Newswise — St. Jude Children’s Research Hospital scientists looking for drugs to improve survival of children with high-risk neuroblastoma found a promising candidate in CX-5461. Then researchers identified safety concerns with the experimental drug that have implications for current clinical trials in adults. The study appears today in Nature Communications. 

CX-5461 is a small molecule that has been studied for more than a decade. It has been widely described as a first-in-human inhibitor of the enzyme RNA polymerase 1. Phase II clinical trials of CX-5461 are underway in adults with leukemia, lymphoma and breast cancer. 

St. Jude researchers demonstrated in this study that CX-5461 killed neuroblastoma tumor cells primarily by targeting and disrupting the activity of the enzyme topoisomerase II beta (TOP2β) and not by inhibiting RNA polymerase 1. 

“These new details of CX-5461’s mechanism of action in cancer treatment have potentially important safety implications for patients,” said Paul Geeleher, Ph.D., St. Jude Department of Computational Biology. He and John Easton, Ph.D., St. Jude Computational Biology, are the study’s corresponding authors. The first author is Min Pan, Ph.D., a scientist in the Geeleher lab. 

“Decades of study of an existing class of chemotherapy agents have shown that off-target drug interactions with TOP2β leave patients at risk for serious and life-threatening side effects such as acute myeloid leukemia or cardiotoxicity that emerge years later,” Geeleher said. “The findings highlight a previously unappreciated safety concern with CX-5461.” 

Search for new high-risk neuroblastoma drugs took unexpected turn 

The study began as a quest to find new treatments for children with high-risk neuroblastoma, whose survival rates have remained about 50% for the last 20 years. Neuroblastoma arises from cells of the developing peripheral nervous system and is diagnosed in about 800 children annually in the U.S. 

CX-5461 showed significant anti-tumor activity in combination therapy in preclinical studies of pediatric neuroblastoma, but safety concerns must be addressed before planning clinical trials in children, Geeleher said. “Patients enrolled in ongoing CX-5461 phase II trials should be closely monitored for these late-emerging TOP2β-related adverse events,” the researchers noted. 

Authors and funding 

The other St. Jude authors are William Wright, Richard Chapple, Asif Zubair, Manbir Sandhu, Jake Batchelder, Jonathan Low, Kaley Blankenship, Yingzhe Wang, Brittney Gordon, Payton Archer, Samuel Brady, Sivaraman Natarajan, John Schuetz, Darcie Miller, Ravi Kalathur, John Patrick Connelly, M. Madan Babu, Michael Dyer, Shondra Pruett-Miller, Burgess Freeman III, Taosheng Chen, Scott Blanchard and Elizabeth Stewart. Additional authors are Brandt Huddle, Weill Cornell Medicine; and Matthew Posgai, Lucy Godley and Siquan Chen, The University of Chicago. 

The research was funded by grants (HG00967903) from the National Human Genome Research Institute; (GM13829301) from the National Institute of General Medical Sciences; (CA26006001) from the National Cancer Institute; (GM079238, HG011563) from the National Institutes of Health; and ALSAC, the fundraising and awareness organization of St. Jude. 


St. Jude Children's Research Hospital

St. Jude Children's Research Hospital is leading the way the world understands, treats and cures childhood cancer and other life-threatening diseases. It is the only National Cancer Institute-designated Comprehensive Cancer Center devoted solely to children. Treatments developed at St. Jude have helped push the overall childhood cancer survival rate from 20% to 80% since the hospital opened more than 50 years ago. St. Jude freely shares the breakthroughs it makes, and every child saved at St. Jude means doctors and scientists worldwide can use that knowledge to save thousands more children. To learn more, visit or follow St. Jude on social media at @stjuderesearch. 

Journal Link: Nature Communications