WUSTL leads study of pediatric brain tumors

The National Cancer Institute (NCI) has awarded a five-year, $4 million grant to researchers at Washington University School of Medicine in St. Louis to use genetically-engineered mice to study the origins and potential treatments of pediatric brain tumors.

David H. Gutmann, M.D., Ph.D., the Donald O. Schnuck Family Professor of Neurology, is principal investigator of the grant, which is part of the NCI’s Mouse Models of Human Cancers Consortium. He is also on staff at Barnes-Jewish and St. Louis Children’s hospitals.

A growing body of research suggests that the support of nearby non-cancerous cells may be important to the formation and development of tumors. Gutmann and colleagues have provided direct proof of this idea in mouse models of neurofibromatosis type 1 (NF1), an inherited cancer syndrome. In these models, researchers have shown that support from non-cancerous cells is required for NF1 tumor formation and development.

“We’ve come to realize that the cancer cell is only one of many cell types involved in the creation of brain tumors, and this insight has forced us to re-examine how we approach brain tumors and other cancers,” says Gutmann, who is director of the Washington University Neurofibromatosis Center of Excellence. “If we can better understand how cancers draw support from the surrounding environment, we can look for ways to disrupt its ability to facilitate tumor formation and growth.”

Gutmann compares the challenges of understanding brain tumor development to a murder mystery.

“Like the detectives in these stories, scientists are studying a cast of characters gathered in a confined area—the regions of the brain where tumors arise,” he explains. “We want to pinpoint the murder suspects, or the cells that help cancers form, and their weapons, which are the signals these cells send that facilitate the formation of tumors.”

To unravel some of these mysteries, researchers will use funding from the new grant to study tumor formation in mouse models of NF1. According to Gutmann, NF1 provides a good model because researchers know that tumors in the mouse model arise consistently in particular locations in the brain at particular times in development.

“This should allow us to develop a much more comprehensive picture of what happens and when, which will help us determine how best to prevent or slow tumor growth,” Gutmann says.

Scientists will also study how tumor cells and cancer treatments affect normal brain cells. In humans, NF1 brain tumors arise along the optic nerve and can lead to vision loss; in the mouse model, tumors create similar visual impairments. Work with the mouse models has indicated that the nerve cells in patients with NF1 may be more vulnerable to death from brain tumors.

This enhanced nerve cell vulnerability may also underlie declines in IQ and school performance often associated with radiation or chemotherapy given to NF1 patients to halt tumor growth. To probe the potential connection, researchers will study how such treatments affect learning and behavior in NF1 mouse models.

“Our ultimate goal is to identify the mechanisms that underlie enhanced nerve vulnerability seen in children with NF1, hoping that we can find ways to reverse those mechanisms and preserve vision and other brain functions in patients with brain tumors,” Gutmann says.

Investigators in the project include longtime Gutmann collaborators Joshua B. Rubin, M.D., Ph.D., and Joel R. Garbow, Ph.D., both of Washington University School of Medicine; as well as Mark H. Ellisman, Ph.D., of the University of California, San Diego and Karlyne M. Reilly, Ph.D., of the National Cancer Institute.

“Collectively, the range of expertise provided by these investigators puts us in a unique position to advance our understanding of pediatric brain tumor development and treatment,” Gutmann says.

Washington University School of Medicine’s 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked third in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.