Neuroblastoma research at Children’s Cancer Institute

Personalised medicine

Zero Childhood Cancer Program.  Zero Childhood Cancer is a national personalised medicine program for children with high risk cancer. Its aim is to give hope to children who are at highest risk of treatment failure, by identifying the best possible tailored treatments for them. A flagship initiative led by Children’s Cancer Institute and the Kids Cancer Centre at Sydney Children’s Hospital, Randwick, the program was launched in 2015 and is currently in a pilot stage. A national clinical trial involving 120 children with the most serious cases of infant, childhood and adolescent cancer, including children with neuroblastoma, will open in 2017. In this trial each child’s tumour cells will be analysed for DNA mutations and drug sensitivities by a range of techniques in order to identify potential drugs with which the child might be treated. The results will be validated in the laboratory, reviewed by an expert panel and provided to the treating clinician to tailor or refine therapy. More information at

Development of approaches for high-throughput drug screening of patient samples. This approach aims to identify drug sensitivities for an individual’s cancer cells in the laboratory using specialised robots that allow examination of thousands of drugs at a time. By screening drugs that have been approved for clinical use, this project has the potential to rapidly identify effective treatments tailored to each patient’s cancer that would not otherwise be possible with routinely used technology.

Identifying new approaches for drug targets and novel agents

DFMO. DFMO is a drug that inhibits a protein that normally generates polyamines, molecules crucial for the rapid growth of cancer cells. DFMO makes the current chemotherapies more effective in killing neuroblastoma cells. DFMO is currently undergoing a Phase I clinical trial run across 14 hospitals in North America and at Sydney Children’s Hospital, based on pre-clinical studies conducted at Children’s Cancer Institute and the Children’s Hospital of Philadelphia. Current laboratory studies aim to identify more effective drug combinations by inhibiting other components of the polyamine pathway.

CBL0137. CBL0137 is a novel drug that prevents cancer cells from repairing DNA damage induced by chemotherapy. Recent pre-clinical data published from Children’s Cancer Institute (Carter et al, 2015 Therapeutic targeting of the MYC signal by inhibition of histone chaperone FACT in neuroblastoma Science Translational Medicine 7(312) pp. 312ra176) indicate that CBL0137 significantly inhibits neuroblastoma tumour initiation and progression. CBL0137 is currently being tested in Phase-1 clinical trials for adult cancers in USA and Russia. On the basis of the promising data produced in Children’s Cancer Institute, a clinical trial to test CBL0137 in paediatric cancers including neuroblastoma is currently being planned as a joint collaboration between multiple centres in the USA and Australia.

Targeting the MYCN pathway. In collaboration with the Cancer Therapeutics Co-operative Research Centre (CTx), Children’s Cancer Institute has a program to develop inhibitors of the MYCN gene, which is well-known to be associated with aggressive forms of paediatric cancer, in particular neuroblastoma. The strategy in this project is to identify either direct MYCN inhibitors or inhibitors of other genes that are essential to the function of MYCN. The MYCN gene belongs to a class of genes, which if mutated or inappropriately switched on can become ‘oncogenes’. Oncogenes have the potential to cause normal cells to become cancerous.

Targeting drug efflux mechanisms. Research at Children’s Cancer Institute has shown that specific multidrug transporters are present at high levels in neuroblastoma cells and are able to pump chemotherapeutic drugs back out of cancer cells, reducing their effectiveness. In collaboration with CTx, Children’s Cancer Institute is developing inhibitors of these multidrug transporter proteins.

Altered gene transcription. Studies into the regulation of gene transcription in neuroblastoma are beginning to identify the mechanisms by which tumour suppressing genes are turned off and tumour initiating genes are turned on. It is now known that a select group of so-called ‘epigenetic genes’ are the master regulators of gene transcription. Understanding these processes may allow the rational use of new drugs that target these mechanisms as well as the identification of new drug targets.

Tumourigenesis mechanisms (understanding the disease)

Understanding tumour initiation: Neuroblastoma arises from cells in the embryo that would normally either not survive or would become nerve cells. Expression of MYCN leads to these cells persisting longer than they should, giving rise to cancer. Investigations into this phenomenon using animal models are uncovering other genes that are essential to this process, with potential implications for early detection or prevention strategies.