Advancing Glioblastoma Treatment

The Challenge

Brain tumours are the leading cause of disease-related death in the paediatric population and are the second most diagnosed cancer in childhood. 

For glioblastoma, the most aggressive form, the outlook is especially poor, with less than 5% of patients surviving beyond five years. This figure has not improved in decades. Current treatments often come with serious side effects and offer limited effectiveness, partly due to the complex and protective environment surrounding the tumour.

Project Overview

What if the key to glioblastoma’s resistance was hidden in a strange, circular fragment of DNA that has gone mostly ignored? That question led Associate Professor Orazio Vittorio and Dr Ensieh Poursani down a new scientific path - one that could change how we treat this devastating cancer.

The research zeroes in on extrachromosomal circular DNA (eccDNA), an unusual form of DNA found outside the chromosomes in many tumour cells. They believe this rogue DNA may hold the key to how glioblastoma grows, spreads, and evades even the most aggressive treatments.

Project Outcomes

• Provide the first clear evidence that eccDNA exists not only in tumour cells but also in immune cells in glioblastoma patients.
• Discover how eccDNA is produced in both cancer and immune cells.
• Show how eccDNA can move between cancer cells, immune cells, and normal neurons.
• Develop a new approach to target and remove eccDNA from cancer and immune cells, with the goal of improving treatment outcomes for glioblastoma.

Key highlights

Researchers began their experiments using a glioblastoma cell line known to contain ecDNA and found that the structure of this DNA changes frequently. This makes it difficult to target, as the genome needs to be re-analysed regularly to stay up to date. The team developed expertise in whole-genome sequencing and analysis to better predict these changing structures, and found that individual cells can carry multiple types of ecDNA, adding to the complexity of treatment.

The researchers found that targeting ecDNA in ecDNA-positive cells is particularly challenging due to the dynamic nature of their genomes, which frequently alters the structure and organisation of ecDNA. They also discovered that individual cells often contain multiple types of ecDNA. 

The team is now refining a CRISPR-based approach (a powerful tool for editing genes) to target ecDNA and investigating whether ecDNA can be transferred between cancer and immune cells.

Measuring Impact

Hearts and Minds measures its impact across six core categories as developed by the Association of Australian Medical Research Institutes. Key highlights include:

Research Capacity Building:

• Sharing of materials: The DNA sequencing data from this project will be made publicly available through a global scientific database, allowing researchers worldwide to access and build on the findings.
• Supporting early-stage Researchers: One early-career researcher is contributing to the project, gaining valuable experience.

Health Impacts:

• Improving quality of life: This research has the potential to reduce the short- and long-term side effects of current treatments and improve health status, thereby improving the quality of life for people living with glioblastoma.

 Informing Decisions:

• Future research and treatment: The findings from this study will help guide future research and therapeutic strategies for glioblastoma.

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This study aims to answer critical questions related to tumour initiation, metastasis, and immune suppression in all types of human malignancies. Its findings have the potential to have a significant impact on treating all types of human cancers. 

This project is supported by Hearts and Minds Investments, as nominated by Core Fund Manager, TDM Growth Partners. For further information and updates, visit UNSW.