcare priority. HPV-positive oropharyngeal carcinoma is associated with highly favourable oncological outcomes. Clinical attention over recent years has been paid to the potential de-escalation of therapy in order to account for the disease’s favourable prognosis, in addition to reducing therapeutic burden in a well-prognosticating, younger patient cohort, for which consequences of radical chemo-radiotherapy strategies may disproportionately impact on longer-term quality of life. Whilst optimising the management of the ever-increasing proportion of HPV-positive oropharyngeal carcinomas is desirable and highly justifiable, it appears the poorer prognosticating HPV-negative oropharyngeal carcinoma has at least in part become overlooked. Oropharyngeal carcinoma is unique in comparison to many other established HPV-related cancers inasmuch as a clear HPV-negative subset exists, to which established aetiological factors (tobacco smoking and alcohol consumption) strongly correlate. For most other HPV- related carcinomas, such as cervical, anal and penile, tumours classified as HPV-negative are either regarded as potentially-virus containing, or else cannot be correlated to a definitive aetiological agent. Comparison of HPV-positive and -negative oropharyngeal carcinoma therefore offers unprecedented insight into the biological significance of each aetiological agent, and how prognostication of each disease may relate to tumour behaviour at a molecular level. Whilst improved outcomes may be attributable in part to greater radio- sensitivity due to preservation of key wild-type genes in HPV-positive tumours, more comprehensive biological differences are likely to underpin the overall behaviour of disease – indeed, surgical outcomes are also favourable in HPV-positive disease. This thesis explores the potential for the tumour microenvironment to differ between HPV- positive and -negative disease. We hypothesised that due to the strictly epitheliotropic nature of the Human Papillomavirus, activation of the tumour microenvironment would potentially be suppressed in order to avoid host clearance of pathogen during the natural history of viral infection, whereas penetrating carcinogens linked to tobacco smoking and alcohol consumption may either directly derange the stroma or, less contentiously, induce an increased mutational load which in turn in turn may offer greater opportunity for tumour evolution towards deranged microenvironmental signalling. i A 2D tissue culture model of the tumour microenvironment was created and used to test the hypothesis of a difference in microenvironmental interactions between HPV-positive versus HPV-negative disease, and normal stroma. Confirmation of an increase in migration- inducing signals from the modelled normal fibroblast stroma in HPV-negative disease led to further investigation at a molecular level using cytokine array technology. Further ELISA quantification and recombinant protein dose-response analysis ultimately identified Human Hepatocyte Growth Factor (HGF) as a primary candidate molecule for driving the additional migration observed in response to activated stroma. IL-6, co-secreted with HGF by stimulated fibroblasts, was also found to have a supporting role through the co-induction of STAT3. Final confirmation of HGF’s principal role in inducing HPV-negative tumour migration was undertaken using the clinically relevant c-Met inhibitors, foretinib & INCB28060 (recently rebranded as capmatinib). Further experimentation using 3D models of HPV-negative tumour spheroid invasion found fibroblast co-culture with tumour lines a necessary prerequisite for invasion. Moreover, disruption of HGF signalling within co-cultures led to near-total abrogation of invasion. ii Acknowledgements I would like to take this opportunity to give thanks for the huge amount of support I have received from colleagues within my direct research team and further afield. I would like to give particular thanks to the following people, who have been instrumental in the progress of my work; I would like to thank my two supervisors, Dr. Keith Hunter and Dr. Bernadette Foran for their ongoing support and guidance throughout the project and its conception, in addition to their efforts in orchestrating collaborations with Leeds hospital for the clinical element of the study aimed to extend beyond the PhD. I would also like to thank Dr. Hunter for taking great personal effort to source, negotiate MTAs and travel to retrieve the cell lines