Blocking neuroblastoma

In a study led by the Children’s Cancer Institute, scientists have identified a critical molecular ‘feedback loop’ that helps initiate and drive neuroblastoma — as well as a drug that has the potential to stop it.

Neuroblastoma is a cancer of the nervous system in children that is triggered in embryonal nerve cells. It 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.

The new study found that an experimental drug known as CBL0137, used in combination with traditional DNA-damaging chemotherapy agents, was much more effective than either drug alone. This was because CBL0137 created a ‘synthetic lethal’ state by preventing the cancer cells from repairing DNA damage induced by chemotherapy, and so ensuring cell death.

The authors also showed in laboratory models of neuroblastoma that the drug could block the very start of the embryonal cancer, paving the way to possible prevention strategies in the future. Their study has been published in the journal Science Translational Medicine.

Children’s Cancer Institute researchers Dr Daniel Carter and Professor Glenn Marshall focused on the genetic and molecular mechanisms behind the feedback loop, which would normally accelerate cancer development, 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.

The Marshall laboratory demonstrated in neuroblastoma cells that FACT not only upregulates the expression of the MYCN gene, but it also prolongs the life of the MYCN protein (the product of the MYCN gene). They found that MYCN directed neuroblastoma cells to produce more FACT, which in turn forced the MYCN levels ever higher, thus driving the cancer.

“We showed that maintenance of high MYCN protein levels is a key issue for this MYCN-driven cancer,” said Professor Marshall. “Neuroblastoma cells often have over 100 copies of the MYCN gene, so they produce an enormous amount of MYCN protein.

“Yet in addition to the very high levels of MYCN protein, the cancer cells have tools to stop that protein being broken down. That says to me ‘here’s a very good treatment target — it must be the Achilles heel of the cancer’.”

In the embryo, MYCN helps guide the normal development of the sympathetic nervous system by directing the division and migration of primitive nerve cells. At some point in the process, MYCN is switched off and excess cells die off. Neuroblastoma arises when the MYCN gene is not switched off — and some cells continue to divide and proliferate after birth.

Professor Michelle Haber, Professor Murray Norris, Dr David Ziegler and Jayne Murray meanwhile focused on the therapeutic potential of CBL0137, both as a single agent and in combination with other drugs. Not only was CBL0137 found to be very effective against the most aggressive neuroblastomas, but in contrast to other chemotherapeutic agents, it does not damage DNA.

“The drug is currently in Phase 1 clinical trials for adults, which means that safe dosage levels are being tested,” said Professor Haber. “Once the adult trials are completed, a Phase 1 trial for children with refractory — or relapsed — neuroblastoma, and also other aggressive childhood cancers, will open in the United States and Australia.”

For CBL0137 to be effective at preventing neuroblastoma, it would have to be safe enough to be given to all children at birth. Professor Marshall explained, “You would give it once or twice to a newborn, as you give vitamin K, as a way of killing off excess cells that should have died prior to birth.”

The next phase of this project will be a clinical trial of CBL0137 in children at children’s cancer centres in the United States and at Sydney Children’s Hospital, Randwick, conducted through the US-based Children’s Oncology Group (COG). The clinical trial in both countries will be led by Dr David Ziegler, a senior researcher at the Children’s Cancer Institute and head of clinical trials at the Kids Cancer Centre, Sydney Children’s Hospital.

Image credit: ©FreeImages.com/Herman Brinkman

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