Imagine a childhood cancer so relentless that it claims the lives of nine out of ten children whose disease returns. This is the grim reality of relapsed neuroblastoma, the most common solid tumor in children outside the brain. But here's where it gets controversial: what if a drug already used for a different cancer could be the key to changing this devastating outcome? Researchers at the Garvan Institute of Medical Research in Sydney, Australia, have uncovered a promising lead. They’ve found that romidepsin, a drug approved for lymphoma, could be a game-changer for treating neuroblastoma, particularly in cases where standard chemotherapy fails.
Published in Science Advances, the study reveals that romidepsin triggers cell death in neuroblastoma through pathways that remain active even when the cancer becomes resistant to traditional treatments. This discovery is crucial because neuroblastoma, while accounting for only 7-8% of childhood cancers, is notoriously aggressive. While low- and intermediate-risk cases have survival rates of up to 98%, high-risk neuroblastoma—which most children have at diagnosis—is far more challenging. Current treatments, including chemotherapy, surgery, radiotherapy, and immunotherapy, often fall short, with fewer than half of high-risk patients being cured. For those whose cancer returns, the five-year survival rate plummets to a mere 10%.
And this is the part most people miss: the resistance that makes relapsed neuroblastoma so deadly often stems from the cancer’s ability to block the JNK pathway, a critical route for inducing cell death with standard chemotherapy. David Croucher, PhD, the study’s senior author, explains, “Finding a way to overcome this resistance has been a major goal for my lab. Romidepsin works independently of the JNK pathway, giving us a new weapon to fight back even when the usual routes are blocked.”
The researchers used a sophisticated approach, combining neuroblastoma cell lines with a pediatric-focused drug screen, to identify romidepsin as a standout candidate. Unlike traditional chemotherapies, romidepsin, a histone deacetylase (HDAC) inhibitor, effectively kills cancer cells regardless of JNK pathway function. In mouse models, combining romidepsin with chemotherapy not only reduced tumor growth but also extended survival—all while using lower chemotherapy doses, potentially reducing long-term side effects.
But here’s the catch: HDAC inhibitors like romidepsin are known for their lack of specificity, which can lead to toxicity. The mouse models showed dose-limiting side effects, highlighting the need for more targeted approaches. Future treatments might leverage next-generation HDAC inhibitors, such as antibody-drug conjugates or PROTACs, to minimize side effects while maximizing efficacy.
The team also uncovered why some chemotherapy combinations fail to deliver strong results. They found that drug synergy isn’t just about combining different mechanisms of action but about how drugs interact with the apoptotic network—a finding that could reshape how we design treatments for relapsed neuroblastoma.
As the Croucher lab prepares for clinical trials, their work challenges us to rethink treatment strategies for high-risk neuroblastoma, especially in relapsed cases where the tumor’s biology has shifted dramatically. But here’s the question: Could this approach not only improve survival rates but also pave the way for more personalized, less toxic cancer treatments? Share your thoughts in the comments—this is a conversation worth having.
