Australian scientists have uncovered a promising new approach to treat neuroblastoma, a childhood cancer that currently claims nine out of ten patients who experience relapse. Researchers at the Garvan Institute of Medical Research in Sydney have identified a drug combination that bypasses the cellular defenses tumors develop, potentially improving outcomes for children with resistant disease.
Published in Science Advances, the study demonstrates that an existing cancer drug can trigger neuroblastoma cell death through alternative pathways when conventional treatments fail. Using animal models, the team showed that combining the drug romidepsin already approved for certain lymphomas with standard chemotherapy reduced tumor growth and extended survival compared with chemotherapy alone.
Neuroblastoma, the most common solid tumor outside the brain in children, arises from nerve cells in the adrenal glands or along the spine and is usually diagnosed before age two. While low-risk cases respond well, high-risk neuroblastoma is aggressive, with many tumors developing resistance to initial therapy or relapsing after treatment.
The researchers discovered that many chemotherapy drugs rely on a cellular ‘switch’ known as the JNK pathway to kill cancer cells. In relapsed tumors, this switch often fails, rendering standard treatments ineffective. Screening a library of FDA-approved drugs, the team found that romidepsin could bypass the JNK pathway and effectively kill neuroblastoma cells, whether or not the pathway was functional.
Romidepsin is a prodrug activated inside cells, where its metabolite inhibits class 1 and 2 HDAC enzymes by binding zinc. Many tumors overexpress HDACs, disrupting gene regulation. HDAC inhibition can restore normal gene expression, inducing cancer cell cycle arrest and apoptosis, counteracting tumorigenesis.
In animal studies, the combination allowed lower doses of chemotherapy to achieve the same tumor-killing effect, potentially reducing side effects an important consideration for young children. While results are promising, further research and clinical trials are needed to confirm safety and efficacy in patients.
Supporting these findings, Panicker et al. reported that romidepsin selectively targets neuroblastoma cells, triggering caspase-dependent apoptosis and suppressing tumor growth both in vitro and in vivo
This represents a big step forward, but the next challenge will be translating these findings into clinical practice. Understanding these molecular mechanisms gives us hope for more effective treatments for patients and families facing limited options.
Reference
- Han JZR, Phimmachanh M, Hastings JF, Leong KH, Ng BH, Ni J, et al. Inclusion of JNK-independent drugs within multiagent chemotherapy improves response in relapsed high-risk neuroblastoma. Science Advances. 2025 Nov 28;11(48):eady5599.
- Romidepsin [Internet]. [cited 2025 Nov 29]. Available from: https://go.drugbank.com/drugs/DB06176
- Panicker J, Li Z, McMahon C, Sizer C, Steadman K, Piekarz R, et al. Romidepsin (FK228/depsipeptide) controls growth and induces apoptosis in neuroblastoma tumor cells. Cell Cycle. 2010 May;9(9):1830-8.