Support one of the highly recommended research projects

Our world class Scientific Advisory Board strongly recommended we fund this project during our recent grants round. The project was supported due to the quality of research and potential to make a difference to treatments.

Help us fund the development of a promising new drug combination for aggressive Neuroblastoma

Venetoclax is a drug which is currently in an early stage trial for children with relapsed cancer in Australia. It is being tested on solid tumors having had some promising results in the area of leukaemia.

Testing in the laboratory has shown that drug combinations are likely to be far more powerful than a drug on its own. This research is focused on identifying other drugs which might work well with venetoclax and provide synergy which would then effectively destroy neuroblastoma cells.

Many of our supporters will be familiar with Dr Jamie Fletcher from Children's Cancer Institute and the incredible research he leads on high-risk neuroblastoma and relapse of children with neuroblastoma. Dr Fletcher has submitted a compelling proposal. He, with the support of Dr Toby Trahair, wants to run an unbiased drug screening and systematic pre-clinical testing program to identify combinations that will work with the drug Venetoclax as a treatment of high-risk neuroblastoma. 

This project which will take place over 12 months needs $125 k – can you help us by donating?

Venetoclax works by attaching to a protein called BCL2 which is found in malignancies. Once it has binded with BCL2 it  releases certain proteins which then dysregulate the cell causing it to die. In the laboratory, it appears some neuroblastoma cells would be killed using it but in other instances they would not be. However, recent research has also shown adding other drugs with venetoclax could kill more types of neuroblsatoma cells and this is where the research could be instrumental in working out which other drugs would be best to use.

Below you will find more information on this initiative.

What makes this and our other research projects so compelling for us can be found in our family pages, the #44KMfor44kids, our Run2Cure Superheroes and all the stories of the families affected by this heartbreaking disease. 

We need the funding for research because the only way children are treated now is they’re hit hard and fast with as much as they can because if it comes back they can’t treat it. They’re given absolutely everything and it’s awful for the kids. Funding and research is needed to reach the point that these precious children are not taken from us or made to suffer so intensely. Max's mum Sharvita

Identifying synergistic therapeutic combinations with the BCL2 inhibitor venetoclax

Dr Fletcher and team in the lab

Hypothesis: Unbiased drug screening and systematic pre-clinical testing can identify combinations with venetoclax that are effective for the treatment of high-risk neuroblastoma patients.

  • Aim 1: To conduct high-throughput, unbiased screening of high-risk neuroblastoma patient cells for approved drugs that synergise with the BCL2 inhibitor venetoclax
  • Aim 2: To confirm synergistic interactions across a panel of high-risk neuroblastoma models ex vivo and test their tolerability in vivo
  • Aim 3: To assess activity of the leading venetoclax combination in an n=1 pre-clinical study using a panel of 30 high-risk neuroblastoma PDX models 

Achieving our mission

This project is very much in line with Neuroblastoma Australia’s mission to develop safer, kinder and more effective treatments. 

More effective treatments for neuroblastoma patients.

Venetoclax has been shown to have remarkable single agent activity in some haematological malignancies and is of intense interest for a broad range of both haematological and solid tumours. Previous laboratory studies suggest that venetoclax is  active against high risk neuroblastoma, and a current Phase 1 study is assessing the safety and pharmacokinetics of venetoclax in paediatric and young adult patients with relapsed or refractory cancer, including neuroblastoma (NCT03236857). Our preliminary data indicates that a while a proportion of neuroblastoma patients may respond to venetoclax monotherapy,combination therapy is more likely to be effective, as has proven to be the case with adult tumours. At present, the optimal approach to venetoclax combination therapy is completely unknown. This study is focused entirely on identifying effective combinations with venetoclax and subjecting the best combination to rigorous pre-clinical testing in representative panel of High Risk Neuroblastoma PDX models. The study is designed to generate the evidence required to support a clinical trial and has the potential to directly impact on survival rates for a high risk neuroblastoma

Reducing treatment toxicity.

Venetoclax is a highly selective targeted agent and is remarkably well tolerated, with the maximum tolerated dose not reached in a number of adult studies. Initial complications arising from tumour lysis syndrome in venetoclax-treated CLL patients were overcome with risk stratification, prophylaxis, increased monitoring, and dose ramp-up. In adult patients, dose adjustment is only required infrequently and venetoclax is expected to be well tolerated as a chronic therapy. Currently, children treated for high risk neuroblastoma experience substantial treatment-associated acute toxicity, and those who survive experience a high prevalence of significant late effects including endocrinopathy, renal dysfunction and hearing loss, all of which heavily impact on quality of life. Survivors also have an increased risk of second cancers. New combinations with venetoclax may prove more effective and better tolerated than current approaches. While not a primary objective of this study, determining the efficacy of venetoclax monotherapy and combination therapy in a large panel of HR-NB PDX models may provide opportunities to identify biomarkers of response. Dr Fletcher and his team have generated a substantial volume of matched genome sequence and RNAseq data for our panel of PDX models, and development of proteomics data is a medium-term goal. A response biomarker could allow identification of children for whom the combination is likely to be effective,and conversely, children for which the combination is unlikely to be work, thus sparing them futile exposure to drugs that would be ineffective and avoiding unnecessary toxicity.

How this builds on Neuroblastoma Australia’s previous support

To achieve this study, Dr Fletcher and his team are leveraging a high-quality pre-clinical testing platform that was established at Children’s Cancer Institute with the generous support of Neuroblastoma Australia. Previous research support to CIs Fletcher and Trahair has enabled to the establishment and characterisation of a diverse panel of high-risk neuroblastomaPDX models that are fundamental to the success of this proposal.

My research is all about improving outcomes for patients … making existing therapies work better, identifying new therapeutic approaches, and understanding disease progression for each patient. Dr Jamie Fletcher

Dr Jamie Fletcher

Dr Jamie Fletcher Dr Jamie Fletcher conducts research into the childhood cancer neuroblastoma at Children’s Cancer Institute. His work contributes to the Experimental Therapeutics and Molecular Diagnostics Programs, as well as the Zero Childhood Cancer national clinical trial.


Jamie’s research focuses on high-risk neuroblastoma – aggressive, difficult to treat cases of neuroblastoma associated with survival rates below 50%. He has worked for many years to develop a panel of highly specialised pre-clinical models (mouse models) of high-risk neuroblastoma, including patient-derived xenograft (PDX) models and models of metastatic disease. 


These models are critical to testing the effectiveness of different drugs and drug combinations, and underpin Jamie’s research aimed at identifying and prioritising new agents to go into clinical trials in children with high-risk neuroblastoma. The models are also utilised by other scientists at the Institute, and elsewhere in the country.


In other research, Jamie is working to improve our understanding of drug resistance mechanisms, asking ‘why do anti-cancer drugs fail in some patients, are there ways to predict which patients will be drug resistant, and are there ways to reverse or avoid drug resistance? Linking in with this is his research into relapse in children with neuroblastoma.


Jamie moved into childhood cancer research as a junior scientist because he wanted to do ‘research with a very clear social and economic value’.

AWARDS AND RECOGNITION

  • 2018 UNSW Supervisor Award
  • 2011 UNSW Faculty of Medicine Dean’s Rising Star Award
  • 2010 Cancer Institute NSW Career Development & Support Fellowship
  • 2008 Balnaves Foundation Young Researcher’s Fund Award
  • 2000 NHMRC Peter Doherty Fellowship, University of Melbourne

More information