A group of scientists have discovered a weak link in the mutational cascade that drives a particularly deadly form of pediatric brain tumors, which may inspire future treatments, according to a study published in Cancer Cell.
Inhibiting protein interactions at one crucial step killed tumor cells, representing a promising therapeutic approach, according to Xiao-Nan Li, MD, PhD, professor of Pediatrics in the Division of Hematology, Oncology, and Stem Cell Transplantation at Ann & Robert H. Lurie Children’s Hospital of Chicago and co-author of the study.
Embryonal tumors with multilayered rosettes (ETMR) are brain tumors with a characteristic “wheel and spoke” arrangement of cells surrounding a central core. Occurring mostly in children under two, the overall survival rates are between 10 and 20 percent, according to the study.
The primary mutation that drives these tumors is an aberrant overactivation of the C19MC microRNA cluster, a group of 46 genes that curb gene expression. Normally, this cluster helps prevent cancer by preventing overactive cell growth, in addition to other functions. But, in ETMR, this gene cluster is fused to a gene promoter, and triggers a mutational cascade that causes a proliferation of primitive neural cells that eventually form tumors.
In the current study, scientists analyzed 80 tumor samples using transcription and epigenetic profiling, finding that the majority of tumors exhibited C19MC amplification. Few other mutations were this prevalent amongst the samples, underscoring the strength and singular ability of this mutation to cause ETMR.
Looking downstream, the investigators determined that interactions between C19MC and gene promoters created “super-enhancers,” short regions of DNA that increase the likelihood of transcribing a certain gene. While these super-enhancers can cause cancer by contributing to rapid cell growth, they also have consistent weaknesses that can be targeted by drugs, according to the study authors.
One emerging class of therapeutics are bromodomain inhibitors, a small molecule that shuts down super-enhancers by binding to them and preventing them from aiding transcription.
When the scientists applied a bromodomain inhibitor in ETMR cells, the cells either stopped growing or died.
While these tumors have been known to be difficult to treat because of their ability to hijack normal cell processes and proliferate nearly indefinitely, their apparently singular etiology may create a weakness that can be exploited. Future studies should examine this bromodomain inhibitor as a potential therapy, according to Li, whose lab created a novel panel of ETMR models that should serve as an important resource for future drug testing.
Li is also a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University and Stanley Manne Children’s Research Institute at Lurie Children’s. His lab created a novel panel of ETMR models through direct implantation of surgical specimen of pediatric ETMR tumors into the brains of immunodeficient mice.
This project was funded by a Canadian Institutes of Health Research (CIHR) grant no. 137011 and b.r.a.i.n. Child grant.