PARP inhibitor could be effective treatment for high-risk childhood neuroblastoma
A type of drug already used to treat breast and ovarian cancer, called a PARP inhibitor, may be useful in treating children with high-risk neuroblastoma, a childhood tumour with a low survival rate, a new study suggests.
Neuroblastoma is a cancer which arises from nerve cells in either the chest or the abdomen. In some neuroblastoma cases there is an abnormal gene called MYCN that makes it particularly difficult to treat. Currently children receive intense chemotherapy, radiotherapy and surgery but, despite this, only about half of children with high-risk neuroblastoma will survive.
Researchers at the University of Sheffield collaborated with The Institute of Cancer Research, London, to conduct research to find a new, more effective and less toxic way to target high-risk neuroblastoma tumours containing increased levels of MYCN.
MYCN affects how tumour cell cells grow and makes them more dependent on a protein called PARP for survival. This means that the tumour cells are specifically killed by a drug that stops PARP working. An advantage of this type of therapy is that normal non-tumour cells are not harmed, so the damaging side-effects often seen with chemotherapy are reduced.
The study, funded by childhood cancer research charity Children with Cancer UK, was led by Dr Helen Bryant and Dr David King in Sheffield, in collaboration with Professor Louis Chesler in London. They found that the use of PARP inhibitors alone, and alongside chemotherapy, was effective in killing neuroblastoma cells, leaving behind healthy cells.
This is one of the first studies to show this in neuroblastoma cells and in tumour models.
Dr Helen Bryant, research group lead and senior lecturer at the University of Sheffield, said: “Our study has examined the way DNA is damaged and repaired – one of the features common in all cancers is that there are changes in that process. We were interested in how that process changes when MYCN is present in neuroblastoma and whether we can exploit the changes to specifically kill cancer cells and leave the normal cells around the tumour unharmed. In this way we hope to develop kinder and less toxic therapies for children.
“PARP inhibitors are being used successfully in women with breast and ovarian cancer so we are optimistic that this can be translated fairly quickly into children with neuroblastoma.”
The concept of using PARP inhibitors to prevent cancer cells from repairing themselves was first identified by researchers at the University of Sheffield. Dr Helen Bryant was part of the team, led by Professor Thomas Helleday, who developed the groundbreaking research into a new approach for killing tumor cells and treating cancer called the synthetic lethal approach.
This approach has been described as one of the most exciting prospects for future cancer treatment and has led to the development of a new cancer drug called Lynparza - which has already been successful in treating patients across the world who carry the BRCA1 and BRCA2 genes.
Dr David King, children’s doctor at Sheffield Children's NHS Foundation Trust and Children with Cancer UK researcher, said: "Children with neuroblastoma and MYCN currently receive some of the most intense treatment used for any type of cancer. The harsh treatment causes numerous side effects and children often have long hospital stays. Despite the treatment, only about half of children with high-risk neuroblastoma will survive.
"PARP inhibitors are known to have very few side effects in adults and we have shown they may be an effective treatment for neuroblastoma. Their use in neuroblastoma could mean more children survive the disease and need less toxic treatment.
"We have shown that PARP inhibitors kill neuroblastoma cells with MYCN in the laboratory. The next step is to see whether they are beneficial in children with neuroblastoma, probably in combination with chemotherapy or radiotherapy. This would be done in a clinical trial."
Mark Brider, Chief Executive Officer of Children with Cancer UK, said: “Neuroblastoma is one of the most common childhood tumours with around 100 children, mostly under five years old, diagnosed every year in the UK. Yet it also has one of the lowest survival rates – in its high-risk form the survival rate is sadly around just 50 per cent. It remains one of the most difficult childhood cancers to cure.
“It is crucial that we find more effective and personalised treatments for children with neuroblastoma. The findings of Dr Bryant, Dr King and the teams in Sheffield and London represent an important step towards the development of new and kinder treatments that reduce the burden of toxicity for young cancer patients and improve survival rates in this aggressive and hard-to-treat cancer.”