Cancer Research UK Children's Cancer Group

Modern intensive chemotherapeutic regimens cure almost 80% of childhood acute lymphoblastic leukaemias. However, we lack an understanding of the biological basis of the response to therapy. For those who relapse or do not respond to treatment, outcome remains poor. Haematopoietic stem cell transplantation has improved the outcome in some categories, but not all. This suggests that further intensification of therapy will not improve outcome and new approaches are required.

We have designed clinical trials to clearly identify those who respond to treatment from those who fail. Using functional genomics, i.e., global differences in gene expression, genotyping and methylation status, we will identify the key genetic differences between these two groups. Differences found will identify novel aberrant regulatory pathways that lead to leukaemogenesis and to the development of chemoresistance. These pathways will be validated by creating cellular and animal models that most closely resemble the alterations seen. Compounds that are capable of antagonising key regulatory molecules in these pathways can then be evaluated for anti-leukaemic action in these models. Those that show activity, can then be developed for phase I trials in the previously described high-risk population.