Scientists identify potential new drug combination for children with incurable brain cancer

Combining two existing cancer drugs could offer promise for some children with an incurable childhood brain cancer, a new study suggests.

Dr Fernando Carceller, Consultant in Paediatric and Adolescent Neuro-Oncology at The Royal Marsden
Dr Fernando Carceller, Consultants in Paediatric and Adolescent Neuro-Oncology at The Royal Marsden

Scientists found that using an existing leukaemia drug alongside a melanoma skin cancer treatment slowed down the growth of cancer cells taken from patients with diffuse intrinsic pontine glioma (DIPG).

The combination was effective in the lab against cells that had evolved resistance to single drug treatment – offering hope that it could help to keep the disease at bay for longer. Researchers next hope to further validate their findings in cell and animal studies before progressing the drug combination to clinical trials.

Dr Fernando Carceller and Dr Lynley Marshall, Consultants in Paediatric and Adolescent Neuro-Oncology, in the Oak Paediatric and Adolescent Drug Development Unit at The Royal Marsden, were part of the research team led by The Institute of Cancer Research, London. The new research aimed to find ways to treat children with DIPG tumours using drugs called MEK inhibitors, which have been approved for several other cancers.

These targeted drugs have been found to often work well initially, only for cancers to evolve resistance to treatment. They had not previously been explored for children with DIPG – most of whom currently die within a year of diagnosis.

The new study is published in the journal Cancer Discovery, and was funded by a range of cancer charities, including Christopher’s Smile, Abbie’s Army, Islastones Foundation, the CRIS Cancer Foundation, Cancer Research UK, Children with Cancer UK, and the Ollie Young Foundation.

Researchers evaluated a MEK inhibitor called trametinib in mice, and found that on its own it had little effect. Further analysis in lab-grown tumour cells revealed the mechanism of resistance: mutations in MEK 1 or MEK 2.

The researchers then tried using the multi-kinase inhibitor drug, dasatinib, alongside trametinib to treat DIPG cells with resistance mutations grown in mice and in the lab.

They found that the combination of these two drugs, each with a different mechanism of action, slowed down tumour growth in the trametinib-resistant cells. The combination had a much greater effect than would have been expected by adding the effects of the two drugs together – reducing growth in cells grown on mouse brain tissue by over 60 per cent.

Trametinib has already been approved for use in adults in combination with dabrafenib to treat melanoma skin cancer and non-small cell lung cancer, while dasatinib is approved to treat chronic myeloid leukaemia and some forms of acute lymphoblastic leukaemia. That raises the prospect that the new drug combination could be tested in children relatively soon, once further validation studies have been completed.

The study ran as a co-clinical trial by using UK DIPG patient samples from the Biological Medicine for DIPG Eradication (BIOMEDE) trial, a phase II clinical trial led by Gustave Roussy in Paris.

The study has shown the benefits of modelling patient-specific responses to identify mechanisms of resistance. Scientists hope to replicate this approach in the future to identify new drug combinations for children with other types of DIPG mutations.

Dr Fernando Carceller, Consultant in Paediatric & Adolescent Neuro-Oncology and Drug Development at The Royal Marsden, said:   

“DIPG tumour cells often develop resistance to targeted therapies. This research suggests a new combination of drugs aimed at overcoming that resistance for a particular drug, highlighting the importance of tissue studies in DIPGs. While this is promising, further work is needed to determine whether this combination can be beneficial for children with DIPG.” 

The Oak Paediatric and Adolescent Drug Development Unit is funded by The Royal Marsden Cancer Charity. Dr Fernando Carceller is part funded by a generous donation from George and the Giant Pledge to The Royal Marsden Cancer Charity. 

To learn more about ways you can support The Royal Marsden Cancer Charity, please visit their website.