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Novel Therapies for High-Risk Leukaemia in Children

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Novel Therapies for High-Risk Leukaemia in Children Novel Therapies for High-Risk Leukaemia in Children Mawar Murni Karsa A thesis submitted to the University of New South Wales in fulfilment of the requirements for the degree of Doctor of Philosophy Children’s Cancer Institute Australia and School of Women’s and Children’s Health Faculty of Medicine The University of New South Wales September 2018 i THESIS DISSERTATION 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 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.’ Signed …………………………………………….......... 6 September 2018 Date …………………………………………….............. ii COPYRIGHT STATEMENT ‘I hereby grant the University of New South Wales or its agents 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 350 word abstract of my thesis in Dissertation Abstract International (this is applicable to doctoral theses only). 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 …………………………………….… 6 September 2018 Dated …………………………….…………. iii 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.’ Signed …………………………………. 6 September 2018 Dated ………………………………….. iv ACKNOWLEDGEMENTS Firstly, I would like to thank my supervisors, Dr. Michelle Henderson and Dr. Klaartje Somers for the opportunity to do my PhD in the Experimental Therapeutics program. I could not have done this project without their endless support, guidance and understanding over the last four years. They have been great mentors and their passion for science have shown me how exciting this field can be. I also thank my co- supervisors, Associate Professor Rosemary Sutton and Professor Richard Lock for their helpful advice over the past years which have proven to be invaluable in the completion of this thesis. I thank my review panel members, Dr. Jamie Fletcher, Dr. Karen Mackenzie and Professor Glenn Marshall for always looking out for me throughout this journey and providing helpful suggestions for the progress of the project. I thank Dr. Anna Mariana, Dr. Tim Failes and Dr. Greg Arndt at the Australian Cancer Research Foundation Drug Discovery Centre for helping is with the drug screening. I would like to acknowledge Dr. Andrew Gifford and Dr. Russell Pickford for their expertise and help for the in vivo toxicity and compound stability part of the project, respectively. I also thank Dr. Chelsea Mayoh and Dr. MoonSun Jung for their help with microarray analyses. Thank you for your time and contribution to this project. I would also like to extend my appreciation to Dr. Amanda Philp for her endless support throughout the years. A huge thank you to colleagues from the MLL research group past and present for sharing their knowledge, never-ending help and encouragement, and friendship. I thank my PhD mates for making this journey much more enjoyable. And thank you to all Children’s Cancer Institute Australia staff especially the Molecular Diagnostics and Experimental Therapeutics groups for the fun, engaging conversations, advice and encouragements during the years. Finally, I wish to express my deepest gratitude to my parents and sisters for their love, understanding, patience and unwavering support. A special thanks to my sister Sari for the sanity checks, the laughter and the great food! I am so lucky to have such an amazing family whom have kept me going and have made this PhD possible. Thank you for believing in me, I couldn’t have done this without you. v ABSTRACT Despite remarkable improvements being made in the treatment of childhood acute lymphoblastic leukaemia (ALL), prognosis remains dismal for certain subgroups of high-risk patients including infants with leukaemia harbouring rearrangement of the Mixed Lineage Leukaemia (MLL/KMT2A) gene. The poor clinical outcome linked to the aggressive disease and the limitations of treatment intensification warrants development of more effective, targeted therapeutics. The approach of drug-repurposing, whereby an approved drug may be applied to target a disease other than that for which it was originally intended, is one that is gaining popularity due to the potential to avoid the rising cost and lengthy process of the traditional drug discovery pathway. To identify novel candidates for high-risk leukaemia, a library of approved drugs and pharmacologically active compounds, was screened against ALL cell lines with or without MLL gene rearrangement, using a cell-based viability assay. The screen identified two MLL-selective bioactive compounds. The purinergic receptor (P2Y) agonist and guanylate cyclase inhibitor, 2-chloroadenosine triphosphate, showed in vitro efficacy against MLL-rearranged (MLL-r) ALL patient-derived xenografts (PDX) whereby sensitivity was associated with decreased expression of several P2Y receptors including P2RY14, which was additionally found to be lowly expressed in MLL-r patients compared to patients without MLL gene rearrangement in a paediatric ALL patient cohort. The second MLL-selective candidate, SID7969543 which targets Steroidogenic Factor-1 (SF-1/NR5A1), showed activity against a subset of MLL-r and CALM-AF10 leukaemia cell lines and synergized with etoposide or cytarabine in vitro. A subsequent secondary screen aimed to select more potent and clinically applicable compounds identified two FDA-approved drugs, auranofin and disulfiram, which revealed a common ROS-mediated mechanism in potently inhibiting the viability of high-risk leukaemia cell lines and PDX in vitro. Preclinical testing of drug combinations revealed auranofin in combination with cytarabine, a drug currently used in paediatric ALL therapy, demonstrated potential in delaying leukaemia growth in an aggressive MLL-r ALL PDX mouse model. Auranofin also demonstrated synergy with disulfiram in vitro which could be promising for future studies. vi In conclusion, this work identified MLL-selective compounds that uncovered potential new targetable pathways in MLL-r leukaemia for further investigation and possible future therapeutic exploitation. The two FDA-approved drugs identified highlighted the therapeutic potential of targeting the ROS pathway for high-risk leukaemia and demonstrated promising clinical utility for these patient subgroups. vii CONFERENCES AND AWARDS Conferences . Karsa, M., Somers, K., Mariana, A., Failes, T., Arndt, A., Haber, M., Norris, M., Sutton, R., Lock R. and Henderson, M. (2017). Repositioning existing drugs as novel therapeutics for high risk leukaemia in children. 22nd Congress of European Hematology Association, Madrid, Spain. Poster presentation. Karsa, M., Mariana, A., Failes, T., Arndt, G. M., Sutton, R., Lock, R. and Henderson, M. (2016). Repositioning existing drugs as novel MLL‐rearranged leukaemia therapies. CTx Higher Degree Research Symposium, Melbourne, Australia. Oral and poster presentations. Karsa, M., Mariana, A., Failes, T., Arndt, G. M., Sutton, R., Lock, R., Norris, M., Haber, M., and Henderson, M. (2016). Identification of molecules with selective inhibition towards MLL-rearranged leukaemia. 10th Biennial Childhood Leukemia Symposium, Athens, Greece. (Also presented at 6th New Directions in Leukaemia Research, Noosa, Australia). Poster presentations. Karsa, M., Middlemiss, S., Richmond, J., Haber, M., Norris, M., Sutton, R., Lock, R. and Henderson, M. (2015). Assessing an in vitro model of cultured patient- derived xenografts for predicting treatment response in vivo. Lowy Symposium, Sydney, Australia. (Also presented at the CTx Higher Degree Research Symposium, Melbourne, Australia). Poster presentations. Awards . Children’s Cancer Institute Top-Up Scholarship (2014 – 2018) . Cancer Therapeutics CRC Top-Up PhD Scholarship (2015 – 2017) . The 22nd Congress of European Hematology Association (EHA) Travel Grant (2017) viii TABLE OF CONTENTS THESIS DISSERTATION .............................................................................................. i ORIGINALITY STATEMENT ..................................................................................... ii COPYRIGHT STATEMENT .......................................................................................iii AUTHENTICITY STATEMENT
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