Genomics and Systems Medicine Funding Summary

When babies develop epileptic seizures in the first year of life they can be very difficult to treat. This form of epilepsy can sadly result in severe disability and early death. We think that 50% of babies with epilepsy have a mutation, or a spelling mistake, in one of their genes. We are now able to do a genetic test which looks at all the genes a baby has to find the spelling mistake. This is called genome sequencing. We can sometimes change the baby’s treatment based on the result of this. It may also be helpful for families to understand their baby’s problems better.

We would like to test whether it is possible and useful to have this test result back quickly, within 3 weeks. In this pilot study of ten families we aim to develop the rapid genome sequencing so that we can then apply for funding to do a much larger study that will go on to look at factors such as whether the result changed treatment and whether other tests were avoided. We will also assess the developmental progress of the babies in the larger study at diagnosis and at 12 months of age.

At the end of the study, we will be able to say how well the genetic testing performed and what impact It had for the babies and their families.

In a variety of human cancers, epigenetic alterations have emerged as common hallmarks in tumour initiation and progression. Epigenetic regulation influences the accessibility of the underlying DNA to transcriptional regulatory factors that activate or repress expression. Unlike genetic changes, epigenetic changes are reversible and do not change your DNA sequence.

Diffuse intrinsic pontine glioma (DIPG) is a very aggressive tumour that mostly affects young children. The prognosis for DIPG is very poor with very few patients surviving past 2 years after diagnosis. Conventional therapies to treat this cancer has shown no benefit for patient and therefore there is an urgent need for novel therapeutic strategies. We have recently discovered a new drug that target a key epigenetic mutation in DIPG. In this project we aim to understand its mechanism of action.

Despite clinical success of modern chemotherapy and risk stratification, leukaemia is still a leading cause of death in children. Discovery of cellular pathways that are hijacked by cancer genes in leukaemia can often reveal new ways to treat this disease, especially in patients who do not respond well to current treatments. We have discovered two such pathways operating in the most common leukaemia types found in children. In this project we aim to examine how these pathways have been deregulated.

We propose in this project to implement a new technology called CUT&Tag to study the impact of new drugs on key epigenetic features in DIPG and leukaemia. CUT&Tag will enable us to study essential epigenetic pathways and the effect of novel drugs faster and with less starting material. In addition, it is economically cheaper compared with classical technique. All these advantages will positively impact our capacity to deliver potential new treatment to children diagnosed with leukaemia and DIPG.

One of the key challenges in treating children with leukaemia is that we cannot reliably predict which children will respond to treatment. If we had more accurate ways of predicting the treatment response, we would be better able to tailor treatment to individual children.

A technique called ‘single cell mRNA sequencing’ can provide an exact readout of how mature each cancer cell is. We believe that by using this technique we will be able to improve existing prediction methods by defining highly precisely for each leukaemia how mature the cancer cells are. Here, we will perform a pilot study of single cell mRNA sequencing of “real life” clinical leukaemia samples, hoping to lay the first step in taking this cutting-edge analytical method to the bedside.