Targeted treatments that attack cancer metabolism could treat some of the most aggressive childhood cancers caused by faulty activation of a gene called MYCN, new research outlines.
MYCN is involved in many cancer types including high-risk forms of childhood cancers such as neuroblastoma and medulloblastoma.
Scientists at The Institute of Cancer Research, London, identified that compounds which attack a cell signaling pathway linked to cancer metabolism called mTOR are highly effective both against neuroblastoma cells grown in dishes and in mice with MYCN-driven cancers.
For many years, researchers have tried to develop therapies that target MYC proteins, but it has proven very difficult to do.
But the MYCN form of MYC may be easier to target because it is present only in tumours, and not in normal, cells.
Now, several mTOR inhibitor drugs are entering paediatric clinical trials, to see how well these drugs work for children with cancers such as neuroblastoma.
Reduction in tumour size
The researchers tested 228 different compounds against neuroblastoma cells in the lab and found the most effective was a molecule known as NVP-BEZ235, an mTOR inhibitor.
The drug was given to mice with MYCN-driven cancer, and 80% survived treatment for 21 days, with significant reduction in tumour size, compared with untreated mice that died within three weeks.
In contrast, drugs that inhibited a related pathway called the PI3-kinase pathway were ineffective when MYCN was present, offering no benefit.
The new study is published in Oncotarget, and was largely funded by Cancer Research UK, with additional grants from the National Institutes of Health.
The researchers found that the reason why NVP-BEZ235 worked so well was because it blocked two different mTOR pathway targets that work to stabilise MYCN protein, which could be important for other mTOR inhibitors entering clinical trials in paediatrics.
NVP-BE235 blocks the complexes mTORC1 and mTORC2, which use two different mechanisms to keep MYCN proteins active in the cell.
Most other drugs, such as PI3-kinase inhibitors, don’t achieve complete inhibition, or inhibit just one of these pathways, resulting in ineffective blockade of mTOR that allows the cancer cell to keep on growing.
Neuroblastoma affects around 90 children a year in the UK and usually develops in children under five. The high-risk version of the disease is more likely to come back and is commonly associated with high levels of MYCN proteins, so new treatments are badly needed.
Study leader Professor Louis Chesler, Professor of Paediatric Solid Tumour Biology and Therapeutics at the ICR, said: “There are many different drugs now going into clinical trials and being tested for their ability to target cancers that are dependent on MYC proteins. But for children suffering with diseases such as aggressive neuroblastoma, where MYCN is a problem, what’s needed is to prioritise which of these drugs is most likely to work, because our data indicate that not all of these drugs are equivalent, and some could in fact offer no benefit.
“Our study highlights that one particular class of drug, very potent allosteric mTOR kinase inhibitors, show particular promise for pediatric patients when MYCN is expressed. And understanding how the drug works — by blocking both mTORC1 and mTORC2 — reveals a crucial vulnerability in neuroblastoma tumours which we hope we can exploit in the clinic.”
Other clinically approved mTOR inhibitors have been shown to be effective, and will enter clinical trials in the UK and Europe later this year and next year.