Identifying combinations of repurposed drugs for new treatments of acute myeloid leukaemia

Leukaemia is the most common childhood cancer. The two main types of childhood leukaemia are acute lymphoblastic leukaemia (ALL) and acute myeloid leukaemia (AML). ALL is more common and generally has a favourable outcome. However, the survival rates for chldhood AML are much poorer, with only 60% of children diagnosed expected to survive more than 5 years. This is compounded by severe treatment side effects including vomiting and hair loss. Our work is focused on finding new drugs that are both effective in fighting the leukaemia and spare young patients these side effects. To do this, we are using an approach called drug repurposing - the process of using drugs already approved for a specific disease in new disease. Drug repurposing is attractive because the time from discovery to patient is quicker and there is reduced cost and risk in drug development.

To find new drugs, we previously tested the effect of 760 drugs in childhood leukaemia cells. This 'screen' identified two drugs called mebendazole (MBZ) and albendazole (ABZ) which are used routinely in GP practices and have few/no side effects. In our studies, MBZ and ABZ are effective against different types of childhood AML, but have minimal/no effect in normal, healthy cells. 

We now want to extend this work to identify repurposed drugs that work effectively in pairs together ('in combination'). In childhood cancer patients, drug combinations aim to 1) improve the likelihood of treatment response 2) improve the level of response and 3) reduce the chances of the treatment stopping working. To find new drug combinations for childhood leukaemia, we will test the effect of half a million possible combinations using a strategy called MuSIC. The most promising combinations will be taken forward for further rigorous testing, using several approaches, with the ultimate aim of progressing these new therapies to clinical trials.

The main aims of the project are to:

• Find new repurposed drug combinations in childhood AML cells - we will test the effects of 1,000 repurposed drugs against each other in every possible combination (500,000 possible pairs) to find the most effective pairs
• Understand how the new drug combinations are working to kill childhood AML cells - before we can test these drugs in patients, it is vital we know exactly how the new combinations are killing the leukaemia cells. We will analyse what genes areafected by the drugs and investigate how the leukaemia cells are being killed.
• Investigate the effect of the new drug combinations in patient samples and in mice that model childhood AML - this experiment will show if the new combination can slow or stop the growth of childhood leukaemia in a living system.