Developing less toxic therapies for children with acute lymphoblastic leukaemia

Childhood B-acute lymphoblastic leukaemia (B-ALL) is the most common paediatric cancer. Despite high cure rates in low-risk cases, B-ALL remains a leading cause of cancer-related death in children. Current treatments are arduous and toxic; lasting up to 3 years they impose considerable burdens on patients and their families. At present 20% of children with B-ALL will die either from relapsed disease or complications of treatment. Those surviving into adulthood may suffer both long-term secondary medical complications and impaired life-chances because of the disruption to their education. There is therefore an urgent need for targeted, less toxic therapies.

Our work in understanding the underlying biology of B-ALL has identified an inherent vulnerability of leukemic cells – an addiction to the gene RUNX1. In our laboratory experiments, a drug blocking RUNX1 kills leukemic cells, including those of high-risk subtypes. Importantly, this drug spares normal blood cells suggesting that RUNX1-targeted therapy would have low toxicity. However, the drug in its current form is not an effective therapeutic due to low potency and stability.

To overcome this, we will use two complementary strategies. First, we will generate a series or variants of the existing drug and test their potency. Secondly, using our knowledge of the pathways regulated by RUNX1, we will select drugs likely to mimic or complement the effects of RUNX1 inhibition and assess their effectiveness against leukemic cells. We will then combine the two approaches to find the most potent combination of drugs with the least toxicity.

We expect that our proposal will deliver novel, less toxic targeted therapies with the potential to advance the current treatment regimens. This will improve current outcomes, reduce side-effects in B-ALL patients and ultimately lead to a better quality of life for patients and their families.