Each child participating in ZERO’s national clinical trial has a sample from their tumour subjected to detailed laboratory analyses, using a wide range of cutting-edge science and technology. This generates data that is not only used to provide potentially actionable recommendations to the child’s treating clinician, but is also being used to inform a variety of child cancer research projects.
Before a therapy can progress to the clinical setting, it must demonstrate the potential to be effective in laboratory models, known as preclinical modelling. Through ZERO, innovative methods such as therapy screening and/or animal surrogates or ‘avatars’ are performed on patient cells to develop clinically relevant models of disease in the laboratory that can be used to test existing and new therapies. This information not only improves our understanding of the biological mechanisms of cancer, but also becomes evidence to support translating effective treatments into the clinical setting.
The enormous amounts of data being generated by ZERO are meaningless without complex and intensive analysis and interpretation. To extract clinically useful information − information that can be used to make potential treatment recommendations for a child with cancer − we rely on the powerful tools of bioinformatics and computational biology, as well as highly skilled genomic and laboratory scientists and molecular oncologists. Correspondingly, data generated through ZERO is being fed back into computational and translational tumour biology research to help answer new questions about childhood cancer as we identify genomic lesions of potential importance.
Predisposition to cancer in children
There is much we do not yet understand about the causes of cancer in children. By analysing the tumours of children with cancer, and interpreting the data generated using bioinformatics, computational biology, and highly skilled subject matter experts, scientists are building their understanding of the underlying factors driving the development of cancer in children − in particular, the contribution of hereditary cancer risk. A more complete understanding of cancer predisposition genes is essential if we are to find ways to prevent cancer in children.
Analysing normal or ‘germline’ DNA of a child with cancer can give insight to the possible inheritance of some genetic abnormalities. In some children, a mutation in their genome may predispose them to developing cancer at some stage in their life. By identifying these genetic changes, scientists and clinicians may be able to better understand a child’s cancer, potentially track how cancer related genes are carried in families and better estimate the risk of childhood cancer.
New therapies for childhood cancer
Most therapies used to treat children with cancer today are still general cytotoxic, non-specific agents that kill healthy cells as well as cancer cells. This is detrimental to growing children and can lead to severe lifelong side effects in child cancer survivors. There is an urgent need for more targeted, less toxic therapies for children with cancer. Tumour analysis being carried out through ZERO is providing us with essential information that can be applied to develop new therapies and repurpose existing therapies that would otherwise not be available to children with cancer. Specifically, the comprehensive genomic profiling being performed for each child in ZERO is allowing researchers to identify potential new molecular ‘targets’ − that existing or newly designed therapies will “attack”, such as an altered gene or pathway in cancer cells.
Liquid biopsy is a pioneering “non-invasive” technique where a sample of blood, plasma or cerebrospinal fluid is taken from a child to look for the presence of circulating tumour cells (CTC) or DNA (ctDNA), without the need for an invasive procedure like surgery. Once this technique is developed for children it will enable clinicians to monitor a child’s disease and response to treatment in real time, rather than wait for the cancer to become more aggressive to find out that the treatment was not working.
Liquid biopsy will also enable researchers to analyse how these relate to cells in the primary tumour. This will provide invaluable information about tumour heterogeneity (the variety that exists within one cancer) and clonal evolution (how cancers change over time; for example, to develop resistance to treatment).
We will leverage the recent successful ACRF funding ($3.5M) awarded to Children’s Cancer Institute for the establishment of the ACRF Child Cancer Liquid Biopsy Program to investigate how ctDNA/CTC can be used to track responses to treatments, measure the evolution of molecular changes occurring while on treatment, and identify the earliest molecular markers of cancer recurrence.
Immune-oncology is an exciting new field of research that involves the study and development of treatments that take advantage of the body's natural system to fight disease − our immune system. A major gap limiting the application of these therapies is the lack of knowledge about the immune microenvironment of child cancers.
The joint ZERO – Peter MacCallum Cancer Centre Paediatric Immuno-Oncology program is developing capacity in immune profiling to predict response and identify novel immunotherapy targets. This program aims to generate the first comprehensive immune-profiling of high-risk child cancer, with the long-term goal to give many more children access to potentially curative immunotherapy trials than is currently possible, by identifying those most likely to benefit. The program will generate new clinical opportunities for CAR-T cell therapies in high-risk child cancer, first by identifying patients who could benefit from CAR-T cell therapies being used or developed for other cancer types and second, by exploring the ZERO sequence data to discover targets for new CAR-T cell treatments. This will further strengthen the ability to create concrete paths to drug access to maximise the potential of precision medicine.
While advances in precision medicine for childhood cancer bring novel treatment options and increased hope, they also introduce new emotional and psychological challenges for families. In parallel with ZERO’s national trial, a prospective psychosocial study was commenced to study the impact of personalised medicine on families, researchers, and health professionals to ascertain their expectations and understanding of personalised cancer therapy, their decision making, satisfaction with the process, and its psychosocial impact. This was the first and largest study worldwide to undertake such an approach, with the intention to inform the delivery of experimental trials in high risk cancer internationally, and we will continue to expand this research to develop and improve communication strategies with families for the ZERO trial and for long term integration into the health system.
Preparing the Health System for Precision medicine
All data generated and collected through the ZERO trial will be fed into additional Health Systems research projects addressing economic, implementation, ethics, and legal challenges that must be overcome to support embedding and sustaining precision medicine in the health system. Data required to address policy challenges associated with Paediatric Precision Medicine will be generated to demonstrate the benefits and comparative value. This will inform policy, funding, clinical decision, and assist with patient/parental decision making and meet the NSW and Australian Government’s objective of delivering a safe, effective, and efficient health care system.