Exploring novel molecular targets for the therapy of myelodysplasia and acute myeloid leukaemia

The current therapy of high-risk MDS and AML is reliant on cytotoxic chemotherapy and is often delivered to all patients with no regard for future potential relapse risk or other biomarkers that will predict the achievement of complete remission or remain in a durable remission. Therefore, alternative therapies are warranted to improve the long-term outcome for these patients. Epigenetic changes refer to stable and heritable changes in gene expression due to modifications in the form of DNA methylation and histone modifications without change in the underlying DNA sequence. Unlike genetic mutations, epigenetic changes are reversible, making the potential for targeting these processes therapeutically attractive. This thesis initially reviewed the epigenetic landscape in myelodysplastic syndrome, which has an extensive overlap with AML. There is an evaluation of underlying epigenetic mechanisms in MDS and the dominant molecular processes modified by hypomethylating agents, which underpin their therapeutic effects. The review summarized the current knowledge of recently identified novel mutations found in MDS and AML, several of which regulate endogenous methylation networks within cells (including TET2, DNMT3A, IDH and EZH2). The relevance of these lesions in being able to predict response to epigenetic modulators and their correlation with epigenetic signatures in MDS are beginning to emerge. These molecular lesions were an ongoing theme as all patients on study in the reported clinical trials were assessed for these known molecular mutations and each mutation was correlated with clinical response to investigational therapy. The thesis includes reports of three early phase clinical trials in myelodysplasia and acute myeloid leukaemia. The program of clinical trials utilising azacitidine as the therapeutic backbone for newly diagnosed patients, those with relapsed or refractory disease or as maintenance therapy in patients who have achieved complete remission after induction therapy. As each of these combinations have not been previously investigated in their particular settings, important Phase Ib data was obtained to evaluate the safety and tolerability of the combination investigational therapy and then each study moved to dose-expansion in Phase II to assess the preliminary efficacy of the the treatment. There were significant findings regarding correlative studies for each of the particular compounds investigated. In conclusion, the findings in this thesis provide important clinical data for the safety, tolerability and preliminary efficacy of novel agents in combination with hypomethylating agents. Further correlative studies have also demonstrated important molecular pathways and in vivo responses that may guide future rational clinical trial design.