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Gene Profiling in Soft Tissue Sarcoma

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Gene Profiling in Soft Tissue Sarcoma #,#0-$'*',%', -$22'113# 0!-+S 0#"'!2'4#4*3#-$', 0!-+3+-30 0-%0#11'-,," 304'4* Paromita (Romi) Das Gupta A Thesis submitted to The University of New South Wales Faculty of Medicine for the Degree of Doctor of Philosophy (PhD) August 2007 COPYRIGHT STATEMENT ‘I hereby grant the University of New South Wales or its agents the right to archive and to make available my thesis or dissertation in whole or part in the University libraries in all forms of media, now or here after known, subject to the provisions of the Copyright Act 1968. I retain all proprietary rights, such as patent rights. I also retain the right to use in future works (such as articles or books) all or part of this thesis or dissertation. I also authorise University Microfilms to use the 400 word abstract of my thesis in Dissertation Abstract International. I have either used no substantial portions of copyright material in my thesis or I have obtained permission to use copyright material; where permission has not been granted I have applied/will apply for a partial restriction of the digital copy of my thesis or dissertation.' Signed ……………………………………………........................... Date ……………………………………………........................... AUTHENTICITY STATEMENT ‘I certify that the Library deposit digital copy is a direct equivalent of the final officially approved version of my thesis. No emendation of content has occurred and if there are any minor variations in formatting, they are the result of the conversion to digital format.’ '%,#"UUUUUUUUUUUUUUUUUTTTTTTTTTTTTTTTTTTTTTTTTTTT 2#UUUUUUUUUUUUUUUUUTTTTTTTTTTTTTTTTTTTTTTTTTTT 2 ORIGINALITY STATEMENT The majority of the work described in this thesis was performed by myself, however important contributions were made by others. Cytogenetic analysis of the newly characterised cell lines was kindly performed by Dr Robyn Lukeis at SydPath, St Vincent’s Hospital, Sydney. TRAP assay for telomerase and APB staining for ALT in the above cell lines was performed by Jeremy Henson at Children’s Medical Research Institute, Sydney. KIT mutation analysis of the GIST-M cell line was carried out in collaboration with Maurice Loughrey and Victoria Beshay at the Peter MacCallum Cancer Centre, Melbourne. TP53 mutation analysis of the LMS-LFS cell line was carried out in collaboration with Dr Rodney Scott and his team at Hunter Area Pathology Service. Statistical analysis of gene expression data was carried out in collaboration with Dr Rohan Williams at the School of Biotechnology & Biomolecular Sciences (BABS), UNSW. 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 contribution made to the research by others, with whom I have worked at UNSW or elsewhere, is 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. Paromita (Romi) Das Gupta August 2007 3 ABSTRACT Despite improvements in the clinical management of soft tissue sarcomas (STS), 50% of patients will die of metastatic disease that is largely unresponsive to conventional chemotherapeutic agents. The aims of this study were to identify genes and pathways that are dysregulated in progressive and metastatic STS. In addition to this, cell lines from fresh tumours were initiated and established, thus increasing the repository of cell lines available for functional studies. Recent advances in the understanding of the molecular biology of STS have thus far not resulted in the use of molecular markers for clinical prognostication. Identifying novel genes and pathways will lead to molecular diagnostic methods to better stratify prognostic groups and could identify cellular targets for more efficacious treatments. Gene expression profiling of sarcoma cell lines of increasing metastatic potential revealed over-expression of genes involved in the epidermal growth factor (EGF) and transforming growth factor beta (TGFβ) pathways. Factors involved in invasion and metastasis such as integrins and MMPs were over-expressed in the cell lines with higher metastatic potential. The developmental Notch pathway and cell cycle regulators were also dysregulated. NDRG1 was significantly over-expressed in the high grade sarcoma cell line, a novel finding in sarcomas. The expression of EGFR, NDRG1 and other genes from the above pathways was validated using quantitative RT-PCR in real time (qRT-PCR). A tissue microarray (TMA) comprising STS of varying tumour grades was constructed for high throughput assessment of target proteins. EGFR, its activated form and its signal transducers were investigated using immunohistochemistry (IHC). Activated EGFR (HR 2.228, p < 0.001) and phosphorylated Akt (HR 2.032, p = 0.003) were found to be independent predictors of overall survival and both correlated with tumour grade. Of the several STS cultures initiated and maintained, two of these cell lines