Professor Richard Lock
Glucocorticoids are one of the most active classes of drugs used in the treatment of childhood acute lymphoblastic leukaemia (ALL) as well as other lymphoid malignancies in children and adults. However, resistance to these drugs develops in some children, leading to treatment failure. In general, glucocorticoid resistance in childhood ALL is indicative of poor treatment outcome.
The mechanisms by which ALL cells develop resistance to glucocorticoids are not well defined. We are making significant advances in our understanding of glucocorticoid resistance through studies utilising our unique experimental model of ALL. This is a living model of leukaemia developed in the laboratory, which closely mimics the disease in children. So far we have been successful in identifying a number of previously undiscovered ways in which leukaemia cells develop glucocorticoid resistance.
Recently we have shown that certain types of ALL cells are able to 'switch off' a gene (known as BIM) critical for glucocorticoid-induced killing of childhood ALL cells. We have also been able to show in laboratory models of the disease that re-activation of the BIM gene, using a class of drugs known as histone deacetylase inhibitors, partially reverses glucocorticoid resistance.
We are currently working towards developing a new class of drugs that reverse glucocorticoid resistance in leukaemia, which will have significant applications for treatment of the disease in patients.