Melbourne: Australian scientists have identified a critical molecular ‘feedback loop’ that helps initiate and drive neuroblastoma, a cancer of the nervous system in children that is triggered in embryonal nerve cells.
The research team was able to identify an experimental drug, which was currently in clinical trials for adult cancer, with the potential to interrupt the loop and halt tumour progression, Australia-based Children’s Cancer Institute said.
This feedback loop massively accelerates cancer development.
The authors showed in laboratory models of neuroblastoma that the drug could block the very start of this embryonal cancer, paving the way to possible prevention strategies in the future.
Neuroblastoma, a cancer that develops from immature nerve cells found in several areas of the body, is the most common ‘solid tumour’ of early childhood, and is generally diagnosed when the disease is advanced.
Around half of all children with neuroblastoma have aggressive tumours, and fewer than half of these patients survive, even after intensive treatment. A potential new drug on the horizon is very good news indeed.
The new study, from the Institute, found that the drug-known as CBL01371 – used in combination with traditional DNA-damaging chemotherapy agents was much more effective than either drug alone because CBL0137 created a ‘synthetic lethal’ state – by preventing the cancer cells from repairing DNA damage induced by chemotherapy, and so ensuring cell death.
These important findings were published today in the international journal Science Translational Medicine.
Michelle Haber AM and Glenn Marshall AM, respective leaders of the Experimental Therapeutics and Molecular Carcinogenesis laboratories at the Institute, worked on two very different aspects of the study.
Daniel Carter and Glenn Marshall focused on the genetic and molecular mechanisms behind the feedback loop, and its interruption by CBL0137.
The feedback loop involves the MYCN gene – already known to be a key driver of neuroblastoma – and a molecule known as FACT, a DNA modifying agent which is the target of CBL0137.
“Our laboratory tests tell us that CBL0137 is likely to be very effective against the most aggressive neuroblastomas, and indeed the most aggressive forms of other childhood cancers, and that is very exciting,” Haber said.
“But what is particularly exciting is that, in contrast to many other chemotherapeutic agents, CBL0137 does not damage DNA, and it is DNA damage that is responsible for the many unpleasant and serious side-effects that frequently affect children after they are cured of their cancer,” Haber added.
Marshall, Director of the Kids Cancer Centre at Sydney Children’s Hospital, Randwick and Head of Translational Research at Children’s Cancer Institute, said, “We showed that maintenance of high MYCN protein levels is a key issue for this MYCN driven cancer.”
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