Title: Key survival pathways in chronic myeloid leukaemia (CML) stem cells and novel approaches to their eradication
Funder: Cancer Research UK

Abstract: CML can be controlled by imatinib but this drug is not curative because it does not kill the cancerous stem cells that cause resistance and relapse. This proposal aims to investigate the genes and proteins that keep the cancerous cells alive and to find new ways to kill the cancerous cells without harming normal cells. Background; CML arises by mutation of a normal haemopoietic stem cell. We have demonstrated the existence of quiescent CML stem cells that are resistant to ABL kinase inhibitors (KI). CML is therefore very unlikely to be cured using KI-monotherapy, suggesting that combination therapy with agents that target CML stem cells will be required for disease eradication. Relevance to cancer; CML is an excellent model of malignancies in which cancer stem cells have been shown to play a fundamental role. Many more malignancies are being associated with constitutively activated tyrosine kinases and CML has historically provided biological and therapeutic paradigms applicable to all of these diseases. An enhanced understanding of the survival pathways operative within CML stem cells, which may lead to eradication of this critical population, would be of the utmost relevance to other forms of cancer. Specific aims of the research, hypotheses and outcomes; We will explore the hypothesis that CML stem cells are dependent on key survival pathways that are deregulated in malignancy, thus offering the possibility of developing therapeutic approaches that are selective for leukaemic versus normal stem cells. The results are hoped to enable curative approaches to be employed in the early chronic phase, most likely by combining a KI with a second agent able to induce apoptosis in cancer stem cells in a selective manner. The programme overall should expand our knowledge of factors that regulate CML and normal stem cell survival and lead to improvements in the clinic. Outline plan of research, proposed methods; The programme will expand on a wealth of exciting preliminary data. Firstly, by comparing the transcriptional profile of CML versus normal G0 stem cells three avenues for further investigation of targets relevant to the survival of CML stem cells have been uncovered and will be investigated in detail. Secondly, mRNA and miRNA data will be derived by performing cross-comparisons for multiple KI across a time-course and sorting for differences common both to the drugs and to individual patients to identify a tractable set of genes regulating proteins/pathways important for KI-resistance in CML stem cells. Thirdly, a farnesyl transferase inhibitor (FTI) made by Bristol-Myers Squibb, BMS-214662, that uniquely, potently and selectively induces apoptosis in CML stem cells, will be used as a tool to understand the mechanism of CML stem cell apoptosis, to uncover novel targets for future drug discovery for agents that specifically target CML stem cells and to assess drug efficacy against cancer stem cells in malignancies other than CML. Last updated 21/07/2010


Research activity codes: 5.1 PHARMACEUTICALS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS