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Fumarate Prodrugs as a Novel Therapeutic Approach in Acute Myeloid Leukaemia
Get PDFFumarate Prodrugs as a Novel Therapeutic Approach in Acute Myeloid Leukaemia Majed Hussain A Alzamanan Submitted in partial fulfilment of the requirements of the Degree of Doctor of Philosophy This work was supported by Saudi Arabia Cultural Bureau in the UK Queen Mary University of London Author’s declaration I acknowledge the ethical use of Generative Artificial Intelligence to support my editing, proofreading and/or reference list generation in this thesis. I confirm that I have kept and can provide (if requested) detailed records of my input into Generative Artificial Intelligence tools, the outputs I received, and how I used these outputs. I used the following GenAI programme(s): Quillbot and OpenAI. I accept that Queen Mary University of London has the right to use plagiarism detection software to check the electronic version of the thesis. I confirm that this thesis has not been previously submitted for the award of a degree by this or any other university. The copyright of this thesis rests with the author and no quotation from it, or information derived from it may be published without the prior written consent of the author. Signature: Majed Hussain A Alzamanan Date: 11 August 2025 Abstract Haematopoiesis occurs in the hypoxic bone marrow (BM) microenvironment, where multipotent haematopoietic stem and progenitor cells (HSPC) differentiate and renew blood cells (1). Acute myeloid leukaemia (AML) is a haematological disorder characterised by clonal proliferation of the HSPC compartment, leading to an increased number of blast cells (myeloid progenitors) in the bone marrow and peripheral blood, causing bone marrow failure and a decrease in erythropoiesis. AML is the most common type of acute leukaemia, accounting for approximately 80% of acute leukemic cases in adults (2). The response to the low oxygen conditions in the BM is orchestrated by the hypoxia inducible factors (HIFs). These factors play a central role in gene expression, controlling cell cycle and cell growth, metabolism, oxygen homeostasis, apoptosis, and autophagy. Previous research in our lab (published, UK patent filed) demonstrated that stabilising HIFs through inhibition of their negative regulators the HIF-PHDs (HIF-prolyl hydroxylase domain enzymes) has potent anti-leukemic effects in vitro and in vivo (3). As such, we explored the potential of therapeutic targeting of fumarate, a natural PHDs inhibitor, involved in the citric acid cycle (TCA) and energy production. Notably, fumarate is highly druggable with fumarate prodrugs dimethyl fumarate (DMF) and diroximel fumarate (DRF) currently used to treat multiple sclerosis and psoriasis (4). Our group is the first to investigate the potential of these FDA-approved fumarate prodrugs for the treatment of AML. Our data shows that both fumarate prodrugs (DMF and DRF) have significant anti-leukaemic effects in vitro. Moreover, combination therapy with either fumarate prodrug plus venetoclax, now a gold standard of AML therapy, shows promising in vitro efficacy. To further exploit the therapeutic potential of fumarate prodrugs, our recent investigations have explored replacing the N-Succinimide group of DRF with hydroxamic acid (IOX-6). Significantly, these chemical alterations increased the anti-leukaemic effect of DRF, opening up the potential of further improving fumarate prodrugs for the treatment of AML
What are the symptoms and concerns of young adults living with life-limiting conditions and how well are they captured by patient reported outcome measures? A mixed-methods systematic review and framework synthesis.
Get PDF‘Commemorating Haley at 60: A Critique of the Statutory Treatment of Disability in Negligence’
No full textAnalysing Students’ Journeys when Learning Programming using the Epistemic Plane from LCT
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Genetic evaluation supports differential diagnosis in adolescent patients with delayed puberty
No full textA Standardised Pipeline for Patient-Specific Aortic Flow Modelling: Turbulent Flow Patterns in Transcatheter Aortic Valve Implantation Therapy
No full text‘Reflecting on Haley Six Decades On; Current Duty of Care Conundrums Regarding Disability in Negligence’, in J Murphy et al, Tort Issues in the 21st Century (Hart Publishing, 2026)
No full textCommunicating Unexpected News to Pregnant Women with Mental Health Conditions in Fetal Medicine
No full textDelivering unexpected news during pregnancy is a complex and emotionally charged task for Healthcare Professionals (HCPs), particularly within Fetal Medicine (FM). While communication training is increasingly recognised as essential, current strategies often overlook the additional needs of women living with Mental Health Conditions (MHCs), who comprise up to 20% of the perinatal population. Poor communication in this context may exacerbate psychological distress and negatively affect decision-making, engagement with care, and pregnancy outcomes. This thesis addresses the gap in evidence-based, inclusive guidance for communicating unexpected news during pregnancy, with a particular focus on the experiences of women with MHCs. The research was conducted in two parts: Part 1 scoped the problem through preliminary data collection and a systematic review. A cross-sectional survey of 71 HCPs working in FM across the United Kingdom (UK) revealed high levels of discomfort and limited formal training in delivering unexpected news, particularly when communicating with women with MHCs. The subsequent systematic review synthesised 43 studies on communication strategies across six clinical scenarios, from early pregnancy loss to stillbirth. Despite variations in context, six recurring themes were identified and summarised in the PRICES acronym: Preparation, Referral, Individualised care, Clarity, Empowerment, and Sensitivity. However, existing guidance was found to be clinician-driven, inconsistently implemented, and largely lacking input from service users (SUs) or consideration of mental health. Part 2, the UNDERSTAND study, sought to explore this gap in depth and co-produce a communication framework grounded in real-life practice. The study employed qualitative methodology across four work packages (WPs). WP1 used applied Conversation Analysis (CA) to examine recorded consultations between FM clinicians and women with MHCs. WP2 and WP3 comprised thematic analyses of in-depth interviews with SUs and HCPs, respectively, exploring their experiences of communication in this context. WP4 brought together both groups in a co-production workshop to develop a shared set of recommendations. Findings across all WPs highlighted that communication challenges extended beyond individual clinician skills. While moments of good practice were identified, such as creating a supportive environment and tailoring information, these were often undermined by systemic barriers: limited time, fragmented care pathways, poor documentation, and a lack of embedded psychological support. Women with MHCs described feeling judged, confused, or unsupported, particularly when clinicians failed to validate their concerns or avoided emotional conversations. HCPs, in turn, reported emotional burden, fear of “saying the wrong thing,” and insufficient institutional support. The co-produced UNDERSTAND framework offers a structured yet flexible tool to support HCPs in navigating difficult conversations with compassion, clarity, and collaboration. It spans the entire consultation journey, from preparation to follow-up, and integrates psychological safety, cultural sensitivity, and equity. This thesis contributes original evidence on how communication of unexpected news in pregnancy can be improved through systems-level changes, not solely individual training. By centring the voices of women with MHCs and embedding co-production throughout, it offers a meaningful step towards more inclusive, humane, and effective prenatal care