Cure Brain Cancer Foundation (CBCF) is thrilled to share an exciting progress update from Dr. Andrew Garvie, Research Fellow at Monash University. Dr. Garvie is spearheading a groundbreaking project to develop targeted therapies for brain cancers characterised by H3.3 and/or ATRX mutations.

In collaboration with Professor Ross Hannan (Australian National University) and his team, Dr. Garvie is exploring the potential of PMR-116, a novel Pol I inhibitor with the ability to cross the blood-brain barrier, as a promising therapeutic avenue. This innovative research, made possible by the Foundation’s 2023 Early Career Fellowship grant of $345,000, aims to pave the way for more novel and effective therapies for patients, particularly children, battling brain cancer.

High-grade paediatric glioblastomas are the most aggressive and common solid cancer in children, with a median survival of 1.5 years. A seminal discovery was the identification of recurrent H3.3 mutations in paediatric glioblastomas: H3.3K27M and H3.3G34R. These H3.3-mutated tumours frequently show concurrent mutations in ATRX and activation of the Alternative Lengthening of Telomeres (ALT) pathway to evade telomere loss and enable cell immortality. There is compelling evidence that paediatric glioblastomas with histone H3.3 and ATRX mutations show severe ribosomal DNA (rDNA) repeat instability and, thus, are compromised in their ability to produce ribosomal RNA (rRNA) and, therefore, are hypersensitive to RNA Polymerase I (Pol I) inhibition.

Dr. Garvie’s research is making significant strides in improving treatment options for people with brain cancers caused by specific genetic mutations in the H3.3 histone protein, particularly H3.3K27M and H3.3G34R. These mutations disrupt essential cellular processes, making tumours with these mutations challenging to treat with conventional therapies. By understanding how these mutations interfere with rRNA transcription, a critical step in cell growth, Dr. Garvie is uncovering new ways to target these tumours more effectively.

Dr. Garvie’s findings suggest that tumours with these mutations are particularly sensitive to PMR-116, which can specifically target the disruptions caused by these mutations. This sensitivity offers a promising avenue for developing treatments that could be more effective and have fewer side effects compared to current options. For patients with these specific brain cancers, this could mean new, more effective therapies and a better quality of life.

In addition to its direct impact on patient care, Dr. Garvie’s is employing advanced techniques such as CRISPR-Cas9 gene editing and immuno-electron microscopy to push the boundaries of what is known about the genetic underpinnings of brain cancer. These innovative approaches will help create precise experimental models and evaluate drug responses in detail. This work not only enhances the understanding of how these genetic mutations drive cancer but also supports the development of targeted treatments.