An international collaboration of researchers has identified several progressive series of mutations that occur in tumor cells responsible for aggressive subsets of neuroblastoma that relapse after chemotherapy. Neuroblastoma, a solid tumor of nerve tissue, is the most common cancer in infants, and its cure rates lag behind those for other pediatric cancers. The investigators, including co-study leader Derek Oldridge from the lab of John M. Maris, MD, at The Children’s Hospital of Philadelphia, performed extensive genetic sequencing of 23 pairs of tumors obtained at initial diagnosis and at relapse from the same patients. This allowed the researchers to compare the tumors’ genetic and molecular characteristics. Among the 23 relapsed tumors, 18 harbored mutations that boosted signals funneling into a biological pathway called RAS-MAPK, which made neuroblastoma progress.
“Our results imply that a clonal selection process occurred — meaning that more aggressive, cancer-driving mutations acquired a selective advantage after chemotherapy, leading to relapse,” Oldridge said.
Clonal selection is a process by which mutations allow malignant cells’ descendants to become more dominant. For example, a mutation that enables a cell to grow and divide rapidly could give it a head start at relapse compared to other cells within the tumor population.
The researchers published their results in Nature Genetics, demonstrating that relapsed neuroblastomas show frequent RAS-MAPK pathway mutations. Their findings offer new prospects to design personalized treatments for children with neuroblastoma. A group of drugs called MEK inhibitors that target those cancer-driving mutations are already available. Previous research in cell cultures and animal studies has shown that MEK inhibitors slowed tumor growth and improved the animals’ survival.
“Our preclinical findings strongly suggest that MEK inhibitors may directly benefit patients who suffer a relapse and have mutations in the RAS-MAPK pathway,” said Dr. Maris, a pediatric oncologist at The Children’s Hospital of Philadelphia who holds the Giulio D’Angio Chair in Neuroblastoma Research. “We think one of the most important conclusions from this work is that we should completely change our approach to relapsed disease. Until now, tumor biopsy was not necessary at relapse as it was very unlikely to change clinical practice. Now that we know that sequencing these resistant cancers can nominate novel therapies, we think we are entering a new era of personalized therapeutic decision making for children with currently incurable disease.”
It is likely that other biological pathways also contribute to the high risk of treatment failure in certain neuroblastoma cases. Dr. Maris recently received a new grant from the National Cancer Institute to investigate the role of the LMO1 gene locus in the initiation, growth, and survival of neuroblastoma, building on his lab’s discovery of LMO1 as a major oncogene in this disease. Greater understanding of key cellular networks such as RAS-MAPK and LMO1 will help researchers to develop rational, evidence-based strategies for precision medicine in neuroblastoma and other cancers.
In the U.S., about 800 new cases of neuroblastoma are diagnosed each year. It accounts for 7 percent of all childhood cancers, but it causes 15 percent of all childhood cancer deaths.
The study that appeared in Nature Genetics also involved Thomas F. Eleveld, MSci, and Jan J. Molenaar, PhD, of the Academic Medical Center of the University of Amsterdam; and Virginie Bernard, PhD, and Gudrun Schleiermacher, MD, PhD, of the Institut Curie in Paris. Funds from the National Cancer Institute, the Children’s Oncology Group, and the University of Pennsylvania Genome Frontiers Institute supported this study.