A way to target Neuroblastoma

Scientists have identified a molecular 'feedback loop' critically driving neuroblastoma, a children's cancer of the nervous system triggered by embryonic nerve cells.

This feedback loop massively accelerates neuroblastoma. Fortunately, scientists have identified an experimental drug — CBL0137 — with the potential to interrupt the feedack loop and halt tumor growth. The drug is also currently being tested in clinical adult cancer trials. Study authors found in modeling neuroblastoma, that CBL0137 could block the very start of this embryonal cancer, paving the way for its prevention.

Neuroblastoma is the most common 'solid tumor' of early childhood, and is generally diagnosed when the disease is advanced.

About half of all children with neuroblastoma have aggressive tumors. Fewer than half survive, even with intense treatment. CBL0137 gives hope.

The new study by Children's Cancer Institute Australia, found that even through CBL0137 is traditionally used in combination with another DNA damaging chemotherapy agent — it is much more effective administered alone. CBL0137 creates a 'synthetic lethal' state in cancer cells, a state that prevents a cell from repairing damaged DNA created from chemotherapy — and ensures cell death. Findings are published in the international journal Science Translational Medicine.

Professor Michelle Haber AM, of the Lowy Cancer Research Centre in the University of New South Wales, and Professor Glenn Marshall AM, of the Kids Cancer Centre and Sydney Children’s Hospital, all in Randwick, New South Wales, Australia, are both respective leaders of the Experimental Therapeutics and Molecular Carcinogenesis laboratories at Children's Cancer Institute Australia. They each worked on two very different aspects of the study.

The MYCN gene is part of the neuroblastoma feedback loop — along with FACT, a histone mediator targeted by CBL0137 .

The Marshall lab found FACT not only regulates "reading" of the MYCN gene, but prolongs the life of proteins produced after each "reading." MYCN then directs neuroblastoma cells to increase FACT, forcing MYCN levels higher and driving the cancer.

Professor Michelle Haber:"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. But what is particularly exciting is that, in contrast to many other chemotherapeutic agents, CBL0137 does not damage DNA. DNA damage is responsible for the many unpleasant and serious side-effects frequently affecting children after they are cured of their cancer." Dr. Haber is Executive Director of Children's Cancer Institute and Head of its Experimental Therapeutics Program.

"The Phase 1 clinical trials for adults, means that safe dosage levels are being tested. Once adult trials are completed, a Phase 1 trial for children with refractory — or relapsed neuroblastoma and other aggressive childhood cancers — will open in the United States and Australia," adds Professor Glenn Marshall, Director of the Kids Cancer Centre at Sydney Children's Hospital, Randwick and Head of Translational Research at Children's Cancer Institute, shares Professor Haber's excitement.

In an embryo, MYCN helps guide normal development of the sympathetic nervous system. It directs the division and migration of primitive nerve cells. At some point in this process, MYCN is switched off and excess cells die off. However, neuroblastoma arises when the MYCN gene is not switched off - and cells continue to proliferate and divide after birth.

For CBL0137 to be effective at preventing neuroblastoma, it would have to be given to all children at birth.

Professor Marshall:"If prevention is to be more than a pipe dream, the medicine would have to be completely safe. 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 leading children's cancer centres in the United States and at Sydney Children's Hospital, Randwick. The trial would be conducted through the US-based Children's Oncology Group (COG), the largest children's cancer study group in the world. This is the first time that a COG trial of this sort would be made available to Australian children.

Abstract
Neuroblastoma is a common pediatric cancer of the nervous system. It is often difficult to treat, and tumors with amplifications of the MYC oncogene are particularly aggressive. Carter et al. have identified a histone chaperone called FACT as a mediator of MYC signaling in neuroblastoma and demonstrated its role in a feedback loop that allows tumor cells to maintain a high expression of both MYC and FACT. The authors then used curaxins, which are drugs that inhibit FACT, to break the vicious cycle. They demonstrated that curaxins work in synergy with standard genotoxic chemotherapy to kill cancer cells and treat neuroblastoma in mouse models.

1. CBL0137 was developed by Drs Andrei Gudkov and Katerina Gurova from Roswell Park Cancer Institute in the United States, long-term collaborators with Children's Cancer Institute and authors on the Science Translational Medicine paper.

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Nov 11, 2015   Fetal Timeline   Maternal Timeline   News   News Archive   

The work on laboratory models of neuroblastoma revealed that CBL0137 could block
the very start of this embryonal cancer, paving the way for its prevention.
Image Credit: Neuroblastoma Foundation