The aim of the Experimental Therapeutics Program is to develop more effective, targeted treatments for neuroblastoma. Neuroblastoma is a cancer of embryonal neural crest cells, and is the commonest solid tumour of early childhood. Most children present with advanced disease, and even with intensive chemotherapy and bone marrow transplantation, have a survival rate of only 40–50%.

Most cancer chemotherapeutics today do not only kill cancer cells, but are also highly toxic to normal tissues. Because of this lack of specificity, one third of child cancer survivors have a major health problem in young adulthood. There is an urgent need for targeted drugs with a high specificity for cancer cells and low toxicity for the normal growing tissues of a child.
Developing targeted treatments requires the identification and validation of molecular targets, and the technology and capability to translate that knowledge into drug discovery, followed by clinical trials.

One of our Program’s key strengths is its demonstrated ability to take promising treatment strategies for relapsed or refractory neuroblastoma directly to the clinic. In 2015 we opened an international early-phase clinical trial of a combination anticancer therapy for relapsed or refractory neuroblastoma. We have another clinical trial due to open in 2019.

Our funding sources include the National Health and Medical Research Council (NHMRC), Cancer Institute NSW, Cancer Council NSW, Profield Foundation, The Kids’ Cancer Project and Neuroblastoma Australia.

    • Targeting the polyamine pathway in neuroblastoma


      Neuroblastoma is the quintessential Myc-driven disease; patients often present with high-level amplification (>100-fold) of the MYCN oncogene in their tumours, which in turn confers a particularly poor prognosis. We and others have shown that high expression of the MYCN oncoprotein is an important causative factor in neuroblastoma.

      The MYCN oncogene regulates a large number of genes that influence neuroblastoma growth and development. One of the best characterised is the ornithine decarboxylase (ODC) gene which codes for the rate-limiting enzyme in polyamine synthesis.

      High polyamine levels are essential for neuroblastoma initiation and maintenance, and high ODC gene expression is associated with rapid cell proliferation and malignant transformation. We showed that depletion of polyamines by treatment with the ODC inhibitor difluoromethylornithine (DFMO) is sufficient to inhibit tumour formation in the TH-MYCN transgenic mouse model of neuroblastoma.

      More importantly, DFMO given in combination with current chemotherapeutic drugs produces prolonged tumour-free survival, with no overt toxicity in either TH-MYCN or human xenograft mouse models. Based on our research, a joint Australia–US Phase I/II clinical trial using a combination of DFMO and standard chemotherapy for relapsed neuroblastoma patients is underway, and early results are very promising. This clinical trial provides strong evidence supporting polyamine depletion, in combination with conventional chemotherapy, as a powerful therapeutic strategy.

      The team has also shown that targeting more than one step in the polyamine pathway enhances therapeutic efficacy in complementary preclinical animal models. As a precursor to a Phase II clinical trial, we plan to test combinations of polyamine pathway depletion agents that either inhibit polyamine synthesis/import or induce polyamine degradation/export, for their ability to potentiate various cytotoxic drug regimens.

    • Inhibiting the chromatin remodelling complex FACT


      The strands of DNA inside each cell are wrapped around proteins called histones, to form tightly-packed structures called nucleosomes. Histone chaperone proteins unpack these structures to facilitate DNA replication (copying), transcription and repair through direct, dynamic interaction with histone proteins. We identified a Myc target gene called FACT (Facilitates chromatin transcription), that is highly predictive of poor neuroblastoma patient prognosis.

      We showed that FACT and MYCN expression have a strong dependent relationship, functioning in a feedback loop that forces very high expression of MYCN — beyond that achieved even by MYCN amplification in neuroblastoma cells.

      We found that a chemical inhibitor of FACT called CBL0137 profoundly inhibits the progression of established neuroblastoma in TH-MYCN transgenic mice and in other in vivo models. CBL0137 also synergises with existing chemotherapeutic drugs used to treat neuroblastoma, by creating a synthetic lethal environment through blocked DNA repair.

      Based on our findings, which we have extended to brain tumours and leukaemias, an Australian Phase I trial, to be conducted jointly with the Children’s Oncology Group (COG), Philadelphia, USA, for all refractory childhood solid and haematological cancers including neuroblastoma, is due to open in 2019, following completion of a Phase I trial in adult cancers.

      Using our in vitro and in vivo models, we plan to determine the best CBL0137 combination treatment for a subsequent Phase II combination trial, and the best timing for delivering this treatment.

    • Inhibition of the drug transporter protein MRP1


      Cancer cells are extremely adaptable, and often find ways to avoid being killed by chemotherapy drugs, a phenomenon known as drug resistance. One of these ways is to efflux drugs (transport them out of the cell) before they can act. We have demonstrated that high levels of the drug transporter protein MRP1 (also known as ABCC1) is an independent prognostic indicator of poor patient outcome, and an important therapeutic target in neuroblastoma.

      In collaboration with our colleagues at Cleveland Biolabs (Buffalo, New York), we identified and patented Reversan as a novel, non-toxic, orally available MRP1 inhibitor. Reversan can sensitise both neuroblastoma and adult cancer cells with high MRP1 expression to standard chemotherapy.

      We have since conducted an extensive medicinal chemistry campaign, which identified a new generation of inhibitors with greatly improved pharmacology, selectivity for MRP1 over other major drug transporters, and excellent in vivo activity. These inhibitors also have the favourable property of producing MRP1-dependent depletion of reduced glutathione (GSH) — a major cellular antioxidant and a critical component of Phase II drug metabolism (the process by which drugs are broken down and made inactive).

      Combining one of these inhibitors with standard chemotherapy could improve the treatment outcomes of patients with neuroblastoma and other types of tumours overexpressing MRP1. In partnership with Cancer Therapeutics CRC (CTx), we will further optimise the properties of these inhibitors, fully characterise them in vitro and in vivo, and conduct preclinical testing. Our goal is to identify a candidate molecule suitable both for licensing to a pharmaceutical company and to take to clinical trial.

Staff List

Group Leader

Professor Michelle Haber AM


Dr Jamie Fletcher


Dr Andrew Gifford


Dr Denise Yu

Dr Caroline Atkinson

Dr Lin Xiao

Dr Vinod Vijayasubhash


Frances Kusuma

Adam Kearns

Jennifer Brand

Madeleine Wheatley


Kimberley Hanssen