Researchers at Children’s Cancer Institute have combined two targeted therapies to come up with a dual treatment strategy they believe may be far more effective against deadly childhood brain cancer than either therapy used on its own.
In a study* published this week in the high-impact international journal, Science Translational Medicine, the researchers focused on a group of notoriously difficult to treat brain tumours known as diffuse midline gliomas. This group includes diffuse intrinsic pontine glioma, DIPG, an incurable and uniformly fatal brain cancer with an average survival time of just 12 months from diagnosis.
Professor David Ziegler and Associate Professor Maria Tsoli, co-senior authors on the study, have been working for several years to find an effective treatment for DIPG.
‘We recognise that no single drug treatment is able to eradicate the most aggressive of brain cancers on its own,’ said Associate Professor Tsoli, Senior Scientist and Levi Wheeler Fellow, Brain Tumour Group, Children's Cancer Institute. ‘We’ve therefore been working on developing rational combination therapies, which we believe are more likely to be effective.’
‘One of the key challenges in targeting diffuse midline glioma is that thousands of genes are activated in the disease, and it has proven extremely difficult to find a way to switch them all off,’ added Professor Ziegler, Group Leader, Brain Tumour Group, Children's Cancer Institute and Senior Staff Specialist, Kids Cancer Centre, Sydney Children’s Hospital, Randwick.
The therapies used in the current study are both new-generation drugs known as epigenetic therapies, and work by disrupting transcription, the process that cells use to activate genes.
‘Diffuse midline glioma cells are driven by a genetic change that causes transcriptional dysregulation, leading to uncontrolled growth,’ explained Dr Holly Holliday, Senior Research Officer, co-first author . ‘In this study, we discovered a promising combination of drugs that successfully shuts down the transcription process, effectively switching off thousands of genes at once.’
The study focused on two proteins known to play a critical role in transcription, FACT and BET, which are highly expressed in cancer cells. In both cases, targeted therapies called inhibitors have already been developed. However, testing has shown that these only have modest activity when used as single agents.
When the researchers used these two inhibitors in combination, they found they profoundly disrupted transcription in diffuse midline glioma cells grown in the lab, ultimately causing their death. These results were also seen in living models of disease (mouse models), leading to tumour death and extended survival in the mice.
Excitingly, the researchers found that the two therapies not only worked together to drive tumour death but also unmasked the cancer cells to the immune system, meaning that the patient’s own immune system could now recognise the cancer cells and help to eliminate them. These findings suggest that adding an immunotherapy, such as CAR T-cell therapy, into the treatment combination could potentially achieve even better results.
The study’s results, which provide ‘proof of principle’, will now be used as a foundation on which to build further research.
‘Both FACT inhibitors and BET inhibitors are in clinical development,’ explained Dr Aaminah Khan, Research Officer, co-first author of the study. ‘The FACT inhibitor CBL0137 has already been tested in children and shown to be safe. The next step is to identify the best BET inhibitor to use in combination with CBL0137, and once it is also shown to be safe in children, the team then plans to test the combination in a clinical trial for children with DMG.’
‘While there’s still much work to do, our hope is that this research will lead to new treatment options for children affected by these devastating brain tumours.’
One such child is Levi Wheeler, who was diagnosed with DIPG when he was seven years old and lost his life to the disease just after turning eight. Described by his mother, Kathryn, as ‘a beautiful spirit and a gentle soul,’ Levi endured brain surgery, 30 rounds of radiation, 14 cycles of immunotherapy, and two months of an experimental drug, all to no avail.
To honour Levi’s legacy, his parents set up Levi’s Project and have since raised millions of dollars for DIPG research.
“We know firsthand the devastating effects of DIPG and are proud that Levi’s Project has helped fund this important study,” Kathryn said. “We desperately need an effective treatment for this terrible disease, and research is the key to finding it.”
This work was supported by grants from the National Health and Medical Research Council, Cancer Institute NSW, The DIPG Collaborative, The Cure Starts Now, The Kids’ Cancer Project, Kids Cancer Alliance, Cure Brain Cancer Foundation, We Love You Connie Foundation, and Levi’s Project.
