Children’s Cancer Institute Australia (CCIA) is one of the world leaders in medical research into childhood cancer and is focused on translational research, taking discoveries from the “bench to bedside”. This “bench to bedside” research has recently led to the commencement of a clinical trial for relapsed neuroblastoma, one of the most aggressive forms of childhood cancer (see clinical trial section below). In addition, CCIA has a number of other new therapies in the research stage that are likely to be in the clinic in the next five years, as outlined below.

  • Clinical trials
  • Drug discovery research
  • Novel drug candidates
  • Prevention research

1. Clinical trials
Clinical trial 1: valproate & gamma-interferon
Sydney Children’s Hospital, Randwick, has commenced the first phase I/II clinical trial using a combination therapy of two existing drugs, valproate and gamma-interferon. This trial has arisen directly from research conducted at CCIA showing that these two drugs cooperate with each other to inhibit cancer growth by blocking tumour blood supply, and that the drugs are much more potent when used together, rather than separately.
Both drugs have anti-cancer action but have not been used for the treatment of childhood cancer before. This phase I/II clinical trial is being led by Dr David Ziegler, who is both a paediatric oncologist at Sydney Children’s Hospital, Randwick and a CCIA scientist.
For further information about this trial, contact:
Sydney Children’s Hospital, Randwick

Jessica Jaramillo

Tel: 02 – 9382 3571

2. Drug discovery research
Genes linked to neuroblastoma:
Central to current neuroblastoma research are a number of genes that have been associated with tumour growth.

MYCN gene
In particular, a gene called MYCN, is found in high levels in neuroblastoma tumours. This gene has been shown to be critical to the development of aggressive neuroblastoma, and patients whose tumours have multiple copies of this gene (as shown by a routine test done at the time of diagnosis) have a particularly poor outcome.
CCIA researchers have shown that two genes, ODC1 and MRP1, contribute to MYCN’s cancer causing properties and often have particularly high levels in neuroblastoma cells by comparison with normal cells.

ODC1 gene
ODC1 stands for ornithine decarboxylase and is involved in the manufacture of proteins called polyamines, which are present at high levels in rapidly multiplying cells. CCIA research has shown that ODC1 is associated with poor prognosis for neuroblastoma patients, as over-expression of the gene contributes to the aggressive biology of this tumour and poor clinical outcome. CCIA scientists have used a laboratory model of neuroblastoma to show that inhibiting ODC1 activity was able to delay or even prevent the development of neuroblastoma.

MRP1 gene
Patients with aggressive neuroblastoma also frequently have high levels of the MRP1 gene in their tumours, and CCIA researchers have shown that these high levels are associated with poor clinical outcome. The MRP1 protein sits inside cancer cell membranes, and protects the cancer cell from cancer-fighting drugs, by acting as a pump to remove the drugs from the cell before they can destroy it. Recently, however, CCIA scientists have also shown that MRP1 has other biological properties apart from acting as an anti-cancer drug efflux pump, involved in the growth and aggressive behaviour of cancer cells, suggesting that the importance of this transporter extends beyond its role in making cancer cells drug-resistant.

TRIM 16 protein
Most children with neuroblastoma present with widely metastatic disease, which is poorly responsive to conventional treatment with chemotherapy, radiotherapy, surgery and retinoid treatment. Retinoids represent an exciting group of compounds that can help make neuroblastoma cells non-tumorigenic. However, following retinoid therapy, more than half of the patients with neuroblastoma will relapse due to the cancer cells becoming resistant to the action of the retinoid.
CCIA scientists have recently identified a protein, called TRIM16, which is vitally important in retinoid therapy. In normal cells, TRIM16 has a role in slowing cell division but in neuroblastoma cells, TRIM16 is switched off.
The next step is to discover novel drugs which can restore TRIM16 function in cancer cells. CCIA scientists will use the ACRF Drug Discovery Centre to do this. It is hoped that these new anticancer drugs will markedly enhance the potency of retinoids in cancer patients.

3. Novel drug candidates

CCIA scientists have discovered a small molecule that switches off MRP1 in cancer cells. Research has shown this small molecule can turn off MRP1 in living cancer models without causing any discernable side-effects. Today, this small molecule, called Reversan, is being developed as a drug candidate for neuroblastoma.
Reversan is not toxic by itself nor does it increase the toxicity of chemotherapeutic drug exposure, whilst at the same time making the tumour more responsive to the chemotherapy. Therefore, Reversan represents a new class of non-toxic MRP1 inhibitor, which may help treat neuroblastoma more efficiently. Reversan is currently being developed for use in clinical trial.

A small molecule drug previously used for curing sleeping illness is now being investigated by CCIA scientists in the laboratory to see if it can help combat neuroblastoma. Difluoromethylornithine (DFMO), as the drug is called, which blocks ODC1 activity, has been tested in laboratory cancer models in combination with standard chemotherapeutic drugs used to treat neuroblastoma, and has been shown to slow tumour progression much more effectively than the chemotherapy drugs used alone. .
CCIA scientists, in collaboration with researchers from the Children’s Hospital of Philadelphia, USA, have further developed this drug candidate combination so that it is ready to be trialled in children with relapsed neuroblastoma. The trial is expected to commence in Australia and internationally within the near future.

4. Prevention research
As with most childhood cancers, neuroblastoma begins in embryonal cells that persist beyond birth and later become cancerous. Using a preclinical model of neuroblastoma, CCIA scientists have demonstrated the critical role of the MYCN oncogene in this cancer initiation process.
Understanding the role of MYCN and other genes during embryo development has the potential to have far-reaching effects on prevention and/or strategies for the early detection of cancer in children. It also allows for the possibility that novel drugs could be developed which specifically target the earliest cells that lead to tumour formation, and CCIA scientists are beginning work to develop such drugs.