CRUK Programme Grant

CRUK Programme Grant

 

Key survival pathways in chronic myeloid leukaemia (CML) stem cells and novel approaches to their eradication

This is a collaborative project between the laboratories of Professor Whetton (Manchester), Professor Holyoake (Glasgow) and Professor Girolami (UCL).

CML arises by mutation of a normal haemopoietic stem cell (HSC). Holyoake has demonstrated the existence of CML HSC which are resistant to the ABL kinase inhibitor (KI), imatinib mesylate (IM). CML is therefore very unlikely to be cured using IM monotherapy, suggesting that combination therapy with agents that target CML stem cells will be required. In this new 5-year CR-UK we are exploring the hypothesis that CML stem cells are dependent on key survival pathways that are deregulated in malignancy, offering the possibility of developing therapeutic approaches that are selective for leukaemic versus (vs) normal HSC. The programme will expand on a wealth of exciting preliminary data. Firstly mRNA profiling data for G0 CML vs normal HSC suggest 3 avenues for further investigation of targets relevant to survival of CML stem cells; secondly gene expression data, derived following exposure of CML HSC to KIs, suggest that by performing cross-comparisons for multiple KIs across a time-course and sorting for differences common to the drugs and to individual patient samples, it should be possible to identify a tractable set of genes regulating proteins/pathways important for KI-resistance in CML stem cells, which could then be targeted with a second agent; and thirdly we have identified a farnesyl transferase inhibitor (FTI) (Bristol-Myers Squibb) that uniquely, potently and selectively induces apoptosis in CML stem cells. A subsequent pro-apoptotic compound has been developed (Infinity Pharmaceuticals) which lacks FTI activity. We are using these drugs to understand the mechanism of CML stem cell apoptosis and to uncover novel targets for future drug discovery, in particular agents that specifically target CML stem cells. Overall the programme should expand our knowledge of factors that regulate CML and normal HSC survival and lead to improvements in the clinic. The need to develop methodologies for drug response assessment in malignant and normal stem cells, or investigate regulatory pathways in such cells, requires numerous technologies, including state-of-the-art flow cytometry to isolate stem cells from primary clinical material, high end mass spectrometry to quantifiably probe global changes in the stem cell proteome, and high-throughput capillary isoelectric focusing (cIEF) immunoassay to validate proteomic observations in fewer than 50 stem cells.