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Host Cell Factors in Ovarian Cancer Influencing Efficacy of Oncolytic Aenovirus Dl922-947 Flak, Magdalena Barbara

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Host Cell Factors in Ovarian Cancer Influencing Efficacy of Oncolytic Aenovirus Dl922-947 Flak, Magdalena Barbara Host cell factors in ovarian cancer influencing efficacy of oncolytic aenovirus dl922-947 Flak, Magdalena Barbara 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 For additional information about this publication click this link. https://qmro.qmul.ac.uk/jspui/handle/123456789/553 Information about this research object was correct at the time of download; we occasionally make corrections to records, please therefore check the published record when citing. For more information contact [email protected] Host Cell Factors in Ovarian Cancer Influencing Efficacy of Oncolytic Adenovirus dl922-947 Magdalena Barbara Flak A thesis submitted to the University of London (Faculty of Science) for the degree of Doctor of Philosophy February 2010 Centre for Molecular Oncology and Imaging Institute of Cancer Barts and the London School of Medicine and Dentistry Charterhouse Square, London EC1M 6BQ 1 I, Magdalena Barbara Flak, hereby confirm that the work presented in this thesis is original and is my own. Work undertaken by others in contribution to this thesis has been clearly indicated. Where information has been derived from other sources, this has been acknowledged and appropriately referenced. Signed ………………………………... 2 Acknowledgments First of all, I would like to thank my supervisor Prof Iain McNeish. He has given me the opportunity to work on this exciting project. But more importantly, Iain, your expertise, encouragment and genuine support have guided me throughout my PhD and allowed me to grow as a scientist and as a person. I owe my deepest gratitude to Jes, without whom I may not have come this far. Your support, neverending patience and love have carried me through the most frustrating, difficult times. Having you as a companion to celebrate the great moments made them all the more precious. You have always believed in me, and I am forever in your debt. I would like to thank my parents. They were always, always there to listen, to share disappointments and successes. You have instilled in me the awe and curiosity of all things around me. You have dedicated your strength to letting me follow my ambitions. This thesis would not have been possible without you. Thomas, I thank you for brotherly supervision of my first “lab experiments” at home, mixing coloured water in test tubes, and for my first microscope. In short, for supporting a dream and putting things into perspective. Z całego serca dziękuję moim kochanym Babcią i Dziadką za pomyślność i modlitwe. Za miejsce w waszych sercach. Many friends have supported me on my path to a PhD, for which I cannot thank enough. Anke has been patient, wise and wonderful from day one. I am grateful to Maren, Mary, Manuel and Charmaine for their great support. I thank Prof B. Volk for encouragment and inspiration. Heartfelt gratitude goes to my wonderful colleagues and friends Kyra, Carin, AM, Sarah, Michael, Lynda, Katrina, Michelle and Claire, for lab wisdom, for listening to my wingeing, for laughter, midnight meetings and chocolate. You have made the past years cheerful and enjoyable. Never forget: Doppelt gemoppelt haelt besser. I would like to thank Katrina, Claire, Sarah and Claude in particular, for contributing valuable work to this thesis. I am truly grateful for your genious heads and hands making these experiments happen. It was an honour and a pleasure to work with all the great people that make the Centre for Molecular Ongology & Imaging. I am very thankful for generous help and interesting discussions. I have met some great people and friends amongst you. I thank all those, whose names do not appear here, despite their contribution to this PhD. Please forgive me. 3 Abstract Adenoviral gene therapy holds great potential for cancer treatment, but is limited by a lack of efficient vectors. dl922-947, an E1A CR2-deleted adenovirus, replicates selectively within and lyses cancer cells. It is believed that its selectivity depends upon abnormalities in the cell cycle regulatory Rb pathway and subsequent G1/S checkpoint, observed in 90% of human cancers. The cytotoxic efficacy of dl922-947 is greater than that of wild-type adenovirus and dl1520 (Onyx-015). Nevertheless, sensitivity to dl922- 947 varies widely among ovarian cancer cell lines, despite similar infectivity. My work aimed to identify host cell factors that influence cytotoxicity and which could be potential biomarkers in clinical trials. Surprisingly, comparison of ovarian cancer lines indicated that cytotoxicity correlated poorly with infectivity, replication and virion production. Immunoblotting suggested correlation between sensitivity