New drug combo for relapsed neuroblastoma shows promise in the lab
Original story from the Garvan Institute of Medical Research (Sydney, Australia).
Researchers have identified a drug that can overcome treatment resistance in relapsed neuroblastoma in animal models.
A discovery from Australian researchers could lead to better treatment for children with neuroblastoma, a cancer that currently claims nine out of ten young patients who experience recurrence. The team at the Garvan Institute of Medical Research (Sydney, Australia) found a drug combination that can bypass the cellular defenses these tumors develop that lead to relapse.
In findings made in animal models, David Croucher and his team have shown that a drug already approved for other cancers can trigger neuroblastoma cell death through alternative pathways when the usual routes become blocked. This discovery could lead to better treatment strategies for children whose cancers have stopped responding to standard chemotherapy.
Neuroblastoma is the most common solid tumor in children outside the brain, developing from nerve cells in the adrenal glands above the kidneys or along the spine, chest, abdomen or pelvis. It is typically diagnosed in children under 2 years old. While those with low-risk disease have excellent outcomes, around half of patients are diagnosed with high-risk neuroblastoma – an aggressive form where tumors have already spread. Of these high-risk patients, 15% don’t respond to initial treatment, and half of those who do respond 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 children at diagnosis and after their cancer returned. This allowed them to track 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 cancer cell death. In relapsed tumors, this switch has often stopped working, meaning treatments are no longer effective.
“Finding a way to overcome the resistant state of relapsed high-risk neuroblastomas has been a major goal for my lab,” explained Croucher. “These tumors can be highly resistant to chemotherapy – and the statistics once patients get to that point are devastating for families. By finding drugs that don’t depend on the JNK pathway, we can still trigger cancer cell death even when this usual route is blocked.”
A promising drug emerges
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 rapidly adopted for clinical use. They identified romidepsin, a drug currently used to treat certain lymphomas, as particularly potent against neuroblastoma cells whether or not the JNK pathway is working.
A cancer cell’s mRNA guide to self-sabotage
By stimulating cancer cells to produce a molecule that activates a signaling pathway in nearby immune cells, scientists have found a way to force tumors to trigger their own destruction.
Through collaboration with the Children’s Cancer Institute (Sydney, Australia), the team used animal models of relapsed neuroblastoma to test whether adding romidepsin to standard chemotherapy could overcome the resistance.
In their models, they found that the new combination reduced tumor growth and extended survival time compared to standard treatment 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 raises the possibility 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, Croucher cautioned that more research is needed before these findings can be translated into patient care. His team is now focused on optimizing the combination treatment schedules and delivery methods for safety and effectiveness.
“This represents a big step forward, but the next challenge will be working on getting these findings into the clinic,” added Croucher. “We’re using this data as 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 accelerate the development of the drug as a new treatment option for neuroblastoma. However, any clinical application requires further testing and clinical trials to establish the combination’s safety and efficacy in neuroblastoma.
“Behind every statistic is someone’s loved one,” concluded Croucher. “Understanding these molecular mechanisms gives us hope 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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