Developing a precision medicine approach to target leukaemic stem cells in AML.

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Acute myeloid leukemia is an aggressive blood cancer with poor outcomes in the majority of patients. The majority of patients are unable to tolerate the intensive chemotherapies offering the prospect of prolonged remissions. Despite chemotherapy, the majority of patients will relapse, and long-term survival is poor once this has occurred. There is therefore an important unmet need to work out why patients relapse, and develop more effective therapies to prevent relapse.We now know that leukaemic stem cells are the underlying reason for resistance to chemotherapy and ultimately relapse. These relatively rare cells are present at diagnosis, and are very different from the majority of leukemia cells. They are not targeted effectively by any current treatments. Proteins are the building blocks of our cells, and are ultimately responsible for how cells behave. Many previous studies have looked in detail at genetic changes in leukemia, but there is a real lack of understanding of how this affects changes to proteins. Recent work has shown that there are lots of differences between leukemia stem cells and other leukaemia cells, which are only seen by looking at proteins rather than genes, and may hold the key to identifying and targeting these cellsThis project plans to identify the particular vulnerabilities of these key cells at a protein level, and use these differences to develop truly targeted and less toxic therapies. The strategy is to develop therapies which protect healthy normal blood stem cells, in contrast to current treatments, reducing the risk of severe infections and the toxic side effects of chemotherapy. This approach has the potential to create a step-change in treatment of AML, opening up opportunities for treating older people safely and effectively despite other health problems, reducing the time people spend in hospital and moving towards home-based treatments which improve both quality of life and long-term survival.