Dr Xu Huang (Cancer Sciences, University of Glasgow) http://www.gla.ac.uk/researchinstitutes/cancersciences/staff/xuhuang/
Prof Robert Liskamp (Chemistry, University of Glasgow)
Dr Mark Drummond (Beatson West of Scotland Cancer Centre/NHS)
There is a significant unmet need for novel therapeutic approaches in blood cancer. Current treatment has evolved little since several decades ago especially for Acute Myeloid Leukaemia (AML). The recent development of several pharmacological inhibitors targeting BRD4 and Dot1L, highlights that such epigenetic regulators could be promising antitumour targets. Based on our previous shRNA screen results, we have identified a histone demethylase, depletion of which in human AML cells promoted AML cancer stem cells terminal myeloid differentiation and rapid cell death but spared normal haemopoietic stem cell function. This suggests that this protein could represent rational target for therapeutic intervention. However, it lacks in-depth understanding of the cellular mechanisms through which this demethylase and its inhibitors selectively target leukaemic cancer stem cells. In this project we will focus on identifying its specific downstream targets in AML, and validate the results in primary AML patient samples and in our established human AML xenograft mouse model. The proposed study will utilise combined systems biology approaches and expects to provide a fundamental scientific understanding to be used to initiate the next stage of drug discovery and propose the effective combination treatments with other standard AML therapies.
Keywords: Acute myeloid leukaemia, Epigenetic regulation, Leukaemia stem cell
Somerville TDD, Wiseman DH, Spencer GJ, Huang X, Lynch JT, Leong HS, Williams EL, Cheesman E and Somervaille TC. Frequent depression of the mesenchymal transcription factor gene FOXC1 in acute myeloid leukemia. Cancer Cell (2015) 28: 329-342.
Jude JG, Spencer GJ, Huang X, Somerville TDD, Jones DR, Divecha N and Somervaille TC. A targeted knockdown screen of genes coding for phosphoinositide modulators identifies PIP4K2A as required for acute myeloid leukemia cell proliferation and survival. Oncogene (2015) 34: 1253-1262.
Huang X, Spencer GJ, Lynch JT, Ciceri F, Somerville TD and Somervaille TC. Enhancers of Polycomb EPC1 and EPC2 sustain the oncogenic potential of MLL leukemia stem cells. Leukemia (2014) 28: 1081-1091.
Lynch JT, Somerville TDD, Spencer GJ, Huang X and Somervaille TC. TTC5 is required to prevent apoptosis of acute myeloid leukemia stem cells. Cell Death and Disease (2013) 4, e573.
Harris WJ, Huang X, Lynch JT, Spencer GJ, Hitchin JR, Li Y, Ciceri F, Blaser JG, Greystoke, BF, Jordan AM, Miller CJ, Ogilvie DJ and Somervaille TC. The histone demethylase KDM1A sustains the oncogenic potential of MLL-AF9 leukemia stem cells. Cancer Cell (2012) 21: 473-487.
C O’Connor FL, Campos J, Ohlsson E, Salomè M, Forde C, Artschwager R, Liskamp RM, Cahill MR, Kiely PA, Porse B and Keeshan K. The presence of C/EBPα and its degradation are both required for TRIB2-mediated leukaemia. Oncogene (2016) 35: 5272–5281.
Brouwer AJ, Alvarez NH, Ciaffoni A, Van De Langemheen H, Liskamp RM. Proteasome inhibition by new dual warhead containing peptido vinyl sulfonyl fluorides, BIOORGANIC & MEDICINAL CHEMISTRY (2016) 24: 3429- 3435.
Postma TM, Liskamp RM. Triple-targeting Gram-negative selective antimicrobial peptides capable of disrupting the cell membrane and lipid A biosynthesis. RSC Adcances (2016) 6: 65418-65421.
Werkhoven PR, Elwakiel M, Meuleman TJ, van Ufford HCQ, Kruijtzer JAW, Liskamp RM. Molecular construction of HIV-gp120 discontinuous epitope mimics by assembly of cyclic peptides on an orthogonal alkyne functionalized TAC-scaffold. ORGANIC & BIOMOLECULAR CHEMISTRY (2016) 14: 701-710.
Slootweg JC , van Herwerden EF, van Doremalen MFM, Breukink E, Liskamp RM, Rijkers DTS. Synthesis of nisin AB dicarba analogs using ring-closing metathesis: influence of sp(3) versus sp(2) hybridization of the alphacarbon atom of residues dehydrobutyrine-2 and dehydroalanine-5 on the lipid II binding affinity. ORGANIC & BIOMOLECULAR CHEMISTRY (2015) 13: 5997-6009.