Melbourne Medical School Collected Works - Theses
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ItemImproving epigenetic therapies for haematological malignancies( 2016)The work presented here is the product of several years of clinical trial and laboratory endeavour focused on the theme of understanding and improving currently available epigenetic therapies for blood cancers, and understanding fundamental aspects of clinical trial design. Several classes of epigenetically active drugs with proven clinical usefulness have received regulatory approval for the therapy of haematological malignancies in the last 5 years. At the same time, advances in high throughput sequencing technologies have provided landmark discoveries that reinforce the hypothesis that epigenetic mechanisms play a central role in the neoplastic process, as well as giving us new opportunities to develop targeted therapies. Some of the most exciting new targeted biological therapies arising from these discoveries such as inhibitors of histone methyl-transferases, the BET bromodomain inhibitors and the isocitrate dehydrogenase inhibitors are only now in the earliest phase of clinical development with initial signals that many of these agents will be both tolerable and active therapies for blood and solid tumours. In the context of the field at the start of 2010, only two classes of agent were available in clinical trials and for early investigator-initiated development. Even today, only these classes of epigenetic agents have marketing approval. As a consequence, histone deacetylase inhibitors and DNA methyl-transferase inhibitors are the focus of this thesis. The thesis presents investigator-initiated trials of agents in these two drug classes as well as the theory associated with the design of the trials. The literature review in Chapter 1 establishes the foundation for the clinical trial work. Here, the mechanism of action of the histone deacetylase inhibitors and the DNA-demethylating agents is reviewed. Activity of these agents in industry-sponsored clinical trials is presented as well as key toxicity data that informs the hypotheses and design of the clinical research presented in the thesis. The theories underlying the combination therapies that form the backbone of the thesis are discussed. Eltrombopag, a thrombopoietin agonist, is given particular prominence for its potential as a supportive care agent. The clinical trials that represent the majority of the thesis were designed to explore the critical questions of improving the tolerability of the DNA-demethylating agent azacitidine, and developing novel combination therapies for HDAC inhibitors. As experimental design is a critical question, a discussion on clinical trial design is presented in Chapter 2, which closes with a relevant case study. Several clinical trials were developed during the conduct of this higher degree from concept through to funding and clinical recruitment. Three, presented in Chapters 3, 4, and 7 have completed accrual and a further trial (Chapter 5) has been interrupted due to administrative challenges and is currently being reworked. The protocol for each study was in itself an extensive body of novel work contributing to the thesis. These are included in the appendices but summarised within the body of the thesis. Chapter 3 presents finalised and novel data analysed in depth of a trial of the combination of eltrombopag, a thrombopoietin-receptor agonist and azacitidine. The purpose of the study was to develop a supportive care therapy for patients with myelodysplastic syndromes, a disease that causes low platelets (thrombocytopenia), and has a risk of transforming to acute myeloid leukaemia, an almost invariably fatal event. Thrombopoietin mimetic agents have a somewhat complicated relationship with myeloid malignancies in the minds of researchers and while the receptor (mpl) and the role of the mpl receptor in haematopoietic stem cell survival and fate has been the subject of the research for at least 20 years, many questions about their theoretical safety remain open. There is considerable debate over the theoretical safety of mpl in agonists in patients with myeloproliferative diseases. Hence, attention is given to the rationale for the choice of eltrombopag for myelodysplastic syndrome in Chapter 1; also, the established body of preclinical data is presented to provide a context. This particular trial, “AzaE”, has been presented in international fora and the data has provided a foundation for a 170-centre, 43-country international randomised study that, if positive, may change clinical practice for patients with myelodysplastic syndrome and thrombocytopenia. Hence Chapter 3 is a central part of the novel data in this thesis. Based on the hypothesis that HDAC inhibition would up-regulate CD20 on the surface of malignant B-cells, a collaborating colleague, Mark Bishton, developed a phase 1 clinical trial of the combination of the radio labelled rituximab and the HDACi panobinostat. Dr Bishton and Prof Seymour wrote the trial protocol. As Principal Investigator of the study, I set up the study, moving it from protocol to execution. I oversaw the conduct of the study as the principal investigator and reviewed and approved the clinical data. The combination was toxic and the lessons learned are cogent and argue against further developing this sort of combination therapy. This study is presented in Chapter 4. In order to address the moderate activity of the HDACi inhibitor romidepsin and to broaden its clinical indications, a phase I/II study was designed in collaboration with academic partners from Yale University. The strategy behind the design of that study, the protocol itself, and initial data from six patients that have been recruited is presented in Chapter 5. That study has been halted due to regulatory challenges in the USA and Yale University that interrupted the research without warning. The trial strategy is discussed and preliminary results are presented. HDACi are highly active in cancers of the immune system, where the symptomatic and physical manifestations are to a considerable extent driven by cytokine changes which serve a both disease epiphenomena and drivers of the malignancy itself. In Chapter 6, I investigate the effect of the HDACi on human monocyte derived dendritic cells, identifying a mechanism by which these agents are likely shift the T-cell populations, altering patient symptoms and potentially inducing clinical responses. The findings support the contention that HDACi are immunosuppressive and do not make suitable partner drugs for treatments that benefit from an intact antigen presentation apparatus. Histone deacetylase inhibitors and DNA demethylating agents are often conceptually explained as driving a single cellular mechanism. However, the effects within the cell are pleiotropic and there are very few studies that provide data on predictors for response, especially so for the HDAC inhibitors. Therefore, a part of this work was to design a clinical trial that enables future scientific studies on predictors of response to HDAC inhibitors. Several academic questions were faced in developing the approach to this study. Chapter 7 presents the approach to the design of the clinical study, and presents the clinical features of the patients who have been recruited and key response data. An overview of planned experiments is presented. Having concerned itself with the design of investigator-initiated clinical trials of novel combinations and presented successes and failures of trial design and execution as well as original laboratory work that may inform combinations, the thesis concludes with a discussion on future directions for the projects arising from this work and epigenetic agents in general.