Children with neuroblastoma could have the option of treatments with fewer side-effects, British researchers reported last night.
Researchers at the University of Cambridge say using differentiation therapy, which does not involve killing cancer cells, but instead involves encouraging cells to become normal non-dividing cells.
Writing in Developmental Cell, they say the new research is still at an early stage and has yet to be trialled in patients, but it involves a combination of palbociclib, a treatment used for certain types of breast cancers, and retinoic acid, used for neuroblastoma patients at most risk of relapse.
Professor Anna Philpott, who led the research at the Wellcome-MRC Cambridge Stem Cell Institute at Cambridge, said: “Its outcomes are very variable. Some children can be cured with surgery or chemotherapy, but others will need to receive a very high dose of chemotherapy – and some of them then relapse and require further treatment.”
Chemotherapy, while effective, is a blunt instrument that kills cancer cells but can also kill cells in other tissue, causing side effects.
In neuroblastoma treatments, some of these side effects are relatively mild and many are temporary, although some can be life-threatening. There is also a significant risk of long-term complications including hearing impairment, growth restrictions and infertility. Some children can also develop second cancers.
Joint first author Dr Kirsty Ferguson, a researcher at the Cambridge Stem Cell Institute said: “From studies of normal development, we know that if you’re able to slow down cell division, then the cells’ programming begins to correct itself and they get back on track in terms of differentiating. We wanted to see if there was a way of encouraging this to happen in neuroblastoma cells.”
In a laboratory setting, the team showed that treating neuroblastoma cells in a dish with palbociclib causes them to slow their division significantly and form mature nerves.
Dr Ferguson said: “Neuroblastoma cells don’t look like nerves, but more like round cells that divide very rapidly. But when we treated them with palbociclib, their division slowed down and they started to grow axons and dendrites, which was an indication to us that they were maturing into nerves.”
With Professor Louis Chesler from the Institute of Cancer Research, they used the drug to treat mice that had grafted human neuroblastoma cells and found it was able to significantly reduce tumour growth. The drug was also effective at extending lifespans in mice that had been genetically altered to develop neuroblastoma.
However, palbociclib was not enough to fully stop the growth of neuroblastoma. They continued to divide, but at a slower rate. To counter this, the team treated the cells in the dish with retinoic acid in addition to Palbociclib and they found this stopped the division of neuroblastoma cells even more effectively.
The team has now received funding from the Medical Research Council and Cancer Research UK to continue their research, including testing the effect of the drug combination in mice prior to taking this to clinical trial in children.
Joint first author Dr Sarah Gillen said: “Children will still need chemotherapy to kill the main tumour, but once that treatment is out of the way, we think the combination of palbociclib and retinoic acid should be enough to stop any remaining neuroblastoma cells in their tracks. And because these drugs don’t need to kill the tumour cells, only to guide them back to the right path, it should be a much kinder treatment with fewer side-effects.”
Professor Philpott added: “Because both of these drugs have already been shown to be safe in people – and one of them is already in use in children – the clinical trial process should be much faster. If it’s successful, then we could see this new treatment being used within the next decade.”
Ferguson KM, Gillen,SL et al. Palbococlib releases the latent differentiation capacity of neuroblastoma cells. Development Cell. 20 September 2023; doi: 10.1016/j.devcel.2023.08.028
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