title: Identification and validation of the dopamine agonist bromocriptine as a novel therapy for high-risk myelodysplastic syndromes and secondary acute myeloid leukemia.
abstract: Myelodysplastic syndromes (MDS) represent a broad spectrum of diseases characterized by their clinical manifestation as one or more cytopenias, or a reduction in circulating blood cells. MDS is predominantly a disease of the elderly, with a median age in the UK of around 75. Approximately one third of MDS patients will develop secondary acute myeloid leukemia (sAML) that has a very poor prognosis. Unfortunately, most standard cytotoxic agents are often too toxic for older patients. This means there is a pressing unmet need for novel therapies that have fewer side effects to assist this vulnerable group. This challenge was tackled using bioinformatic analysis of available transcriptomic data to establish a gene-based signature of the development and progression of MDS. This signature was then used to identify novel therapeutic compounds via statistically-significant connectivity mapping. This approach suggested re-purposing an existing and widely-prescribed drug, bromocriptine as a novel potential therapy in these disease settings. This drug has shown selectivity for leukemic cells as well as synergy with current therapies.
authors.affiliation: Centre for Cancer Research and Cell Biology (CCRCB), Queen's University Belfast, Belfast, United Kingdom.
authors.forename: Fabio Giuseppe
authors.initials: FG
authors.lastname: Liberante
authors.affiliation: Centre for Cancer Research and Cell Biology (CCRCB), Queen's University Belfast, Belfast, United Kingdom.
authors.forename: Tara
authors.initials: T
authors.lastname: Pouryahya
authors.affiliation: Centre for Cancer Research and Cell Biology (CCRCB), Queen's University Belfast, Belfast, United Kingdom.
authors.forename: Mary-Frances
authors.initials: MF
authors.lastname: McMullin
authors.affiliation: Centre for Cancer Research and Cell Biology (CCRCB), Queen's University Belfast, Belfast, United Kingdom.
authors.forename: Shu-Dong
authors.initials: SD
authors.lastname: Zhang
authors.affiliation: Centre for Cancer Research and Cell Biology (CCRCB), Queen's University Belfast, Belfast, United Kingdom.
authors.forename: Kenneth Ian
authors.initials: KI
authors.lastname: Mills
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D014408:Biomarkers, Tumor / Q000235:genetics; D015153:Blotting, Western; D001971:Bromocriptine / Q000494:pharmacology*; D016022:Case-Control Studies; D049109:Cell Proliferation / Q000187:drug effects; D018491:Dopamine Agonists / Q000494:pharmacology*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D009190:Myelodysplastic Syndromes / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D016609:Neoplasms, Second Primary / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D014407:Tumor Cells, Cultured
chemical_list: D014408:Biomarkers, Tumor; D018491:Dopamine Agonists; D001971:Bromocriptine
keywords: acute myeloid leukemia (AML); bromocriptine; myelodysplastic syndromes (MDS); re-purposed; therapy