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Understanding how epigenetic abnormalities lead to brain cancers;

Lead PI: Dr Lee Wong, Monash University, VIC

Dr Lee Wong 

Research idea

Understanding the epigenetic changes which result from ATRX/histone H3.3 mutations will aid the development of targeted therapies for brain tumours.

Problem

Glioblastoma multiforme (GBM) has a median survival rate of just 1.5 years. Despite advances in treatments of other cancers, outcomes for GBM have remained essentially unchanged for the past 30 years. Developing treatments for GBMs has remained challenging due to limited understanding of the molecular defects which underlie these tumours. The team’s aim is to determine how mutations in the epigenetic regulators ATRX and H3.3 (found in 44% of GBMs) alter the genome to promote genomic instability and tumourigenesis. Understanding the molecular pathogenesis of GBMs will help in developing better and more appropriately targeted drugs in the future. 

Solution

This project involves precise genetic engineering to recapitulate the initial driver events in the epigenetic pathway which promote gliomagenesis. While cancer lines used in most studies are generally adequate, the presence of multiple mutations can complicate data analysis. The team will generate accurate mutations of ATRX/H3.3 in the context of a ‘clean’, otherwise normal, background for detailed investigations on the epigenetic changes which occur in the absence of other confounding factors. This systematic approach to understanding this crucial component of gliomagenesis will provide insights which cannot be obtained using any other methods. 

"We want to use genetic engineering to create normal cells that carry these mutations, H3.3 and ATRX, and understand how this could start the changes in epigenetic codes and how they may drive cancer in the beginning."

-Dr Lee Wong

Why now?

  • Advances in technologies: The rapid development and reduced costs of next-generation sequencing technologies have allowed the characterisation of multitudes of cancer epigenomes. We will apply these technologies to define the alterations within the epigenome of GBMs.
  • International collaborations: This proposal will be performed in collaboration with Prof. Philippe Collas, an expert in genome-wide bioinformatics analysis.
  • Resources: The team have access to mouse embryonic stem cells with 1) ATRX knockout, 2) H3.3G34R targeted mutation and we can rapidly generate the ATRX/H3.3G34R double mutant. We also have ATRX/H3.3 mutant GBM cells.

Approach

Completion of this project would lead to an enhanced understanding of how ATRX/H3.3 mutations disrupt the normal epigenome and lead to GBM formation. It allows the team to identify the factors which promote abnormal gene expression and genome instability in GBMs. With this information, they can isolate both genes and pathways which are essential for cell survival in GBMs and identify targets which might be vulnerable to therapeutic interventions. This knowledge could then be used in future drug screening projects to identify compounds which disrupt these specific genes and pathways with high precision and efficacy.

Impact

GBMs are devastating due to the age group affected and the zero survival rates. The team’s work will produce insights into the comprehensive epigenetic changes induced by H3.3/ATRX mutations and facilitate the development of novel therapeutic strategies targeting these changes. It will provide a better understanding of the role of H3.3/ATRX mutations in the formation of other cancers (osteosarcomas, pancreatic cancers), which are frequently mutated for ATRX/H3.3. The knowledge will help them understand and prevent cancer progression. Direct measures will come from high-impact publications and potential development of cancer intervention procedures. 

Team & Partners

Dr Lee Wong was the first to report that ATRX and H3.3 were important for maintaining the epigenetic environment at telomeres (Wong etal. 2007, 2009 Genome Res cited >150x). This discovery predated the discovery of high rates of mutation of these genes in cancers. PI Wong has the ideal team and collaborative links to study H3.3/ATRX mutations, extending findings at telomeres to a genome-wide setting. She has assembled a team with broad expertise including Next-Gen sequencing, ChIP and RNA-seq analyses. Principal Investigator 2, Hsiao Voon has an in-depth experience with genome-wide data (Law, Lower, Voon et al. 2010 Cell cited >100x).

  • PI: Dr Hsiao Voon, Monash University
  • Co-Investigator: Prof Philippe Collas, University of Oslo 

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