A world-leading research collaboration between QIMR Berghofer and Emory University has shown that a potential new targeted therapy for childhood brain cancer is effective in infiltrating and killing tumour cells in preclinical models.
The team has hailed the findings as potentially transformative for the treatment of the most common childhood brain cancer, medulloblastoma, and could apply to other brain cancers such as glioblastoma (GBM) and diffuse intrinsic pontine glioma (DIPG).
The research has been published in Nature Communications.
Brain cancer is the second leading cause of death in children in the developed world. For the children who survive, standard treatments have long-term impacts on their development and quality of life, particularly in small children and infants. When medulloblastoma recurs, the prognosis is usually extremely poor.
The research teams collaborated with US biopharmaceutical company, Curtana Pharmaceuticals, which has developed an experimental drug, CT-179. The researchers found that the drug effectively targets the protein OLIG2, which is a known stem cell marker crucial in the initiation and recurrence of brain cancers.
Professor Bryan Day, who leads QIMR Berghofer’s Sid Faithfull Brain Cancer Laboratory and is Co-director of the Children’s Brain Cancer Centre in Australia, described the findings as a breakthrough.
Professor Bryan Day
“Brain cancer is an incredibly tough puzzle to solve. As researchers, what gets us out of bed every day is trying to solve that puzzle. This global research could potentially lead to new combination therapies that are less toxic, more effective, and improve outcomes for these young patients,”
“Our study demonstrated that the drug CT-179, used in combination with standard radiation therapy prolonged survival in a range of preclinical medulloblastoma models, delayed recurrence of the disease, and increased the effectiveness of radiotherapy,” he said.
QIMR Berghofer post-doctoral researcher Dr Yuchen (Michelle) Li, who was joint first author on the study, is hopeful this translational research can improve the quality of life of children with brain cancer in future.
“The blood-brain barrier is a big obstacle in terms of treating brain cancer. As a small molecule drug, CT-179 can penetrate the blood-brain barrier and could also be taken orally, making it easier to administer to young patients,” Dr Li said.
“In our experimental models in the lab, the drug ‘hangs around’ in the brain. When used in combination with radiotherapy, the hope is that overall treatment is more effective and less toxic, which reduces the long-term therapy-induced side effects that have such an impact on patients.”
“This has been a long-running study and it is very rewarding to see it published. We are incredibly grateful for the funding support that helped make this research possible, including from Queensland’s Children’s Hospital Foundation in Australia,” Dr Li said.
Children’s Hospital Foundation CEO Lyndsey Rice said: “Brain cancer kills more Australian children than any other disease. Every child diagnosed with brain cancer deserves the best chance of survival, and that starts with funding life-changing research. Since 2019, the Foundation has been providing funding through the Children’s Brain Cancer Centre, and despite no improvement in survival rates for over 30 years, we are giving hope to families by driving advancements in treatments and moving closer to a cure.”
Emory University Professor Timothy Gershon, who is also a Paediatric Neurologist at Children’s Healthcare of Atlanta and Director of the Children’s Center for Neurosciences Research, said the findings significantly advanced understanding of the biological processes behind tumour growth and recurrence.
“Current treatments, including radiation and chemotherapy, often eliminate most of the tumour, but sometimes fail to eliminate cancer stem cells which can regrow the tumour causing fatal recurrence. Our research showed that CT-179 treatment specifically disrupts cancer stem cells,” Professor Gershon said.
“Combining CT-179 with treatments such as radiation therapy treats the whole tumour more effectively, including both the cancer stem cells and other types of tumour cells. Adding CT-179 to combinations of treatments may bring new efficacy to brain tumour therapy,” he said.
The QIMR Berghofer and Emory University findings complement the results of another study, published concurrently in Nature Communications, led by Professor Peter Dirks from the University of Toronto and Neurosurgeon-in-Chief and Senior Scientist at The Hospital for Sick Children (SickKids) in Canada.
“Our study demonstrated that the OLIG2 protein is a critical driver of the complex early stages of medulloblastoma tumour formation, making it a highly promising treatment target,” Professor Dirks said.
“We showed that inhibiting the OLIG2 protein with the CT-179 drug prevented cancer stem cells changing to a proliferative state, effectively blocking the growth and recurrence of tumours. This could have potentially profound implications for treatment in the future.”
The international collaboration included institutions in Canada, Australia, the United States, Korea, and Sweden.
Professor Bryan Day said the next step was to undertake clinical trials.
“We've been working hard toward this goal with our collaborators, particularly in the United States and here in Australia, and we are now seeking funding to advance to first-in-human clinical testing of CT-179 in patients with brain cancer,” Professor Day said.
The QIMR Berghofer and Emory University paper is available at this link https://www.nature.com/articles/s41467-024-54861-3 on publication in Nature Communications with DOI 10.1038/s41467-024-54861-3.