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Studying Human Prostate Cancer Radioresistance

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Studying Human Prostate Cancer Radioresistance Studying human prostate cancer radioresistance LEI CHANG A thesis submitted in fulfilment of the requirements for the degree of Doctor of Philosophy St George and Sutherland Clinical School Faculty of Medicine University of New South Wales August 2015 i ORIGINALITY STATEMENT ‘I hereby declare that this submission is my own work and to the best of my knowledge it contains no materials previously published or written by another person, or substantial proportions of material which have been accepted for the award of any other degree or diploma at UNSW or any other educational institution, except where due acknowledgement is made in the thesis. Any contributions made to the research by others, with whom I have worked at UNSW or elsewhere, are explicitly acknowledged in the thesis. I also declare that the intellectual content of this thesis is the product of my own work, except to the extent that assistance from others in the project's design and conception or in style, presentation and linguistic expression is acknowledged.’ Signed …………………………………………….............. Date …………………………………………….................. ii Abstract Radiotherapy (RT) plays a prominent role in the treatment of prostate cancer (CaP) alone or as an adjuvant therapy. However, radioresistance is a major challenge in CaP RT. This thesis provides an overview of the literature regarding the mechanisms of CaP radioresistance, radiosensitisers research as well as radioresistance-related biomarkers discovery using proteomic approaches. The aims of the study were to: 1) investigate the roles and association of epithelial-mesenchymal transition (EMT), cancer stem cells (CSCs) and the PI3K/Akt/mTOR signalling pathway in CaP radioresistance; 2) identify proteins involved in CaP radioresistance using liquid chromatography tandem mass spectrometry (LC-MS/MS), validate the identified potential proteins and perform functional study; 3) investigate the therapeutic potential of combination therapy with PI3K/mTOR inhibitors and RT in CaP-radioresistant (RR) cell lines; 4) investigate the therapeutic potential of combination therapy with a PI3K/mTOR dual inhibitor BEZ235 and RT in CaP-RR tumour xenografts. I developed three novel CaP-RR cell lines (PC-3RR, DU145RR and LNCaPRR) by fractioned RT and found enhanced EMT/CSC phenotypes, activation of cell cycle checkpoints, autophagy, DNA repair as well as the PI3K/Akt/mTOR pathway and inactivation of apoptosis proteins in these cell lines. I identified 19 potential proteins in three paired CaP cell lines using LC-MS/MS proteomics. I also chose one identified potential protein marker-ALDOA for functional study and demonstrated that the depletion of ALDOA combined with RT effectively increased radiosensitivity in CaP- RR cells. In in vitro study, I found, in comparison with the combination of single PI3K or mTOR inhibitors and radiation, low-dose of dual PI3K/mTOR inhibitors combined with radiation greatly improved treatment efficacy. I also established PC-3-luc (from PC-3 by transduction) and PC-3RR-luc (from PC-3-luc cell line using fractioned radiation) tumours in subcutaneous (s.c) and orthotopic mouse models, and demonstrated BEZ235 combined with RT could significantly reduce tumour growth iii compared with RT or BEZ235 alone or vehicle control in PC-3RR-luc s.c and orthotopic models. Collectively, findings from my PhD study suggest that CaP radioresistance is related to by multifactorial traits especially associated with EMT, CSCs, PI3K/Akt/mTOR and other signalling pathways. Targeting these proteins or signalling pathways is promising for CaP radiotherapy to overcome radioresistance. iv Acknowledgments I would never have been able to finish my dissertation without the guidance of my dear supervisor, my group members, and support from my family and my friends. Foremost, I would like to express my sincere gratitude to my supervisor Associate Professor Yong Li for his patience, motivation, enthusiasm, and immense knowledge. His encouragement and help have been invaluable for my thesis and my development as a researcher at large. In particular, he supported me during all my research work, encouraged me to apply for several awards and travel grants, supported me to attend several international and domestic conferences and taught me a lot about how to improve my observations, basic experimental skills, manuscript writing, conference presentation and response to all comments; he even personally revised my papers word by word. His guidance helped me in all the time of research and writing of this thesis. I could not have imagined having a better advisor and mentor for my PhD study. Besides my supervisor, I also would like to thank my co-supervisor Associate Professor Peter Graham. He has taken time out of his busy schedule to help me with radiation experiment design in in vitro and in vivo