were fully characterised in terms of cytogenetics, telomerase and alternate lengthening of 4 telomeres (ALT) status, KIT and TP53 mutation and the expression of certain biomarkers using both qRT-PCR and IHC. In summary, transcript profiling identified several potential biomarkers of tumour progression and metastasis in STS. Crucially, activated EGFR and pAkt were found in a cohort of STS samples to correlate with clinical outcome, identifying them as potential diagnostic and therapeutic targets in the treatment of STS. Activated EGFR can be used as a diagnostic marker for patient selection, as well as for target effect monitoring. Furthermore, the cell lines established in this project will serve as valuable tools in future preclinical studies. 5 ACKNOWLEDGEMENTS The translational laboratory based research that this PhD involved, required in a sense, a new beginning – the promise and challenge of being able to bring clinical and surgical training and knowledge to a different sphere of personal and mental growth. But as with most new challenges, one has to begin at the beginning and I am grateful to many people who were generous with their time and skills, for pointing me in the right direction. I owe a debt of gratitude to my supervisor, Prof Phil Crowe, who has been a mentor and a sounding board through much of my surgical training as well as during the period while the Masters evolved into a PhD – because as always, there was more to do. It has been a tremendous support to have his encouragement, not just in the research realm but also at the coal face of personal and professional issues. To my other supervisor Dr Jia Lin Yang, I owe many thanks. His perceptive help with the nuts and bolts of research strategy and enormous contribution to the statistical analysis of the patient data has been invaluable. Prof Ian Dawes, as another co- supervisor, was similarly insightful in his direction at the outset, when the research strategy was being formulated. Without his support and generosity, I would not have been able to carry out a substantial part of this research at the Ramaciotti Centre in UNSW. I am indebted to Prof Pam Russell for taking me under her wing and over the years providing the right advice and encouragement. Her ability to perform rescue missions at precisely the right moments is a gift. I have greatly valued her enthusiasm and wisdom. If one of the goals in embarking on a PhD is to acquire unofficial supervisors and turn them into lifelong friends, then I have executed this with aplomb. Dr Ruby Lin who happened to be at the Ramaciotti Centre, was co-opted into this role, which she willingly filled. As friend, co-conspirator and “supervisor”, her advice on matters intellectual, technical and otherwise, has been the source of much support over this time. 6 Many others at the Oncology Research Centre at Prince of Wales, at the Ramaciotti Centre, UNSW and other facilities have given of their time and provided much needed company in the midst of cell culture and RNA extraction. To Kim Ow, I owe many thanks, for his gentle instruction in immunostaining and his conversations on the more important things in life. Alex, Liz, Sheri, Hung, Lara and Michelle, who cheerfully answered my most basic questions at the start of this road. Ben, Bronwyn, Helen and Shining at the Ramaciotti Centre for company during those long microarray experiments. I am grateful to Dr Robyn Lukeis at St Vincent’s Hospital for her patience and guidance as I attempted to grasp the rudiments of cytogenetics. I also owe a debt of thanks to Drs Maurice Loughrey and Victoria Beshay at Peter Mac, Melbourne, Dr Jeremy Henson and Prof Reddel at CMRI, Westmead, Prof Rodney Scott at Hunter Area Pathology Services and Dr Louise Evans for their help in various aspects of this research. On a more personal note, this work would simply not have been possible without my extended family and friends. The Wallace clan, from whom I have had much love and support. Ten tsi, my faithful hound and study buddy in the long hours of writing, Buddhist meditation dog, cannot go unmentioned. My husband, Mark, best friend and kindred spirit, there when all else is crashing. His unwavering love and belief in my ability has been an integral part of my sustenance. Finally, and most importantly, everything I am and everything I strive to be, comes from my parents, Nikhil and Jharna. The best of childhoods was mine and ours was a house of laughter and love where I learnt what was most important and what cannot be taught. Romi 7 &'15-0)'1"#"'!2#"2-+7$2&#0 &-*'4#"5'2&/3'#25'1"-+,"3, 0'"*#"#,2&31'1+ ,"*#$25'2&!-30%#,"%0!#3,2-3!&#" 8 PRESENTATIONS, AWARDS AND ABSTRACTS JL Yang, R Das Gupta, IW Dawes, P J Crowe “Potential application of EGFR targeted therapies in different types of sarcomas” American Association for Cancer Research (AACR) 97th Annual Meeting, Washington D.C, April 2006.
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