| Project title | Epigenetic Defects in Glioma: Towards a New Therapeutic Strategy |
|---|---|
Grant Amount | $200,000 |
Institution | Monash University |
Investigator Team | Principal investigators A/Prof. Lee Wong and Dr. Joanna Voon with associate investigator A/Prof. Jeffrey Mann |
Grant Type | 2018 Innovation Grant |
Years | 2018 – 2020 |
A/Prof. Lee Wong’s team at Monash University’s Biomedicine Discovery Institute will study changes in gene expression (epigenetics) that can lead to gliomas – the most common form of brain cancer. They will look at how mutations in epigenetic regulators (ATRX, H3.3 and IDH1) lead to abnormal gene expression and genome instability, which fuel the development of these tumours. It’s hoped this research will shed new light on how gliomas form, leading to improved diagnosis and treatments.
“This work will provide an in-depth understanding of how disruptions in the epigenetic profile of a cell lead to glioma. This new information on how gliomas are formed—from the initial epigenetic disruption to the final disease state—is essential for the development of effective diagnosis and treatment.”
A/Prof. Lee Wong
Progress: First annual progress report (October 2019)
ALT (Alternative Lengthening of telomere) is a common feature in brain tumours. Our success in inducing ALT in several mutant cells verifies our model that ALT activation is a multifactorial process. It is the first example of ALT activation in a normal, primary cell model which is crucial for investigating key factors and events associated with stepwise activation of ALT.
Potential outcomes:
- Until recently, progress in this field has been hampered by a lack of knowledge and technical limitations. Thus far, we have only been able to observe ALT once this process is well underway in tumours, and the early stages of ALT remain a complete mystery. Our bottom-up approach is completely unexplored and has never been attempted. We have now created prototypic ALT lines which validate this approach. These lines will allow us to study ALT from inception to completion for the very first time and identify the individual factors which drive ALT throughout the process. This not only contributes greatly to knowledge gain but has the potential to open up multiple new avenues for therapies of brain tumours.
- There is a high degree of overlap between ATRX and IDH1 mutations in adult lower-grade gliomas, and ATRX with H3.3G34R in paediatric gliomas. We have identified inhibition of KDM4B as a common factor between these two groups of tumours, strongly suggesting that this may be one of the enigmatic secondary mutations required for ALT. Our research suggests that KDM4B is a key player in ALT – this would be a paradigm-shifting breakthrough in our conceptual understanding of ALT cancers. This concept is likely to apply to all ALT cancers, not just gliomas, and would help us to identify secondary mutations in other ALT cancers.