used within this project, donated as kind gifts by Prof. Eric Blair (Leeds) and Dr. S. Thavaraj (London). Particular thanks go to those who have helped with my training in tissue culture and directly related experimental techniques, including Dr. Vanessa Hearnden, Dr. Lav Darda, Dr. Fahad Hakami, Dr. Jill Callaghan, Dr. Sally Thomas and Dr. Taznuva Kabir. I would like to extend these thanks to acknowledge the particular efforts of Dr. Vanessa Hearnden, who has been invaluable in establishing a reproducible method of undertaking migration assay, in addition to patiently working through flow cytometry analysis of mitomycin treatments with me. I would like to point out the inclusion of a graph relating cell line UD SCC2 (Figure 1.6b), which represents Dr. Hearnden’s own work undertaken with my support, used as a demonstration case for other cell lines. Special thanks also should be extended to Dr. Sally Thomas for the collaborative work on the western blot data depicted in Figures 5.6 a & b. I would like to give additional thanks to Jill Callaghan for her guidance in PCR analysis, including her assistance in the sourcing and reconstitution of custom TaqMan probes. I would also like to give thanks to Dr. Fahad Hakami, Dr. Lav Darda, Dr. Genevieve Melling and Brenka McCabe for their advice in running PCR experiments. Specific thanks also to Drs. Daniel Lambert, Craig Murdoch, Simon Whawell, Lynne Bingle, Eileen Crawford, Ali Khurram and Abigail Pinnock for offering direct guidance and sharing access to a number of resources and consumables, without which progress in particular elements of the project would have been unfeasible. I would also like to give thanks to Jason Heath, Brenka McCabe, Michelle Gaunt, David Thompson and Hailey Stanhope for their help in accessing and ordering a host of materials, in addition to guidance in the use of histopathology equipment and assistance with specimen processing. iii Finally, I would like to extend my thanks to Yorkshire Cancer Research and Cancer Research UK for the joint-funded Clinical Research Fellowship which has allowed this research to be undertaken. iv Contents Literature Review Page 1. Introduction 1 2. The Human Papillomavirus (HPV) as a causative agent in cancer 5 3. Epidemiology of HPV-positive Oropharyngeal Carcinoma (OPC) 14 4. Mechanism of HPV-related carcinogenesis 17 5. Accounting for prognosis 22 6. Methods of HPV detection in OPC 25 7. Management of HPV-positive disease 28 8. Management of HPV-negative disease 29 9. Stromal Derangement 31 10. Hypothesis, aims and objectives 34 Chapter 1: Confirmation of HPV Status, Validation of Cell Lines & Optimisation of Migration Assay 1. Introduction 37 2. Methods 40 3. Results 51 4. Discussion 62 Chapter 2: 2D Modelling of the Microenvironment in HPV-positive & -negative Disease 1. Introduction 65 2. Methods 67 3. Results 74 4. Discussion 82 Chapter 3: Cytokine Array Analysis of Tumour & Fibroblast Conditioned Media 1. Introduction 85 2. Methods 88 v Page 3. Results 91 4. Discussion 113 Chapter 4: Investigation of a CXCR-2/IL-6 Basis of Fibroblast Recruitment and Support 1. Introduction 122 2. Methods 125 3. Results 133 4. Discussion 146 Chapter 5: Progressive Analysis of Candidate Molecules Identified by Cytokine Array 1. Introduction 152 2. Methods 158 3. Results 168 4. Discussion 180 Chapter 6: The Role of HGF in 2D Modelled Migrations 1. Introduction 187 2. Methods 195 3. Results 209 4. Discussion 237 Chapter 7: Conditioned Media Induction of Fibroblast Senescence 1. Introduction 246 2. Methods 248 3. Results 250 4. Discussion 254 Chapter 8: Determining Validity of 2D Experimental Findings 1. Introduction 256 2. Methods 258 vi 3. Results 265 4. Discussion 280 Chapter 9: Further Work Page 1. Introduction 283 2. Further Work I 288 3. Further Work II 295 4. Further Work III 306 5. Further Work IV 307 6. Further Work V 309 7. Further Work VI 311 References 313 Appendices 345 vii List of Abbreviations 2D Two dimensional 3D Three dimensional ALI Air-liquid interface B2M Beta-2-microglobulin CAF Cancer-Associated Fibroblast CDK Cyclin-Dependent Kinase CK Cytokeratin c-Met Human Hepatocyte Growth Factor Receptor CXCL Chemokine CXC-motif Ligand DAB Diaminobenzidine DDR DNA damage reponse DED De-Epidermised Dermis DeESCALaTE Determination of Epidermal growth factor receptor-inhibitor (cetuximab) vs Standard Chemotherapy early and Late Toxicity Events in Human Papilloma Virus Positive Oropharyngeal
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