Integrated analysis finds vulnerabilities to target in a high-risk pediatric tumor
Newswise Aug 26, 2018
St. Jude Children’s Research Hospital investigators have completed the most comprehensive analysis yet of a common pediatric solid tumor, identifying weaknesses to target and a promising precision medicine that is now in clinical trials. The findings appear today in the journal Cancer Cell.
The research, part of the St. Jude Children’s Research Hospital—Washington University Pediatric Cancer Genome Project, focused on the muscle and soft-tissue tumor rhabdomyosarcoma. The tumor occurs in about 350 children and adolescents nationwide each year. Cure rates are 75% for patients whose tumors have not spread, but long-term survival is 30% or less for those with metastatic disease or those whose tumor returns. For these high-risk patients, overall survival has not improved significantly in 15 years.
“Recent advances in technology allowed us to extensively profile rhabdomyosarcoma to better understand its cellular origins as well as identify and prioritize vulnerabilities that extend beyond just the somatic (tumor) mutations,” said Elizabeth Stewart, MD, an assistant member of the St. Jude Department of Oncology. Stewart, Hong Wang, PhD, and Xiang Chen, PhD, of St. Jude, and Justina McEvoy, PhD, formerly of St. Jude, are co-first authors.
Researchers identified several signaling pathways that are disrupted in tumor cells. AZD1775, or adavosertib, inhibits an enzyme in one of the newly identified disrupted pathways. Extensive pre-clinical testing followed, results of which prompted the Children’s Oncology Group to expand a multicenter phase 1/2 clinical trial of AZD1775 and the chemotherapy agent irinotecan to include high-risk pediatric rhabdomyosarcoma patients.
“This research offers a template for exploring the origins and vulnerabilities of solid tumors by looking not only at somatic mutations, but also at epigenetic changes and, ultimately, differences in how those changes manifest in protein expression and activity,” said senior and corresponding author Michael Dyer, PhD, chair of the St. Jude Department of Developmental Neurobiology and a Howard Hughes Medical Institute investigator. “The research also highlights how pre-clinical models and extensive pre-clinical testing can help prioritize and streamline drug development.”
“As genome sequencing technology improves, we continue to learn new information—not just about about the genetic alterations underlying certain cancers but about epigenetic changes and pathways disrupted by cancer,” said Robert Fulton, director of technical development at Washington University’s McDonnell Genome Institute. “This knowledge is critical for developing more effective drugs and treatment strategies.”
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