Newsletter Signup x
Neuroblastoma is a rare cancer derived from nerve cells that usually affects infants and primary school children.
Radiotherapy-induced neurocognitive deficits in medulloblastoma: Human-equivalent modelling and randomised pre-clinical trials to identify effective pharmacological interventions for clinical application
Dr Helen Bryant
University of Sheffield
Sheffield, S10 2RX
1 January 2025
24 months
£147,570
Neuroblastoma is a rare cancer derived from nerve cells that usually affects infants and primary school children. It causes lumps in the abdomen and chest and often spreads to other parts of the body. The disease which is most difficult to treat is known as “high-risk”. Current treatment for high-risk neuroblastoma predominantly consists of very high doses of chemotherapy, surgery, radiotherapy and a treatment using the immune system all of which have a lot of short and long-term side effects. Despite this treatment around half of children with high-risk disease will not be cured.
We know that there are a lot of genetic changes (changes in the DNA) in neuroblastoma that reduce patient survival. One of the most important is when there is an increase in the number of copies of a gene (a section of DNA that tells the cells what to do or be) called MYCN. This change occurs in about 20% of cases. Our laboratory and others have previously shown that having too much MYCN can affect the way that Neuroblastoma cells repair broken DNA and that this can be targeted by new treatments. This is because DNA is constantly being damaged in our cells and DNA repair is essential for survival of the cancer.
We have access to new drugs that stop DNA being repaired. These are currently being tested in adults with cancer and we think that these new drugs may be effective in high-risk neuroblastoma with too much MYCN. We want to test this in laboratory models of high-risk neuroblastoma so we can see if the drugs are effective and if they are, how they work. We also want to see whether they can be combined with traditional chemotherapy or radiotherapy.
We think that CDK12/13 inhibition could be a new, more effective treatment for neuroblastoma. However, we need to prove this in the laboratory before it can be tested in children. If our work shows that the drugs could be effective this means they can be tried in children. This could be through a clinical trial or alternatively drug companies will sometimes give doctors drugs to test if there is enough evidence in the laboratory they might work.
As a by-product of our studies we will also learn more about the fundamental processes that underlie how neuroblastoma develops and progresses. Understanding a disease is often key to developing future new therapies.
The benefits of this project for children with cancer are two-fold. Firstly, it may identify a new drug which could work for children with neuroblastoma and have less side effects than current treatments. Secondly, it may also tell us how CDK12/13 inhibitors kill cancer cells more generally. This knowledge may suggest CDK12/13 inhibitors or similar drugs could be effective in other childhood cancers.
Professor Bryant has worked in cancer research for more than 20 years with a particular interest in how DNA is repaired in cancer cells. She leads a large group of scientists from a range of backgrounds focused on developing new treatments which will have a direct impact on patients. Some of her early work led to the development of a new drug (PARP inhibitors) which is now used in thousands of patients around the world with breast, ovarian and prostate cancer. She has been working with clinicians and other scientists trying to develop more effective therapies for neuroblastoma for the last decade.
Dr David King is a consultant paediatric oncologist working at Sheffield Children’s Hospital. He studied for a PhD in Professor Bryant’s laboratory examining how DNA repair is altered in neuroblastoma. He now works with Professor Bryant on a number of other projects in childhood cancer and has an excellent understanding of how her scientific expertise can be translated to address urgent unmet clinical needs in paediatric oncology.
Every human cell has around 20,000 genes (pieces of information that tell the cell what to do/be), one of our aims is to see how these change when CDK12/13 is inhibited. Dr Ian Sudbury is an established scientist with large expertise in computational processing of large data sets. He uses this expertise provide insight into disease processes including cancer. His skills and experience will allow us to understand the complex changes that likely occur in Neuroblastoma after CDK12/13 inhibition.
Patient Story – Jacob
Jacob was diagnosed with neuroblastoma in April 2008 when he was just four years old. His mum Louise tells
Read more
