New clues to improving childhood leukaemia treatment

More and more children are surviving cancer, thanks to advances in treatment

Thanks to scientific progress, we’ve seen a dramatic improvement in childhood cancer survival rates since the 1960s.  Back then, only a quarter of kids survived cancer, compared with three-quarters who survive today.

Acute lymphoblastic leukaemia  (ALL) – the most common type of childhood cancer –  is one of the big success stories.  Around four in five children with ALL are now successfully treated with chemotherapy.  But despite this improvement, it still means that one in five doesn’t respond to treatment, significantly affecting their chances of survival.

That’s  why a new discovery by Cancer Research UK- and Leukaemia Research-funded scientists, published today in the Journal of Clinical Investigation, is important.  It could help explain why this small but significant group of children with ALL don’t respond to chemotherapy.  Although there’s still a lot of work to do, the new results could mean that even more children will be cured in the future.

Treating childhood ALL
Amino acids are the building blocks of proteins, and nutrient-hungry cancer cells can produce most of the amino acids they need to grow themselves. However, ALL cells have a weak spot.  They often lack a molecule called asparagine synthase, which prevents them from making an essential amino acid called asparagine.  So they have to rely on asparagine dissolved in the blood.

At the moment, virtually all children with ALL in the UK are treated with a drug called L-asparaginase. It’s a biological molecule that rapidly breaks down asparagine circulating in the bloodstream, depriving the leukaemia cells of this vital nutrient and making them much more susceptible to chemotherapy.

The L-asparaginase used to treat ALL is produced synthetically by two specially grown species of bacteria, either Escherichia coli (which produces a drug called ASNase) or Erwinia chrysanthemi (which produces Erwinase).  In the UK, children are mostly treated with a modified form of ASNase.

L-asparaginase treatment is extremely effective, and around 80 per cent of children with ALL respond rapidly to the drug. But the 20 per cent of children who don’t respond so fast tend to go on to have worse outcomes.

In some cases, the drug provokes an allergic reaction, meaning that treatment has to be stopped. But in other cases, the drug simply doesn’t work – but no-one knows quite why.

So Cancer Research UK’s Professor Vaskar Saha and his team set out to discover why these children don’t respond to L-asparaginase treatment, with the aim of helping more kids survive ALL in the future.

Uncovering the culprit
The team’s previous work had led them to suggest that an enzyme called  ‘asparaginyl endopeptidase’ (AEP) could potentially be responsible for breaking down L-asparaginase and triggering allergic reactions in some children treated with the drug.

So Professor Saha and his team measured the levels of AEP in laboratory-grown leukaemia cells (cell lines) derived from different types of ALL.

They found that AEP levels tended to be higher in the cell lines that came from ‘high risk’ forms of ALL, associated with poorer outcomes. This was the first clue as to why some children don’t respond to L-asparaginase treatment.  Perhaps their leukaemia cells produce high levels of AEP, breaking down L-asparaginase before the drug has a chance to act in the body. But did this hold true for leukaemia cells taken from patients?

To find out, the researchers then looked at AEP levels in a number of samples from children with ALL and found that some of them produced very high amounts – supporting the idea.

The next step for Professor Saha and his team is to test whether their findings bear up in a clinical trial involving ALL patients – not just samples in the lab.  They are currently recruiting children from 18 childhood cancer centres across the UK to find out whether levels of AEP activity are related to how they respond to treatment.

Future prospects
If the relationship between AEP and failure to respond to treatment holds true, then it could lead to a test to help doctors  predict whether ALL patients will respond to treatment or not, or if they might have an allergic reaction.

This research could also lead to an AEP-resistant version of L-asparaginase. As part of this research, Professor Saha and his team produced a version of the drug that had been modified so it could no longer be attacked by AEP. Unfortunately it wasn’t as effective as the normal treatment, but this could be a fruitful avenue for future development.

Currently, all children with ALL are started on ASNase, then switched to Erwinase if the treatment doesn’t work, or if they have an allergic reaction. But knowing that a patient has high levels of AEP means they could be offered Erwinase from the start, saving precious time.

Finally, the discovery also reveals a potential path to improving treatment for children with ALL. Chemicals are available that could block AEP and prevent it from destroying ASNase, although these need more work before they are suitable for use as drugs in patients.

This discovery highlights the importance of research into the genes and molecules that underpin the development of cancer, and how these vary from person to person.  Such research is paving the way for ‘personalised medicine’, based on the molecular signature of an individual’s tumour.  And this will ultimately lead to better treatments and improved survival for more children – and adults – with cancer.

Kat

You can watch videos about Professor Saha’s research, and donate to directly support his work via MyProjects.

References:

Strefford, J. et al (2006). Complex genomic alterations and gene expression in acute lymphoblastic leukemia with intrachromosomal amplification of chromosome 21 Proceedings of the National Academy of Sciences, 103 (21), 8167-8172 DOI: 10.1073/pnas.0602360103

Patel, N. et al (2009). A dyad of lymphoblastic lysosomal cysteine proteases degrades the antileukemic drug l-asparaginase. Journal of Clinical Investigation DOI: 10.1172/JCI37977