Grant: Op. Gr: NI grants in MRC&Y Health - M, R and Childhood and Adolescent Cancers

The goal of this project is to identify drugs that can target the rare cells that cause treatment failure in leukemia - leukemic stem cells (LSCs). AML is sustained in a patient by LSCs that act somewhat like normal stem cells, although cancerous, in that they are the 'root' of the disease and need to be eliminated to achieve a cure. Therapy for childhood acute myeloid leukemia (AML) involves extremely intense toxic treatment. This can impair the development of children, cause long term cardiac dysfunction, affect fertility and cause secondary cancers later in their life. Even with this aggressive treatment, approximately 40% of these patients do not respond to therapy or the leukemia returns later. Therefore novel treatment approaches are desperately needed to improve outcome and reduce toxicity. We have taken data on the activity of genes in LSCs and regular leukemic cells and combined it with data sets on how drugs cause changes in gene activity to identify 152 compounds that we predict would specifically eliminate LSCs. We have directly tested 83 of these compounds and found that 12 of them do preferentially target LSCs in human leukemia. We propose to examine these 12 compounds in depth and determine how well they work against multiple leukemia samples, what exactly they do, and how safe they are. Our efforts to understand their mechanisms of action and their effectiveness in primary leukemic cells from patients will yield novel insight into the unique functioning of LSC in this type of leukemia. This increase in our knowledge of LSC and leukemia biology will in turn enable additional gains in prognosis, therapy and prevention. Any improvement in AML treatment will benefit children in particular since they are most vulnerable with regard to the long-term side effects of current treatments.