Next-gen therapies could treat high-grade gliomas

A Newcastle-led research team, backed by national and international experts, is forging ahead in its mission to develop a life-saving treatment for high-grade gliomas (HGG) — an extremely aggressive and lethal form of brain cancer — following the announcement of an $18.7 million grant through the Frontier Health and Medical Research initiative, supported by the Australian Government’s Medical Research Future Fund. The initiative is providing $700 million over 10 years to support research that delivers a ‘moonshot’ by creating a treatment for a currently serious and incurable health condition.

The team, led by University of Newcastle Professor Matt Dun, will test a suite of next-generation therapies it has developed, including drugs designed to overcome the blood–brain barrier. The aim is to bring one of these new treatments to clinical trials within the next five years, changing the outlook for what Dun describes as “one of the most underfunded and devastating cancers globally”.

HGGs are one of the deadliest brain cancers, striking more than 2000 Australians every year. In children, the most common form of HGG is diffuse intrinsic pontine glioma (DIPG), which sees most children surviving less than 12 months, even with radiotherapy. In adults, glioblastoma accounts for 65% of all brain cancer deaths and still has no effective treatment.

HGGs, including DIPG and glioblastoma, are hard to treat because of the following factors:

• They grow in very sensitive parts of the brain, making it difficult to remove.
• Typical chemotherapies do not provide a benefit because they do not penetrate the blood–brain barrier (a protective shield around the brain).
• The tumours have complex genetic and immunological features that make them hard to target.
   

Now, Dun and his team have identified a critical gene that drives the growth and survival of HGGs. Their research has shown that blocking this gene with new brain-penetrant drugs, especially when combined with radiotherapy and targeted therapy, can extend survival in preclinical models by more than 150%.

“We’ve developed a suite of next-generation therapies designed specifically to reach the brain and target the tumour,” Dun said.

Despite decades of research, Dun said therapeutic progress to treat HGGs had been minimal, largely due to the challenges of delivering drugs into the brain and the complex biology of these tumours. “Our research directly addresses these barriers by developing novel, brain-penetrant therapies that target dependencies of these cancers,” he said.

“By advancing both a lead therapy and an additional, similar treatment, we’re building a robust, adaptable pipeline with real potential to improve patient outcomes, offering hope, where currently none exist.”

In 2018, Dun’s two-year-old daughter Josephine was diagnosed with DIPG. Through genetic sequencing of Josephine’s tumour and an extensive literature review, Dun and his team identified genes critical for DIPG survival, and a combination of drugs to target the tumour. Josephine became the first child in the world given a new therapy called paxalisib that slowed the tumour’s growth, but she ultimately passed away 22 months after her diagnosis.

“This grant holds particular significance for me, as it builds on the research we began in response to my daughter’s diagnosis,” Dun said.

“For too long, people diagnosed with high-grade glioma, both children and adults, have been met with a sense of hopelessness. This funding represents a turning point.”

Image credit: iStock.com/dani3315