For nearly 50 years, doctors have known that the drug retinoic acid helps treat neuroblastoma, a type of solid tumor that occurs in children.
However, it only works after chemotherapy, once most of the primary tumor is gone.
Scientists at St. Jude Children’s Research Hospital have now solved the mystery of why this happens.
Their findings, published in Nature Communications, reveal that retinoic acid hijacks a normal developmental process to kill cancer cells in certain conditions. This discovery could lead to better treatments for neuroblastoma and other diseases.
Why retinoic acid works after chemotherapy
Neuroblastoma is a high-risk childhood cancer that spreads from its original location to other parts of the body, such as the bone marrow.
While retinoic acid increases survival rates by 10–15%, it only works in post-chemotherapy treatment, called consolidation therapy.
Scientists have long wondered why it helps destroy remaining cancer cells but has little effect on the primary tumor before chemotherapy.
The new research found that the answer lies in the microenvironment—the mix of chemicals, proteins, and signals that surround cancer cells. In the bone marrow, a special signaling process called the BMP (bone morphogenetic protein) pathway is highly active. This pathway makes neuroblastoma cells much more sensitive to retinoic acid, helping the drug work more effectively in those areas.
How retinoic acid “hijacks” normal development
During normal embryonic development, BMP signaling plays a key role in cell growth and differentiation.
The researchers discovered that when neuroblastoma cells are in the bone marrow, they react to BMP signals in the same way as developing cells do.
Dr. Min Pan, one of the study’s lead authors, explained:
“We found that neuroblastoma cells with high BMP activity were very sensitive to retinoic acid. This explains why the drug works so well during consolidation therapy but not before chemotherapy, when the cancer is still in the primary tumor.”
Using gene editing technology, the team identified the specific genes involved. They discovered that if many BMP-related transcription factors (proteins that control gene activity) are already present in the cell, retinoic acid combines with them to trigger cancer cell death.
Dr. Paul Geeleher, senior author of the study, emphasized the importance of this discovery:
“This is the first time we’ve found a way to use a normal developmental process in cancer treatment. Now, we can look for similar strategies in other diseases to create more effective and less toxic treatments.”
This groundbreaking research explains a long-standing mystery about retinoic acid and could lead to new treatments that target cancer cells more precisely.
By identifying other normal biological processes that cancer cells rely on, scientists may develop safer and more effective therapies for neuroblastoma and other cancers.
