Improving outcomes of childhood neuroblastoma

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Published: 1 Jun 2013
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Dr Garrett Brodeur - Cancer Center at The Children’s Hospital of Philadelphia, USA

Dr Garrett Brodeur talks to ecancer at the 2013 ASCO Annual Meeting in Chicago about childhood cancer neuroblastoma, ALK and being awarded ASCO's Pediatric Oncology Award.

 

ASCO 2013

Improving outcomes of childhood neuroblastoma

Dr Garrett Brodeur - Cancer Center at The Children’s Hospital of Philadelphia, USA


Neuroblastoma is the most common solid tumour in children, it accounts for about 8% of all childhood cancers but 15% of deaths from childhood cancer so it’s disproportionately lethal. So the more we understand about the disease the better off we’ll be. We know that 1-2% of patients with neuroblastoma have a family history of developing this disease and our goal was to identify the genes that were responsible for that predisposition. That has been done by our group and others but we played a major role in identifying a gene called ALK which is mutated, actually activated, in about 80% of all families who inherit this strong predisposition.

There is a lot of discussion around ALK as well, correct?

That’s true. So ALK is activated by translocation, so joining part of ALK with part of another gene to make a new gene. That was first found in adult large cell lymphomas but it has also been found in non-small cell lung cancer and in inflammatory myoblastic tumours. So there are different translocations in each of those but ALK is activated by that so drugs that target ALK are used to treat patients who have this feature. So 80% of patients who inherit this predisposition have an ALK mutation in all the cells of their body but it’s only when ALK is further activated in the tumour do we target it in those cases.

Are there any other genes that signal predisposition?

There’s a small percentage of patients, about 5%, who have one of two other genetic features. One is called congenital central hypoventilation syndrome or Ondine’s Curse. Basically when these children go to sleep they may not wake up because they stop breathing so they frequently need to be on respiratory support for the rest of their lives and some of them develop neuroblastoma. There’s also a disease called Hirschsprung's disease where there’s a problem of nerve cells not getting to the distal part of your colon so you’re very constipated at birth and surgeons have to remove that part of the colon. So both of these features are associated with this PHOX2B gene but depending upon the type of mutation in PHOX2B they may also develop neuroblastoma.

Are there any cases not related to those?

That’s correct. Another 15% are not accounted for by those two genes so we’re looking for those genes now.

Are you also looking at tumour DNA and tumour profiling?

Almost thirty years ago we identified a feature of neuroblastomas that was characteristic of very aggressive behaviour. It was called MYCN amplification. So cells, instead of having two copies of a gene, one from their mother, one from their father, they would have 200 copies of the gene so they’d overexpress the gene, overexpress the RNA and protein and that would make these cells very aggressive. That was found in about 22% of neuroblastomas.

Can understanding the molecular profile help with prediction?

We started using this feature even back in the late ‘80s to predict outcome but other features have been identified, such as deletion of the short arm of chromosome 1, deletion of the long arm of chromosome 11, the diploidy or the number of chromosomes in the tumour and so forth. So right now those are the features we’re using in addition to age and stage to predict outcome but in the near future we’ll be doing more global profiling of the entire genome and all the genes that are expressed and developing patterns that are predictive of behaviour that are more precise than what we’re using now.

What are some of the drugs used to target this?

There are a number of targets but two in particular. So I mentioned ALK was a gene responsible for predisposition so the mutations were in the normal DNA. But sporadic tumours that develop without a family history also can have ALK mutations or activation and that’s found in 8-12% of tumours. Tumours that have that feature are very susceptible to killing with a drug called crizotinib; so crizotinib is also used to treat these other tumours we mentioned, the adult non-small cell lung cancer, the adult large cell lymphomas and so forth but it’s very useful for a subset of neuroblastoma patients, particularly those that have this ALK mutation or activation. 50-60% of high risk neuroblastomas have what’s called autocrine activation of this TrkB gene so they make the ligand, it goes outside the cell, binds to the receptor and activates it and that drives the cell to survive and become more invasive, metastatic, angiogenic and drug resistant. So it’s a very strong driver of aggressive behaviour but if we block that pathway many of the cells will die and the ones that survive are more sensitive to killing by chemotherapy. So we did preclinical studies in mice and then did a clinical trial in patients with neuroblastoma and actually had a very good success rate. At least 50% of the patients we treated had a very good response and there are two important aspects of that. One is the responses, when they occurred, tended to last a long time, a median of ten months but sometimes over two years. The second thing is the drug itself was very non-toxic so patients had failed very intensive chemotherapy, radiation therapy, surgery, immunotherapy, they got treated with this drug which they take twice a day by mouth, it didn’t make them sick, they didn’t have any pain and they had a comfortable life for months and years.

What does this mean for practising doctors?

I think this is the future of treating cancer in adults and children, that we’re going to be using these targeted therapies and because they’re targeted they really focus on a particular aspect of the tumour and have very little effect on the rest of the normal cells of the body. So we won’t see the incredible nausea, vomiting, low blood counts and other side effects that we see with conventional chemotherapy.

What are you doing for neuroblastoma?

So we’re still using crizotinib and that’s being used in phase II trials now. The lestaurtinib drug is no longer commercially available because another company bought the company that was making this and they stopped making it. But we’re working with other companies that are developing second generation TRK inhibitors which should be more specific for this target. Nanoparticles are wicked cool so nanoparticles are basically drug delivery vehicles that are in the order of 50-200nm in size. Normal tissues have very tight junctions in the blood vessels; tumour blood vessels are leaky so nanoparticles can pass through into tumour tissue and they won’t get into the normal tissue. So the drug accumulates in the tumour and you can deliver it that way. You can also label the nanoparticles so you can image them and you can also attach features to the outside that make them stay in the tumour or stick to the tumour and even being taken up into the tumour like a Trojan horse so they can be even more effective. We find we can deliver 5-10 times the dose of drug to the tumour as we can with just giving free drug.

What do you think is the take home message from all of this?

I think the future of paediatric and adult oncology increasingly is going to be profiling of the patient and their tumour to identify what the patient might be sensitive to so they don’t have undue toxicities but, more importantly, what the tumour is sensitive to so we can kill it more selectively. Therapy will be tailored to individual patients and their tumours. The second thing is the development of the targeted agents to do that.