There was great excitement when researchers linked cancer-causing gene ALK to a children’s cancer called neuroblastoma back in 2008.
Although we live in an era of personalised medicine for many adult cancers, progress has been much slower in children.
One of the limiting factors has been finding the genes that are driving children’s cancer, understanding their biological effects, and finding ways to target them with drugs.
Discovering ALK was involved in neuroblastoma gave new hope that molecularly targeted drugs could be developed for the illness.
In a new review just published, researchers here at The Institute of Cancer Research have described the difficult journey travelled from the momentous discovery in 2008 to the use of new treatments in the clinic.
Researchers immediately grasped the importance of the ALK discovery. They were aware ALK had been shown to have a role in other cancers – including a type of lung cancer where a drug inhibiting ALK, crizotinib, had already been developed.
So not only did researchers working on neuroblastoma have access to important information about the biological role of ALK, there was also a precedent for treating the disease by targeting the gene.
Neuroblastoma is the most common childhood cancer that occurs outside of the brain, and unlike some adult cancers it had not yet benefited from the new generation of molecularly targeted treatments.
As further research was carried out, the case for targeting ALK mutations became even clearer. The mutations were found to be associated with poorer outcomes for children with the cancer. So finding new drugs looked like the key to tackle some of the most difficult to treat cancers.
But things are rarely straightforward when developing new cancer medicines. From the beginning, researchers and clinicians anticipated that cancers might become resistant to ALK inhibitors – and this soon proved to be the case for lung cancer.
Trying to stay ahead of the game, between 2010 and 2013, 40 patent applications were submitted for next-generation ALK inhibitors for non-small cell lung cancer. Through this work a new ALK inhibitor, known as ceritinib, was approved by the US Food and Drug Administration.
Meanwhile, children’s cancer researchers were working to characterise the role of ALK in neuroblastoma. They found that neuroblastoma patients with ALK mutations fell roughly into two categories. Children who had a family history of cancer tended to have a mutation known as R1275 that responded relatively well to ALK inhibitors, while children without a familial connection tended to have a different ALK mutation, known as F1174L. The F1174L mutation, unfortunately, seemed to confer intrinsic resistance to ALK inhibitors such as crizotinib and ceritinib.
How to tackle treatment of children with the F1174L mutation was now the big challenge.
In the laboratory researchers were able to show that the F1174L mutation changed the shape of the ALK gene product in a very subtle way – but one that was able to confer resistance to both crizotinib and ceritinib ALK inhibitors.
So researchers needed to go back to the drawing board and investigate new approaches. They developed an innovative mouse model of the ALK F1174L mutation, alongside another common neuroblastoma mutation, MYCN. This model was able to predict that crizotinib would not work in neuroblastoma patients with the F1174L mutation and is now an invaluable resource to develop new drugs.
The mouse model helped researchers understand that combinations of drugs might hold the key to overcoming resistance in these patients. For example, recent studies suggest that combining crizotinib with another drug, the mTOR inhibitor Torin 2, could stop cancer growth. This drug combination is now being pursued in the clinic and a number of other drug combinations are being explored.
So the future is beginning to look brighter for children with neuroblastoma with an ALK F1147L mutation, but there is still some way to go.
Developing new cancer treatments for children is particularly challenging because of the small number of patients involved. Traditionally clinical trials need large groups of patients in order to show a statistically significant impact. Researchers will need to develop highly effective targeted treatments if they want to progress them through trials.
The smaller number of childhood patients also means there is less potential for profit, and so some pharmaceutical companies do not seem to pursue treatments for children as vigorously as for adults. It is striking that there are seven ALK inhibitors now available for use in adults with non-small cell lung cancer, with only two in trials for neuroblastoma.
At the ICR, we have been vocal in calling for increased access to clinical trials for children with cancer. We would like to see change to EU regulations that ensure that cancer drugs developed for adults are also tested in children whenever they could be effective.
Focusing only on adult cancer in the case of ALK mutations would be short-sighted. Using the mouse model of the ALK mutation F1174L is likely to yield insights on how we can overcome drug resistance in both adult and childhood cancer.
For researchers and clinicians to really make progress treating cancers with ALK mutations, we need to stop thinking of developing treatments for children or adults and realise that research in both fields can advance our understanding. With a better understanding of how cancer becomes resistant, we stand a chance of finding ways to cure cancer, regardless of the age of the patient.
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