Funded by The Little Princess Trust and administered by CCLG
Lead investigator: Dr Joan Boyes, University of Leeds
Award: £61,556.33
Awarded July 2024
Our DNA is the set of instructions that control how our cells behave. This means that it is very important to understand the DNA in cancer cells, which are cells that behave out of control. Scientists have recently found small circles of DNA in cancer cells that can contain cancer-causing genes. These tiny circles are thought to drive cancer development and make it worse.
In childhood acute lymphoblastic leukaemia (ALL), the circles do not contain cancer-causing genes - but they are still dangerous. Dr Joan Boyes’ research team at the University of Leeds has found that the DNA circles bind to proteins in the cancer cells. This makes a ‘complex’ that damages the DNA in white blood cells, the cells in which leukaemia starts. There is evidence to suggest the DNA circles, through this complex, causes the mutations that lead to ALL.
In a previous Little Princess Trust project, Dr Boyes found that having lots of DNA circles at ALL diagnosis is strongly linked to later relapse. Her team also found an increase in relapse-related mutations in the time between diagnosis and relapse. This suggests that the DNA circles, if there are enough of them, can continue to trigger the mutations that eventually cause relapse.
However, levels of DNA circles do not stay the same – they can divide to produce more. This happens more in patients who relapse, compared to those who stay in remission. This difference seems to be linked to a gene pathway called ‘mTOR’ that promotes DNA amplification. Dr Boyes believes that preventing the DNA circles from dividing, and making fewer DNA-damaging complexes, would lead to fewer relapse-linked mutations.
In this project, Dr Boyes will test whether suppressing division of the dangerous circular DNA is a new way to prevent relapse. Her team will look at whether drugs that work against the mTOR gene pathway affect the amount of new DNA circles made. As the levels of circular DNA are too varied in patient ALL samples, the researchers will develop leukaemia models in the lab to test the treatment.
The drugs that work against the mTOR pathway are already used in other conditions. This means that, if these experiments are successful, a treatment could be developed quickly for young ALL patients. Dr Boyes also hopes that these findings may translate to other cancers with high levels of circular DNA.