Experimental Therapeutics

We are working on developing effective treatments for children with neuroblastoma, and extending these to other aggressive cancers including brain tumours, leukaemias and sarcomas.

Group Leader

What we do

The aim of the Experimental Therapeutics Group is to develop more effective, targeted treatments for neuroblastoma − a cancer of embryonal neural crest cells and the most common solid tumour of early childhood. Most children with neuroblastoma present with advanced disease, and even with intensive chemotherapy and bone marrow transplantation, many do not survive.

Most cancer chemotherapeutics used today do not only kill cancer cells, but are also highly toxic to normal tissues. Because of this lack of specificity, many childhood cancer survivors experience serious health problems in 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 and preclinical testing, followed by clinical trials. One of our Group’s key strengths is its demonstrated ability to take promising treatment strategies for relapsed or refractory neuroblastoma from concept through to the clinic. We opened an international early-phase clinical trial of a combination anticancer therapy for relapsed or refractory neuroblastoma in 2015, and this led to a major international trial being undertaken by the Children’s Oncology Group (USA) in over 200 hundred hospitals worldwide. Two other major international clinical trials are now being planned, using this same combination anti-cancer therapy.

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.

Research projects

Targeting the polyamine pathway in neuroblastoma

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Contact: Professor Michelle Haber AM, MHaber@ccia.org.au; Dr Ruby Pandher, RPandher@ccia.org.au; Dr Lin Xiao, LXiao@ccia.org.au

Neuroblastoma is the quintessential Myc-driven disease. Patients often present with high-level amplification (>100-fold) of the MYCN (N-myc) 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. Our group has shown 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 was undertaken. A number of patients who completed the study had a positive response, with their tumours shrinking, leading to extended survival. This clinical trial provides strong evidence supporting polyamine depletion, in combination with conventional chemotherapy, as a powerful therapeutic strategy. A subsequent trial is currently being conducted by the US Children’s Oncology Group, in which DFMO is being tested as a standard treatment for children with relapsed neuroblastoma.

We have continued to work to further enhance these polyamine inhibition strategies. DFMO prevents neuroblastoma cells from creating their own polyamines, but it cannot stop them from taking polyamines up from their surroundings. We have therefore combined DFMO with the polyamine transport inhibitor, AMXT 1501, and shown that this combination, particularly when administered with chemotherapy, provides a powerful new potential therapeutic strategy for treating children with neuroblastoma and also those with a childhood brain cancer called diffuse intrinsic pontine glioma (DIPG), a devastating disease that is currently 100% fatal. This new combination therapy (DFMO/AMXT 1501) is now being tested in the USA in adult patients with a broad range of cancers, and planning for childhood cancer trials is well advanced.

Inhibiting the chromatin remodelling complex, FACT

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Contact: Professor Michelle Haber AM, mhaber@ccia.org.au; Dr Lin Xiao, LXiao@ccia.org.au; Dr Klaartje Somers, ksomers@ccia.org.au

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, 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 prognosis in children with neuroblastoma.

Our work has shown 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 also 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, a joint Australian−US Phase I trial for all refractory childhood solid cancers, including neuroblastoma, is due to open in 2021. 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

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ContactDr Jamie Fletcherjfletcher@ccia.org.au

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 indicator of poor prognosis, 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 that contain 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.

Combining one of these inhibitors with standard chemotherapy could improve the treatment outcomes of patients with neuroblastoma and other types of tumours that overexpress MRP1. In partnership with the Cancer Therapeutics Cooperative Research Centre (CTx), we are further optimising the properties of these inhibitors, fully characterising them in vitro and in vivo, and conducting preclinical testing. Our goal is to identify a candidate molecule suitable both for licensing to a pharmaceutical company and for taking to clinical trial.

Synergistic therapeutic combinations with the Bcl2 inhibitor venetoclax

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Contact: Dr Jamie Fletcher, jfletcher@ccia.org.au; Dr Alvin Kamili, akamili@ccia.org.au

At present nearly half of all children diagnosed with high-risk neuroblastoma either do not respond to therapy or initially respond but subsequently relapse with incurable disease. This is an unacceptably low success rate.

Venetoclax is a relatively new drug that is proving effective against a range of cancers. Our initial studies suggest that venetoclax may also be effective against high-risk neuroblastoma, however the experience with adult cancers suggests that it is likely to be most effective in combination with other drugs. At present, the optimal approach to venetoclax combination therapy is completely unknown.

Our study is focused on identifying effective combinations with venetoclax and subjecting these combinations to rigorous preclinical testing in representative panel of patient-derived laboratory models of high-risk neuroblastoma. The study is designed to generate the evidence required to support subsequent clinical trials and has the potential to directly impact on survival rates. This project is supported by Neuroblastoma Australia.

Improving relapse prediction for high-risk neuroblastoma

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Contact: Dr Toby Trahair, toby.trahair@health.nsw.gov.au; Dr Jamie Fletcher, jfletcher@ccia.org.au

High-risk neuroblastoma has one of the lowest survival rates of childhood cancers, causing a disproportionate number of childhood cancer deaths. This project links clinical trials to laboratory-based studies to increase our understanding of how patients with high-risk neuroblastoma relapse, to improve our ability to detect residual disease and to predict relapse in advance.

We aim to develop sensitive liquid biopsy based minimal residual disease (MRD) tests to measure disease burden and treatment response in each individual patient and to determine whether these tests can reliably monitor disease course and predict impending relapse. We also aim to conduct genomic analysis of neuroblastoma patient samples to determine the origin of relapse. The project builds on the expertise of the research team in high-risk neuroblastoma, clinical trials, patient-derived xenograft development, genomics and minimal residual disease testing and is supported by Children’s Cancer Foundation.


Principal Scientist

Dr Jamie Fletcher

Clinical Research Fellow

Dr Andrew Gifford

Research Officers

Dr Caroline Atkinson

Dr Lin Xiao

Dr Vinod Vijayasubhash

Dr Alvin Kamili

Program Officer

Dr Jayne Murray

Research Assistants

Erin Mosmann

Adam Kearns

Jennifer Brand

Madeleine Wheatley

Emma Ronca

PhD Students

Kimberley Hanssen

Leigh Gao

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