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Combination therapy could be effective against resistant childhood cancer

Using two targeted drugs at once could be an effective treatment strategy for children with an aggressive form of cancer who develop resistance to a single targeted drug, a new study shows.

Scientists showed that the use of the cancer drug crizotinib combined with an additional inhibitor reduced tumour growth by up to 85 per cent in human cells implanted into mice.

Their findings suggests the drug combination could be a promising treatment for patients with neuroblastoma – a devastating disease that accounts for about 15 per cent of all childhood cancer deaths.

The research was conducted at the University of Gothenburg in collaboration with The Institute of Cancer Research, London, and it was published in the journal Science Signaling.

Crizotinib, which is already licensed for use in adults, targets the ALK gene, which is mutated in the tumours of children with neuroblastoma.

Early results in initial clinical trials in children have been positive, but there is evidence that children with cancer eventually develop resistance mutations in part of the ALK protein. The study found that ALK stimulates the production of a protein called ERK5. This protein enhances activity of an oncogene called MYCN, and eventually stimulates aggressive tumour growth.

The researchers suggested that the ERK5 protein was a key regulator of the ALK signalling pathway and so might also be targeted therapeutically.

Their studies in mice found that targeting both ALK and ERK5 at the same time was more effective in reducing tumour growth than hitting either target alone.

Dr Louis Chesler, Reader in Paediatric Solid Tumour Biology and Therapeutics at the ICR, who took part in the study, has already developed combination strategies to treat resistant cancer cells that have abnormalities in ALK. He said: “In this study we wanted to more clearly outline how the ALK protein sends cancerous signals to cells. Since patients develop resistance to drugs that target ALK itself because of mutations in the ALK protein, we sought to identify a critical secondary signalling protein that is switched on when these mutations develop. ERK5 is such a protein, and we established that combinatorial targeting of ALK and ERK5 could be more effective in situations where ALK inhibitors alone lose potency.”


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