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04
Mar
2014

Breaking down the barriers to treating childhood cancer

 

Treatments for childhood cancer have improved greatly in recent decades – over 80% of children with cancer now survive their disease. But that figure, on the surface encouraging, hides the alarming truth that many children who do survive cancer are left with lifelong side-effects. As many as 40% of children who survive cancer are still suffering serious or even life-threatening side-effects 30 years after diagnosis.

The reason rates of side-effects are so high is that we still know far too little about the underlying biology of childhood cancers, and children still tend to be treated with older-style, nonspecific and toxic chemotherapy drugs designed for adults.

Here at The Institute of Cancer Research, London – one of the world’s leading centres for research into paediatric cancers – we believe that the way to improve outcomes for children with cancer is to understand the whole disease process from the initial genetic changes to the accumulation of further molecular changes within tumours, and to use this information to pinpoint new targets within cancer cells. It is an approach that is central to our scientific strategy, and on which we have based a fundraising appeal aiming to raise money for our childhood cancer research.

Understanding the molecular biology of childhood cancer will allow the development of new targeted therapies which are more precise in their action and less likely to cause side-effects. We then seek to either match an existing targeted therapy to the tumour, or if one does not exist, to design a new one, with personalising of therapies to individual patients since one tumour type can display huge genetic diversity across a population.

Dr Chris Jones – Leader of the Glioma Team at the ICR – and his team are looking into the genetic causes of glioblastoma, which is a rare but lethal form of brain cancer in children. Dr Jones explains: “We found that a mutation of a histone protein called H3F3A – which acts as a gene scaffold – unleashes a chain of genetic activity that can lead to the development of certain subtypes of glioblastoma. Specifically, this mechanism switches on a gene called MYCN which is known to drive cancer. Drugs targeted at this genetic activity have already been developed for use in other cancer types here at the ICR, and elsewhere. One promising class of drugs is the aurora kinase A inhibitors, and now we plan to use these for the first time in clinical trials in children.”

One of the most common types of childhood cancer is neuroblastoma which is a cancer of developing nervous tissue. Around half these cases are ‘high risk’, meaning that they are resistant to all current treatments and are frequently fatal, and almost all of these cases harbour an overactiveMYCN gene. Preclinical studies of aurora kinase A inhibitors show that the drugs disrupt the growth of cancerous neuroblastoma cells with an overactive MYCN gene. Dr Louis Chesler, Reader in Paediatric Solid Tumour Biology and Therapeutics at the ICR and Honorary Consultant at The Royal Marsden NHS Foundation Trust, says: “These initial results are really promising. But much work remains to establish if the MYCN targeted drugs are safe and effective for children in the clinic, so the next step will be to trial these drugs in children who aren’t responding to conventional treatments, and those whose disease has relapsed. We are very hopeful that our work will help towards a new clinical strategy to directly target cancer-causing genes in childhood cancer, using drugs specifically designed for children.”

“We need to deliver the same kind of step change in the way children's cancers are treated that we are already seeing in adult cancers, using drugs targeted at specific molecular mechanisms.”

Another driver implicated in neuroblastomas the ALK gene. Crizotinib, a drug already licensed for use in adults, targets the ALK gene and has shown positive early results in its first clinical trial in children with cancers, including neuroblastoma. But early experience suggests that these tumours eventually stop responding to treatment after developing additional mutations in the ALK gene targeted by the drug. Dr Chesler’s team have come up with a new strategy of combining crizotinib with a second class of drugs – mTOR inhibitors –  (which also target MYCN) to overcome the resistance of cancer cells. Dr Chesler says: “Combined changes in the ALKand MYCN genes led to more aggressive crizotinib-resistant neuroblastoma, because ALK switches on an mTOR pathway. But giving an mTOR inhibitor with crizotinib prevents the growth of neuroblastoma by simultaneously inhibiting the ALK and MYCN genes, overcoming the resistance of these tumours to treatment with crizotinib alone.”

Despite the groundbreaking discoveries in childhood cancers during the past 30 years, leading cancer experts have now warned that children with cancer suffer delays in access to and in some cases are denied – new, potentially life-saving drugs, even if scientific evidence shows that they could extend or save lives. This is because EU rules are allowing pharma companies to gain exemptions from carrying out expensive testing of cancer drugs in patients under the age of 18, even where a drug’s mechanism of action suggests it could work in children. The ICR is calling for a change in the implementation of the 2007 EU Regulation on Paediatric Medicine, which has a loophole allowing pharma companies to avoid testing drugs in children in cases where the adult cancer the drug is developed for does not occur in children. This is completely out of step with what research has shown us about cancer, which is that it is not the location of a cancer in the body which matters, but the molecular drivers of the cancer – and the great majority of these are common to both adult and children’s cancers. Where it is the case that a molecular target exists in both adult and children’s cancer, such as in the case of the ALK gene, we believe that drugs targeting these mutations should not be exempted from paediatric investigation.

“The case for the development of safer and more effective molecularly targeted drugs is overwhelmingly clear and without question of most urgency for children,” says Dr Chesler. “We need to deliver the same kind of step change in the way cancers are treated that we are already seeing in adult cancers, using drugs targeted at specific molecular mechanisms.”

Our ultimate aim is develop tailored treatments, for all children, in the fastest possible time, with maximum benefit and minimum side-effects. And by changing how EU regulations are implemented, we hope that children will also have access to a goldmine of potential cancer drugs which have currently only been tested in adults.

Images: Glioblastoma cells by Dr Chris Jones, the ICR.

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