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Targeting a Weak Link in Pediatric Brain Cancer

New Class of Treatment Shows Promise

This article was originally published in Northwestern University Feinberg School of Medicine News Center. It has been modified for the Northwestern Medicine content hub, HealthBeat.

A group of scientists has discovered a weak link in the process that drives a particularly deadly form of pediatric brain tumors known as embryonal tumors. This discovery may inspire future treatments, according to a study published in Cancer Cell.

Preventing 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 Northwestern University Feinberg School of Medicine, who co-authored the study. Dr. Li is also a member of Robert H. Lurie Comprehensive Cancer Center of Northwestern University at Northwestern Memorial Hospital and on staff at Stanley Manne Children’s Research Institute at Ann & Robert H. Lurie Children’s Hospital of Chicago.

About Embryonal Tumors With Multilayered Rosettes (ETMR)

After leukemia, brain and spinal cord tumors are the second most common cancers in children, and account for about one in four childhood cancers.

Embryonal tumors of the central nervous system are cancerous tumors that start in the fetal cells in the brain. Though there are a number of types, this particular study focused on embryonal tumors with multilayered rosettes (ETMR), which have 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 percent and 20 percent, according to the study.

The primary genetic mutation that drives these tumors is an abnormal 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 triggers mutations causing the growth of cells that eventually form tumors.

Promising Research

In the current study, scientists analyzed 80 tumor samples. They found that the majority of tumors exhibited C19MC amplification – or an increased number of copies of one gene disproportionate to other genes. 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. For example, bromodomain inhibitors can shut down the work of the super-enhancers. When the scientists applied this type of treatment in ETMR cells, the cells either stopped growing or died.

Looking Ahead

While ETMR tumors have been known to be difficult to treat because of their ability to hijack normal cell processes and reproduce at a rapid rate, their apparent origin has a weakness that can be exploited. According to Dr. Li, future studies should examine the use of bromodomain inhibitors as a potential therapy.

Dr. Li continues to explore other genetic mechanisms leading to disease, which can help lead to targeted treatment options.