28 July 2023
At the Centre for Cancer Biology* a research team, led by Professor Greg Goodall and Professor Yeesim Khew-Goodall, from SA Pathology, and Associate Professor Quenten Schwarz, from UniSA, is combining decades of research acumen to improve outcomes for kids with neuroblastoma by fast-tracking the development of diagnostics and treatments.
Yeesim and Greg bring a good understanding of the drivers of the disease to this effort, having spent more than 20 years working in the cancer research field, including holding key roles on the Kids’ Cancer Project. Quenten’s focus is the biology of neural crest cells, a critical stem cell population of the embryo which gives rise to multiple cell types in the embryo and adult, including the cells that give rise to neuroblastomas.
Neuroblastoma forms in utero when a neural stem cell, or neuroblast, fails to develop normally into mature sympathetic neurons (nerves). As a result, the neuroblast continues to divide to form a tumour. Neuroblastomas are most commonly found on the adrenal glands, which sit on top of the kidneys, but can also develop in the stomach, chest, neck, pelvis and bones. The neural stem cells that give rise to neuroblastomas arise from neural crest cells.
Despite being a rare disease, affecting 1 in 100,000 children in Australia, neuroblastoma is the most common extracranial solid tumour in children aged under five years. According to the Neuroblastoma Australia website, neuroblastomas claim more lives of children under the age of 5 than any other cancer.
The disease is quite variable – in some children it is aggressive and metastasizes to other parts of the body, while in others it resolves without treatment. This is typically seen in patients with more differentiated tumours – those tumours that are thought to arise from neuroblasts that fail later in the pathway to neurons.
Yeesim says "The current treatment regime includes surgery, chemotherapy and radiotherapy, which can predispose these young patients to other cancers, as well as other long-term issues linked to radiation therapy, including infertility, deafness, and cognitive issues."
Being able to identify which kids will develop aggressive disease and need intense treatment, and which have tumours that could resolve without treatment, would have life-changing impact for these kids. Currently clinicians do not have this ability in their toolkit.
The team believe the key to faster diagnosis, better treatment and a potential cure lies in understanding what went wrong, when, and why at the molecular level.
To identify the moment when the neuroblast stopped developing and gave rise to a tumour, the team are comparing the gene expression profile of tumour cells with the gene expression profiles of cells that arise during normal development.
This is a challenging approach. As Quenten notes, the disease arises in the womb and those cells that form in development are “embryonic cells [that] only exist in the embryonic phase, they no longer exist once a child is born.”
To overcome this challenge, the team are taking a back-to-basics approach, modelling the entire development process in the lab, from the earliest stem cell of the embryo to mature sympathetic neurons, and characterise the gene expression profiles of these cells.
This generates a gene expression barcode for each developmental stage. The gene expression pattern of a patient’s neuroblastoma can be compared to these barcodes and it becomes an exercise in matching the patterns – the closer the similarity of the tumour gene expression pattern to a barcode, the more likely that the neuroblast stopped developing at that stage.
By coupling this approach with clinical outcomes, the team hopes to be able to use neuroblastoma gene expression profiles to predict which tumours are likely to be aggressive and which are not.
This provides only one part of the puzzle the team is working to solve.
It is already known that a neuroblast's failure to develop reflects a problem within the cell. It’s not yet understood what the nature of that problem might be.
Greg says "Neuroblastomas tend to have chromosomal rearrangements which mean they have a loss or gain of genes that gives either not enough or too much of certain gene products, and presumably they are the gene products driving the differentiation in the final steps to neurons.
We’re trying to find what these genes are so we can correct that deficiency."
Using patient derived tissue, the team are comparing what’s seen in high-risk tumours in children who don’t survive versus those who do and looking for the differences, hypothesizing that within the differences will be clues to what genes are involved.
Greg says the results so far have been promising.
"We have one microRNA where we have quite extensive study now that it seems to be a candidate for being causally involved."
While this breakthrough is exciting, the team says this is just one of many genes that are involved in the process.
By identifying the molecular changes and the key drivers of neuroblastoma, the team hope to one day be able to deliver a therapeutic intervention that stops the disease in its tracks by forcing the tumour cells to resume development to neurons.
Quenten says there’s already a precedence for this type of treatment, currently used for children who are in remission.
"Currently, children with high-risk neuroblastoma go through multimodal therapy including retinoic acid, which acts to stop cell growth and induce cell differentiation, with good outcome."
By combining expertise in neural crest biology, a deep knowledge of cancer and access to patient samples, this team has found a synergy that’s leading to a better understanding of the disease which they hope will deliver better diagnostic tools to guide clinical treatment.
Stay tuned for more developments.
*The Centre for Cancer Biology is an alliance between SA Pathology and the University of South Australia.
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