A breakthrough by Australian researchers could lead to better treatment for children with neuroblastoma, a cancer that currently claims 9 out of 10 young patients who relapse. The team at the Garvan Institute of Medical Research in Sydney, Australia, has found a combination of drugs that can bypass the cellular defenses these tumors develop that lead to relapse.
In findings made in animal models and published today in scientific progress, Associate Professor David Croucher and his team have shown that a drug already approved for other cancers can cause neuroblastoma cells to die through alternative pathways when the usual pathways are blocked. This discovery could lead to better treatment strategies for children whose cancer has stopped responding to standard chemotherapy.
Neuroblastoma is the most common solid tumor in children outside the brain, growing from nerve cells in the adrenal glands above the kidneys or along the spine, chest, abdomen, or pelvis. It is usually diagnosed in children under the age of two. While those with low-risk disease have excellent outcomes, about half of patients are diagnosed with high-risk neuroblastoma — an aggressive form where the tumors have already spread. Of these high-risk patients, 15 percent do not respond to initial treatment, and half of those who do will see their cancer return.
Why treatments stop working
The researchers first investigated why neuroblastoma becomes resistant to treatment. They studied lab-grown neuroblastoma cells and compared tumor samples from the same children at diagnosis and after their cancer returned. This allowed them to track the changes that occur as the cancer develops resistance.
They discovered that many standard chemotherapy drugs rely on the same cellular “switch” called the JNK pathway, to trigger the death of cancer cells. In recurrent tumors, this switch has often stopped working, meaning treatments are no longer effective.
Finding a way to overcome the refractory state of high-risk recurrent neuroblastomas has been an important goal for my lab. These tumors can be extremely resistant to chemotherapy – and the statistics once patients reach this point are devastating for families. By finding drugs that do not depend on the JNK pathway, we can still cause cancer cells to die even when this normal pathway is blocked.”
Associate Professor David Croucher, Garvan Institute of Medical Research
A promising drug appears
Looking for treatments that don’t rely on this cellular switch to induce cell death, the team then screened a large collection of FDA-approved drugs with pediatric safety data, aiming to find those that could be quickly adopted for clinical use. They identified romidepsin, a drug currently used to treat certain lymphomas, as being particularly potent against neuroblastoma cells, regardless of whether the JNK pathway was working or not.
Through collaboration with the Children’s Cancer Institute, the team used animal models of recurrent neuroblastoma to test whether adding romidepsin to standard chemotherapy could overcome resistance.
In their models, they found that the new combination reduced tumor growth and prolonged survival time compared to standard therapy alone, indicating lower resistance to treatment. Also, in combination with romidepsin, lower doses of standard chemotherapy achieved the same cancer-killing effect as higher doses of chemotherapy alone. This increases the likelihood of reduced side effects in future treatment – an important consideration when treating young children.
Next steps: towards clinical application
While the lab results are encouraging, Associate Professor Croucher says more research is needed before these findings can be translated into patient care. His team is now focused on optimizing combination treatment programs and delivery methods for safety and efficacy.
“This represents a big step forward, but the next challenge will be working to bring these findings into the clinic,” says Associate Professor Croucher. “We are using this data as a proof of principle to develop the best ways to deliver these treatments.”
Romidepsin is already approved for use in other cancers and has been tested for safety in children, which could potentially speed up the drug’s development as a new treatment option for neuroblastoma. However, any clinical application requires further testing and clinical trials to establish the safety and efficacy of the combination in neuroblastoma.
“Behind every statistic is someone’s loved one,” says Associate Professor Croucher. “Understanding these molecular mechanisms gives us hope that we can develop more effective treatments for patients and their families who currently face limited options – and that’s what drives us every day.”
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