Our Impact Our research projects Current projects Children’s Cancer Institute (CCI), Sydney What is CBL137? CBL137 is a novel drug developed for adult cancer in USA. It had not been tested for childhood cancer until the CCI looked at its qualities to target neuroblastoma tumours; specifically, those types of neuroblastoma that are linked to the MYCN gene which produces a protein in high volumes that is proven to create the metabolic environment for this cancer to grow aggressively. Early results in laboratory models show the effectiveness of CBL137 in reducing aggressive neuroblastoma tumours. Not only does this research indicate the drug is very effective at reducing the cancer when used in combination with chemotherapy, but also that CBL137 does so with few damaging side effects because it does not damage DNA. It is DNA damage that is responsible for these side effects and if CBL137 can mean the cancer can be treated with lower dosages of toxic chemotherapy then this will not only improve cure rates but also reduce long term damage to the children treated. The research project involved identifying whether this drug could be effective in treating high-risk neuroblastoma in laboratory models as a single agent, at the next stage this single agent will go to a phase one clinical trial to confirm the acceptable dosage of CBL137 to treat this aggressive cancer in children. PROJECT #1 CBL137 single agent clinical trials CBL137 is in clinical trial for adults in USA and Russia, these trials will establish the optimal dosage required to kill the cancer without serious side effects to patients, currently the trials are continuing due to the success of the drug and the lack of side effects suffered. As soon as the adult clinical trial is completed the dosage for children will be established as 80% of that identified as optimal for adults. The next phase of this project will be a clinical trial of CBL137 for children at leading children’s cancer centres in the United States and at Sydney Children’s Hospital, Randwick, conducted through the US-based Children’s Oncology Group (COG), the largest children’s cancer study group in the world. This is the first time that a COG trial of this sort would be made available to Australian children. The clinical trial in both countries will be run in the hospitals by Dr David Ziegler, a senior researcher at CCI and Head of Clinical trials at the Kids Cancer Centre, Sydney Children’s Hospital (Randwick). PROJECT #2 CBL137 combination with other targeted therapies The next research project focuses on how CBL137 will work in combination with other targeted therapies with the aim that it can be optimised by to treat the cancer cells most effectively but with less damage to healthy cells. CCI has already identified an agent that looks promising in laboratory models combined with CBL137, now this needs to be tested further to understand how it is working, if there are bio-markers that indicate this combination should be effective in particular children and the procedures for monitoring the combination drug usage and effect. Funding for this type of pre-clinical research is essential as often other funding sources focus on capital equipment and infrastructure rather than the senior scientists required to complete this ground-breaking work. CBL137 has been researched by CCI through groups led by Professors Michelle Haber, Murray Norris and Glenn Marshall. Articles and videos: Experimental drug giving hope to kids with cancer (SBS) A way to target the Achilles heel of neuroblastoma (CCIA) Neuroblastoma our battle (CCIA) PROJECT #3 Characterisation of high-risk neuroblastoma models to support translational research Under the leadership of Dr Jamie Fletcher and Dr Toby Trahair, we are supporting a new CCI project that hopes to develop highly detailed models representing the diversity of neuroblastoma. The project will conduct molecular characterisation of patient-derived xenograft (PDX) models from Australian and New Zealand patients enrolled in an international, multicentre, randomised clinical trial. These models will play an invaluable role in current and future basic and translational research studies for this disease. Clinicians and researchers could make use of this panel of PDX models to improve the accuracy with which they assess new therapeutic approaches prior to clinical trials. This would help prioritise approaches that are more likely to be effective in children. PROJECT #4 Optimisation of high-risk neuroblastoma model development Under the leadership of Dr Jamie Fletcher and Dr Toby Trahair, we are supporting an additional project aimed at decreasing the time required to generate PDX models and increasing the success rate of their development. PDX models allow high quality lab-based testing of treatment approaches and can be an important part of testing for individual patients in the context of clinical trials. Quicker and more reliable PDX development increases the number of patients that can benefit from these approaches in a clinically relevant time frame. Improvements to PDX model development can be rapidly adopted for high-risk neuroblastoma patients enrolled on the Zero Childhood Cancer clinical trial and can influence the model development approaches of other groups in the neuroblastoma field internationally, including those involved in personalised medicine trials. PROJECT #5 Improved preclinical efficacy of CBL0137 by combination with HDAC inhibition We are supporting a new project which aims to improve preclinical efficacy of CBL0137 by combination with a TGA/FDA-approved drug, panobinostat. Preliminary work in high-risk neuroblastoma mouse models from the Children’s Cancer Institute has shown that CBL0137/panobinostat combination markedly prolonged disease-free survival compared with either of these two drugs alone, or compared with conventional chemotherapy drugs for neuroblastoma. The team will further test if CBL0137/panobinostat can sensitise relapsed/resistant PDX models to standard chemotherapy backbones that are often ineffective for these tumours. This study also aims to understand how CBL0137 and panobinostat interact to specifically target tumour cells. Understanding of the underlying mechanisms will help reveal potential drug targets and develop safe and highly efficacious treatments for high-risk neuroblastoma.