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Ulixertinib may change childhood brain tumour treatment

New research suggests that ulixertinib may offer one of the first targeted therapies for the most common form of brain tumour in children.

scientist in a lab using a microscope to work on on ulixertinib

The study, part-funded by The Brain Tumour Charity, found that ulixertinib, which is a type of drug known as an ERK inhibitor, slowed the growth of paediatric low-grade glioma brain tumour cells and significantly improved survival in studies in mice.

Ulixertinib is developed by BioMed Valley Discoveries. It is a potent orally-administered drug that works by blocking proteins ERK 1 and 2 from sending signals to tumour cells to promote their growth.

Ulixertinib is a promising step forward

The drug is already being trialled globally in advanced childhood cancers with genetic mutations in the MAPK pathway where ERK proteins are important. But this study now suggests it may also be effective in treating slow-growing gliomas, the most commonly diagnosed brain tumour in children and young people.

The breakthrough findings by scientists at the Hopp Children’s Cancer Center Heidelberg (KiTZ), the German Cancer Research Center (DKFZ) and the Heidelberg University Hospital (UKHD), are now set to be translated into an international clinical trial next year. This will assess whether ulixertinib could be an effective targeted therapy in children whose low-grade gliomas have relapsed after initial treatment.

Experts described the findings as a “very promising step towards the first targeted, kinder treatment” for many children diagnosed with low-grade gliomas, which commonly recur after treatment.

What is a low-grade glioma?

Low-grade gliomas are the most common form of brain tumour in children, accounting for around 40% of all cases in children and young people. Standard treatment usually includes surgery to remove as much of the tumour as possible, as well as chemotherapy and radiotherapy.

Thanks to research progress and advances in care, nearly 90% of children diagnosed survive for 10 years, and over 80% survive for 20 years. But, despite encouraging survival rates, children affected remain at high risk of recurrence following treatment, with over 40% seeing their brain tumour progress or return within ten years. They are also seeing the disease and its treatment having a major long-term impact on quality of life for many.

In recent years, scientists have identified the MAPK (mitogen activated protein kinase) pathway as a key target for new targeted therapies, finding that almost all paediatric low-grade gliomas are driven by significant changes within this pathway.

The MAPK pathway is comprised of three core proteins, BRAF, MEK and ERK. These send signals to tumour cells to survive and grow – with BRAF inhibitors such as dabrafenib and MEK inhibitors such as trametinib already having shown encouraging results in clinical trials for brain tumours.

An important breakthrough in childhood brain tumour treatment

In this new research, scientists at the Hopp Children’s Cancer Center Heidelberg (KiTZ), a joint institution of the German Cancer Research Center (DKFZ), the Heidelberg University Hospital and the Heidelberg University, investigated whether the ERK inhibitor ulixertinib could effectively target and kill paediatric glioma cells.

In studies in cells in the lab, the researchers — led by Professor Till Milde at The Everest Centre for Research into Paediatric Low-Grade Brain Tumours at the KiTZ —found that ulixertinib effectively reduced the growth of the tumour when used alone or in combination with two other types of drugs.

The scientists then found in studies in mice that ulixertinib appeared able to cross the ‘blood-brain barrier’ at sufficient concentrations and both slowed tumour growth and led to significantly increased survival in mice (median survival 48.5 days, compared to 30 days in the control group).

Providing comprehensive evidence of the clinical potential of ulixertinib, the findings — published in Neuro-Oncology — could now be accelerated into an international phase I/II ‘umbrella’ trial within the next year for children with relapsed low-grade glioma.

The trial will test whether ulixertinib — alone or given with other promising drugs (BRAF/MEK inhibitors and BH3-mimetics) as a ‘pincer’ combination therapy — could provide one of the first effective targeted treatments for low-grade glioma, with children given access to the appropriate treatment arm based on the genetic make-up of their tumour.

The study was funded by BioMed Valley Discoveries, The Brain Tumour Charity in the UK and the German Cancer Consortium, with additional support from the German Research Foundation and the Ministry for Science and Culture of the State of Baden-Württemberg – and made possible through collaboration between, and pooling of data across, many teams at the KiTZ.

Lead author Professor Till Milde, Consultant Paediatric Oncologist at the Hopp Children’s Cancer Centre (KiTZ) in Heidelberg, said:

“New approaches to treat paediatric low-grade glioma are urgently needed, because complete removal of the tumours through surgery is not always possible, and because standard chemotherapy is not sufficient in all cases to kill all the tumour cells.

“Our work provides proof that the new drug ulixertinib has significant potential to effectively treat low-grade gliomas and we now eagerly await an upcoming clinical trial, hoping it may offer an effective new treatment option for many children worldwide.”

Dr David Jenkinson, Chief Scientific Officer at The Brain Tumour Charity, which helped fund the study, said:

“This is a very promising step towards the first targeted and kinder treatment for hundreds of children diagnosed with a low-grade glioma, which commonly return after treatment.

“Children diagnosed with this form of brain tumour can go through many rounds of treatment, including surgery, chemotherapy and radiotherapy, which can have a profound long-term effect on their quality of life. New treatments to help reduce this harm and improve long-term outcomes for children are urgently needed.

“It’s really exciting to see this new, first-in-class drug showing such promise in targeting low-grade glioma cells, and that these findings are now set to be swiftly translated into an international clinical trial. Kinder treatment options for paediatric brain tumours cannot wait.

“While brain tumours remain relatively rare in children and young people, if you’re worried and your child’s symptom persists or they experience a combination of symptoms, we’d encourage you to speak to your doctor, to help rule a brain tumour out. Anyone concerned can also find out more about the possible signs and symptoms at headsmart.org.uk. We’re here for you.”