The latest discovery from Hudson Institute's cancer researchers packs a double punch - identifying a genetic target for childhood brain cancer, plus a way to determine which patients are mostly likely to benefit from it.
Brain cancer is the leading cause of cancer-related deaths among Australian children and paediatric high-grade gliomas (pHGGs) are the most aggressive form of brain tumour in children.
Lead researcher, Dr Shazia Adjumain said that unlike adult gliomas, childhood gliomas have distinct biological features requiring specific treatment strategies, and there is an urgent need to develop treatments that are both more effective and less toxic than conventional therapies.
Her research, published in the Journal of Clinical Investigation Insight, focussed on the anti-cell death gene MCL1, which plays a critical role in the survival of brain cancer cells.
"We showed that blocking MCL1 function with targeted drugs induces significant anti-tumour effects," Dr Adjumain said. "We also identified a unique DNA modification in the BCL2L1 gene that can predict a tumour's response to MCL1-targeting treatments, offering a strategy to identify patients who would benefit most from these therapies."
"This work provides important insights into developing tailored treatments for childhood brain cancers," she said.
Supervisor, Professor Ron Firestein, underlined the importance of this research: "Despite significant overall improvements in survival rates over the past 50 years, cancer remains the leading disease-related cause of death among Australian children."
Using samples from actual cancers, as part of the Childhood Cancer Model Atlas, Hudson Institute's Next Generation Precision Medicine team tests a vast range of potential treatments, and combinations of treatments, to determine which are most likely to benefit patients.
The study discovered that high levels of DNA methylation (chemical modification) at specific sites within the BCL2L1 gene correlate with a tumour's reliance on MCL1 for survival. This epigenetic marker was validated as a predictor of MCL1-targeted drug response in vitro across multiple paediatric tumour types.
Dr Adjumain believes these findings are a big step toward new drugs to tackle some of the most difficult-to-treat paediatric cancers.
"Our discovery of the unique BCL2L1 methylation mark as a biomarker enables a precision medicine approach, allowing for the identification of patients most likely to respond to MCL1-targeted drugs," she said.
"This study bridges basic research and clinical application, paving the way for trials of MCL1-targeted drugs in paediatric cancers, potentially improving survival outcomes for children with these devastating malignancies."
These findings – for which a patent has been applied – address the pressing need for novel therapies, providing hope for more precise, effective treatments that could reduce the devastating burden of this disease on children and their families.
Dr Adjumain paid tribute to the funders who made her research possible.
"This project would not have been possible without the generous and unwavering support of the Gratzer family and the Robert Connor Dawes Foundation over the past three years," she said. "I'm honoured to have made this significant discovery, which was funded in memory of Gideon Gratzer, who tragically passed away due to an aggressive form of glioma called Glioblastoma."