to dl922-947 and overexpression of p21, p27, Cyclin D, cdk4 and p16. Subsequent experiments confirmed a role for p21 in dl922-947 cytotoxic activity. In vitro and in vivo, Hct116 p21+/+ cells were significantly more sensitive to dl922-947 than matched p21-/- cells. p21 knock-down by siRNA in TOV21G and IGROV-1 cells reduced dl922-947 cytotoxicity, whilst re-expression in ACP-WAF1 cells increased activity. p21 expression was also greater in sensitive transformed TOSE cells compared to resistant normal IOSE25 cells. Results suggest that p21 promotes dl922-947 activity by stabilising Cyclin D thus promoting cell cycle progression. Comparative microarray analysis in TOSE1, 4 and IOSE25 cells and in MRC5 and MRC5-VA cells suggested determinants of dl922-947 activity beyond the Rb pathway, which may also prove valuable biomarkers. Moreover, pathways and processes emerged, correlating with sensitivity, and meriting future investigation. Together, my results suggest that a cellular environment conducive for dl922-947 function includes mediators of proliferative capacity, amongst which p21 plays a role in enhancing activity of the virus. 4 A scientist in his laboratory is not a mere technician: He is also a child confronting natural phenomena that impress him as though they were fairy tales. Marie Curie 5 Contents 1 Introduction ................................................................................................ 18 1.1 Ovarian Cancer .................................................................................... 19 1.2 Stratified Medicine ............................................................................... 24 1.3 Gene Therapy ...................................................................................... 25 1.3.1 Oncolytic gene therapy.................................................................. 27 1.3.2 Oncolytic viruses in cancer therapy ............................................... 28 1.3.3 Deletion mutants for cancer therapy ............................................. 30 1.4 Adenoviridae ........................................................................................ 33 1.4.1 Structure and Genome .................................................................. 34 1.4.2 Early genes ................................................................................... 35 1.4.3 Life cycle of Adenovirus ................................................................ 39 1.5 Oncolytic adenoviruses ........................................................................ 43 1.5.1 Second Generation Adenoviral Vectors ........................................ 44 1.5.2 dl922-947 ...................................................................................... 46 1.5.3 dl922-947 in cancer cells ............................................................... 46 1.5.4 Immunogenicity of Adenoviral vectors ........................................... 47 1.5.5 Further limitations of dl922-947 and other adenoviruses .............. 48 1.5.6 Future of virus-based therapy in cancer ........................................ 49 1.6 The Rb pathway and cell cycle control ................................................ 51 1.6.1 Rb pathway and cell cycle regulation ............................................ 51 1.6.2 Rb pathway and cancer ................................................................. 64 1.6.3 E2F and the Rb pathway in ovarian cancer ................................... 66 1.7 Aims of this study ................................................................................. 68 2 Materials and Methods .............................................................................. 69 2.1 Cell lines .............................................................................................. 70 2.1.1 Human ovarian cancer cell lines ................................................... 70 2.1.2 Other human cell lines................................................................... 70 2.2 Adenoviral mutants .............................................................................. 70 2.3 Virus amplification ................................................................................ 71 2.4 Viral particle count ............................................................................... 72 2.5 Viral titration by TCID50 assay .............................................................. 72 2.6 Virion detection in serum samples by TCID50 ...................................... 73 2.7 Sensitivity of cells to adenoviral cytotoxicity ........................................ 73 2.8 Infectability with adenoviral vectors ..................................................... 74 2.8.1 Flow cytometry .............................................................................. 74 6 2.8.2 Quantitative PCR .........................................................................
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