studies, and provided radiation facility for me to carry out all the in vitro radiation experiments. In the past several years, he had always kindly financially supported my research project and funded me to attend several international conferences. I am so lucky to have Peter as my co-supervisor. I would like to thank Dr Valerie Wasinger from Bioanalytical Mass Spectrometry Facility. She led me to the proteomics world and taught me from zero. Val spent plenty of time explaining to me the meaning of proteome, designing proteomics study, carried out experiments, analysing all the data with me, and reviewing my papers and conference abstracts. v I also wanted to thank all collaborators of our group in the animal study. Dr. Carl Power demonstrated and taught me how to establish the orthotopic animal model. Dr Eric Hau helped me to design lead container for mice radiation in animal study. Dr Kevin Qian Wang from Centenary Institute of Cancer, University of Sydney kindly provided me PC-3-luc cell line for my animal study. Dr Martin Bucknall aided me to analyse drug pharmacokinetics in mice. Dr Josephine Joya and Ms Katrina Blazek gave me lots of helpful advice from aminal ethics applications, experiment designing, experiment techniques, to data analysis. I also learned a lot from them about animal experiments and research ethics. Without them, the animal experiments would not have been completed. The same sincere acknowledgement goes to Associate Professor Paul Cozzi for kindly providing constant financial support for my studies and Dr Joseph Bucci for his help for my radiation study and clinical consultant for radioresistance in prostate cancer. I also want to thank Mr Ken Hopper, Mr Ese Enari, Mr Alex Wallace and Mr Peter Treacy from Cancer Care Centre, St George Hospital for their technical support in my radiation studies. In addition, I thank all funding bodies including NHMRC; ARC; Cancer Research Trust Fund at Cancer Care Centre, St George Hospital; Cancer Institute NSW; St George and Southerland Medical Research Foundation; Urology Research Fund; Prostate and Breast Cancer Foundation and China Scholarship Council for their generous supports. Furthermore, my appreciation also extends to my past and present colleagues in the Cancer Research Group in St. George Hospital. Dr. Julia Beretov helped me with all animal histology preparation in this thesis; Dr. Jingli Hao has taught me all the biology and animal experimental skills. We faced the problems, and then discussed and solved them together. She is more like a sister to me and always cares about my morale and my life. Dr. Jie Ni and I helped each other and pulled through together during my whole PhD life. He is always there to support me not only in my study but also in my life. Dr. Junli Deng, and Dr. Ning Li also kindly supported my study and we shared happiness and sorrow together in the past years. vi My very special note of thanks to my dear friends Ms Ning Liu, Ms Lingxi Wu, Ms Xiaoyu Gu, Mr Huizhong Li, Mr David Wei, who brought me lots of joyous time in the past four years. Last but not least, I want to thank my beloved parents, Ms Aijie Zhang and Mr Guoxiang Chang, both of whom have been there for the whole time and exceptionally tolerant and patient throughout. Without my dear parents, I could never fly from China to Australia to achieve my dream. My parents helped me survive all the stress from the past four years and not let me give up. They give me their unlimited love and support throughout my life. vii List of Publications, Presentations and Awards Publications as the first author 1. Chang L, Graham PH, Hao JL, Ni J, Bucci J, Cozzi PJ, Kearsley JH and Li Y. "Acquisition of epithelial–mesenchymal transition and cancer stem cell phenotypes is associated with activation of the PI3K/Akt/mTOR pathway in prostate cancer radioresistance." Cell Death and Disease (2013) 4(10): e875-e875. 2. Chang L, Graham PH, Hao JL, Bucci J, Cozzi PJ, Kearsley JH and Li Y. "Emerging roles of radioresistance in prostate cancer metastasis and radiation therapy." Cancer Metastasis Review (2014) 33(2-3): 469-496. 3. Chang L, Graham PH, Hao JL, Ni J, Bucci J, Cozzi PJ, Kearsley JH and Li Y. "PI3K/Akt/mTOR pathway inhibitors enhance radiosensitivity in radioresistant prostate cancer cells through inducing apoptosis, reducing autophagy, suppressing NHEJ and HR repair pathways." Cell Death and Disease (2014) 5: e1437. 4. Chang L, Graham PH, Hao JL, Ni J, Bucci J, Cozzi PJ, Kearsley JH and Li Y. " Targeting PI3K/Akt/mTOR signalling pathway in the treatment of prostate cancer radioresistance." Critical reviews in Hematology/Oncology. 2015 in press. (DOI: http://dx.doi.org/10.1016/j.critrevonc.2015.07.005) 5. Chang L, Graham PH, Hao JL, Bucci J, Malouf D, Gillatt D, Li Y. Proteomics discovery of radioresistant cancer biomarkers for radiotherapy. Cancer Letters. 2015 in press. (DOI:10.1016/j.canlet.2015.09.013.) viii 6. Chang L, Graham P, Hao JL, Ni J, Deng JL, Bucci J, Malouf D, Gillatt D, Li Y.
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