My research interests focus on mechanisms of disease initiation and maintenance and the identification and validation of novel therapeutic targets in myeloid leukaemias. Specifically I study the role of adaptive responses to current therapies, including novel targeted therapies, in several subtypes of myeloid leukaemias and at leukaemic stem cell level, with a specific focus on the role of metabolic adaptations, as a mechanism of resistance not driven by genetic mutations.
Bone Marrow Mesenchymal Stem Cells Support Acute Myeloid Leukemia Bioenergetics and Enhance Antioxidant Defense and Escape from Chemotherapy. Cell Metabolism (2020) 32(7) 829-843.e9. PMID: 32966766
Glutaminolysis is a metabolic dependency in FLT3ITD acute myeloid leukemia unmasked by FLT3 tyrosine kinase inhibition. Blood (2018) 131(15):1639-1653. PMID: 29463564
JAK2/STAT5 inhibition by nilotinib with ruxolitinib contributes to the elimination of CML CD34+ cells in vitro and in vivo. Blood (2014) 124(9):1492-501. PMID: 24957147
Acute myeloid leukaemia (AML) is the most prevalent acute leukaemia in adults and a cancer of unmet need with long-term survival rates of less than 30%. Sequencing and mechanistic studies have improved our understanding of the biology of several subtypes of myeloid leukemics. This has in turn resulted in the development of more targeted and scientifically validated therapies. However, the overall treatment outcomes, even with the introduction of novel agents, remain suboptimal for most patients, mainly as a result of disease relapse. AML arises in a haematopoietic stem or progenitor cell, which has the ability to self-renew, following the acquisition of recurrent driver mutations. This cell of origin, usually named the Leukaemia Stem Cell (LSC), represents the reservoir for relapse due to its inherent or acquired resistance to current therapies. Therefore, an improved understanding of the molecular mechanisms causing disease relapse, particularly at the LSC level, is required to improve patient outcome.
My research interests focus on mechanisms of disease initiation and maintenance and the identification and validation of novel therapeutic targets in myeloid leukaemia and studies the role of adaptive responses to current therapies, including novel targeted therapies, in several subtypes of myeloid leukaemias and at LSC level, with a specific focus on the role of metabolic adaptations, as a mechanism of resistance not driven by genetic mutations. Metabolic alterations are a hallmark of AML, and are often responsible for the development of chemoresistance arising from the bottleneck of extreme metabolic stress during intensive chemotherapy. Several metabolic pathways have been reported by our groups and others to be essential for leukaemic cell maintenance and resistance to therapy. For example we have shown reliance on glutamine and other energy sources from bone marrow niche to feed tricarboxylic acid cycle activity, oxidative phosphorylation and glutathione generation to drive therapy resistance and the role of mannose metabolism in modulating the ability of AML cells to switch the majority of energy dependence on fatty acid oxidation in response to standard and novel therapies.
In the laboratory, we use a combination of forward genetic screening, functional and mechanistic studies to characterise the clonal dynamics in leukaemic cell populations under therapeutic stress, characterise the mechanisms leading to therapy resistance and identify novel therapeutic vulnerabilities to be targeted in combination with standard therapies. We are also interested in the bidirectional cross-talk between altered metabolism and aberrant signalling and transcriptional programmes and its role in the establishment of myeloid leukaemias. We specifically study how metabolic intermediates interact with transcriptional programmes/altered signalling in AML and conversely how specific driver mutations impact on cellular metabolism to enable leukemic transformation.
We use cell lines, primary patient samples and murine models and study the functional effects of targeting novel vulnerabilities by combining complementary approaches such as RNAseq, Proteomics, Phosphoproteomics, Metabolomics, Lipidomics, in vivo imaging and drug screening.
Key words: signalling, transcription, patient samples, in vivo models, microenvironment
Loss of MPI leads to cell death in AML through inhibition of FAO leading to PUFA accumulation and ferroptosis.
Wild type AML cells treated with therapies are able to escape cell death by adapting their metabolism, in this case by switching from glycolysis to fatty acid oxidation. AML cells with inhibited or depleted MPI have activation of the unfolded proteins response which causes ATF6 activation, inhibiting fatty acid oxidation. This is paired with increased uptake of fatty acids, particularly polyunsaturated fatty acids, by MPI depleted cells. These PUFAs undergo lipid peroxidation which leads to ferroptotic cell death in these cells (Figure for ongoing project A and B).
Mannose metabolism inhibition sensitizes acute myeloid leukemia cells to cytarabine and FLT3 inhibitor therapy by modulating fatty acid metabolism to drive ferroptotic cell death.
A) Standard AML therapy reduce disease bulk but do not eradicate resistant LRC and LSC which often utilise metabolic adaptations to survive and in turn lead to relapse. B) We aim to identify such adaptations and by targeting them promote durable remission and cure.
Inhibition of Stearoyl-CoA Desaturase Has Anti-Leukemic Properties in Acute Myeloid Leukemia Dembitz V, Lawson H, Philippe C et al. Blood (2022) 140(10) 3058-3060
Molecular MRD Assessment Is Strongly Prognostic in Patients with NPM1 Mutated AML Receiving Venetoclax Based Non-Intensive Therapy Othman J, Tiong IS, Mokretar K et al. Blood (2022) 140(10) 2033-2035
Real-World Experience of Asciminib: Factors Associated with Response Innes AJ, Hayden C, Orovboni V et al. Blood (2022) 140(10) 6796-6797
Targeting HIF-Hydroxylases Compromises Disease Initiation and Propagation, and Synergises with Current Therapies to Eliminate Cancer Stem Cells in AML Lawson H, Holt-Martyn J, Dembitz V et al. Blood (2022) 140(10) 8731-8732
AML gets upSET when its dietary needs are unMet Gallipoli P Blood (2022) 140(7) 2003-2004
A phase I/II open-label study of molibresib for the treatment of relapsed/refractory hematologic malignancies. Dawson MA, Borthakur G, Huntly B et al. Clin Cancer Res (2022) (2)
P706: ASCIMINIB USE IN CML: THE UK EXPERIENCE Innes A, Orovboni V, Claudiani S et al. HemaSphere (2022) 6(10) 601-602
The UK SPIRIT 1 trial in newly diagnosed chronic myeloid leukaemia Gallipoli P, Clark RE, Byrne J et al. British Journal of Haematology (2022) 196(7) e55-e57
Gilteritinib for Relapsed Acute Myeloid Leukaemia with FLT3 Mutation during the COVID-19 Pandemic: Real World Experience from the UK National Health Service Othman J, Afzal U, Amofa R et al. Blood (2021) 138(10) 1254-1254
Mannose Metabolism Is a Metabolic Vulnerability Unveiled By Standard and Novel Therapies in Acute Myeloid Leukemia Woodley K, Dillingh LS, Giotopoulos G et al. Blood (2021) 138(10) 508-508For additional publications, please click here