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Breakthrough Discovery Sheds Light on Decades-Old Cancer Treatment Mystery
March 1, 2025 – Scientists at St. Jude Children’s Research Hospital have resolved a nearly 50-year-old mystery about how the drug retinoic acid works to treat neuroblastoma, a solid tumor that primarily affects children. The study, published today in Nature Communications, explains why the drug is effective in post-chemotherapy consolidation but not against primary tumors.
Neuroblastoma, particularly in high-risk cases, has a poor prognosis. Decades ago, researchers found that adding retinoic acid to neuroblastoma treatment improved survival rates by 10–15%. However, this benefit was only observed in patients after chemotherapy, leaving scientists puzzled about its precise mechanism—until now.
Hijacking a Developmental Pathway to Kill Cancer Cells
The new study reveals that retinoic acid exploits a normal developmental pathway to trigger cancer cell death in metastasized neuroblastoma. The researchers found that the drug’s effectiveness depends on the cellular microenvironment—the surrounding signals and chemicals unique to each part of the body.
According to Dr. Paul Geeleher, co-corresponding author and senior researcher at St. Jude’s Department of Computational Biology, “We’ve come up with an explanation for a decades-long contradiction about why retinoic acid works in post-chemotherapy consolidation but has little impact on primary neuroblastoma tumors.”
The study highlights the role of the bone morphogenetic protein (BMP) pathway, which is highly active in the bone marrow microenvironment. Metastasized neuroblastoma cells often migrate to the bone marrow, where they become more susceptible to retinoic acid due to increased BMP activity.
“Unexpectedly, we found that cells expressing genes from the BMP signaling pathway were very sensitive to retinoic acid,” said Dr. Min Pan, co-corresponding author. “This finding explains why the drug is effective in treating cancer cells during consolidation therapy but not in targeting primary tumors.”
Genetic Insights Unlock New Treatment Potential
Using advanced gene editing technology, the scientists identified genes in the BMP pathway that influence retinoic acid’s effectiveness. Their findings indicate that the same signaling mechanism involved in normal embryonic development is being co-opted to drive cancer cell death in the right microenvironment.
“If there are a lot of BMP-signaling pathway transcription factors already on DNA, retinoic acid combines with it to promote the expression of genes related to cell death,” explained Dr. Yinwen Zhang, co-first author of the study.
The research represents a major step forward in understanding neuroblastoma treatment and could pave the way for improved combination therapies. Dr. Geeleher emphasized, “We are the first to uncover such an example of ‘hijacking’ a normal embryonic developmental process preserved in cancer that we can exploit therapeutically. Now, we can look for similar processes in other diseases to design less toxic and more effective treatments.”
Implications for Future Cancer Treatments
This discovery opens the door to new treatment strategies for neuroblastoma and potentially other cancers. By better understanding the relationship between developmental pathways and cancer, researchers may be able to develop targeted therapies that enhance drug efficacy while reducing side effects.
For now, the findings provide a long-awaited answer to a decades-old scientific puzzle, offering new hope for children battling neuroblastoma.
Disclaimer:
This article is for informational purposes only and does not constitute medical advice. Patients should consult their healthcare providers before considering any changes to their treatment plans.
