Old drug holds promise against childhood brain tumors, mouse model shows

Scientists studying a common childhood brain tumor have uncovered a pleasant surprise: evidence that the tumors may be vulnerable to a class of drugs that has been in use for years.

“We identified a new target for chemotherapy in these tumors, and we don’t have to start from scratch because these drugs are already approved chemotherapy agents,” says senior investigator David H. Gutmann, M.D., Ph.D., the Donald O. Schnuck Family Professor of Neurology, professor of genetics and of pediatrics at Washington University School of Medicine in St. Louis and co-director of the neuro-oncology program at the Alvin J. Siteman Cancer Center.

Gutmann and colleagues conducted the study using a mouse brain tumor model of a human condition known as neurofibromatosis 1, a common genetic disorder that makes children prone to brain and other cancers.

In a study published in the April 1 issue of Cancer Research, the team reports evidence that the drug rapamycin normalizes growth rates of brain cells of mice with a mutation in Nf1, the gene linked to human neurofibromatosis 1.

“The same pathway that rapamycin acted on in the mouse cells also is abnormally activated in neurofibromatosis-associated brain tumors from human patients, so we’re very excited about the possibility that this may be an effective treatment in children with neurofibromatosis 1,” says Gutmann, who also is also director of the neurofibromatosis clinical program at St. Louis Children’s Hospital.

Previously, researchers had been trying to treat tumors associated with neurofibromatosis 1 by shutting down the activity of a family of molecules known as RAS. One of the normal roles of the Nf1 gene is to deactivate RAS; however, studies have shown that anti-RAS therapies have not been very effective treatments in people with neurofibromatosis 1.

“RAS was the most logical place to start, but it was becoming obvious that additional therapeutic targets must be sought,” Gutmann says. “So we teamed up with Jason Weber, who is an assistant professor of medicine and of cell biology and physiology, to take an unbiased look at how dysfunction in the Nf1 gene changes protein expression in astrocytes, the cells from which brain tumors associated with neurofibromatosis 1 develop.”

“We went looking for other cellular pathways that Nf1 might regulate in addition to RAS,” Weber explains. “We compared normal astrocytes and astrocytes that lack Nf1 expression to learn which proteins are abnormally expressed or activated as a consequence of Nf1 loss.”

Weber worked with Biplab Dasgupta, Ph.D., and Yijun Yi, Ph.D., both postdoctoral fellows in Gutmann’s laboratory. They found unusually high levels of expression of several key proteins in the Nf1-deficient astrocytes. The proteins they identified were involved in a process called translation control, which directs the production of protein from messenger RNA. Collectively, the proteins that control this function are regulated by the mammalian target of rapamycin (mTOR) pathway. The drug rapamycin inhibits the pathway.

Although mTOR had been linked to other tumor types, scientists had not previously identified its connection to neurofibromatosis 1. Doctors have used rapamycin and its analogues for years to treat other tumor types where the mTOR pathway is overactivated.

“The next logical step for us is to begin treating the Nf1 brain tumor-prone mice with rapamycin,” says Gutmann. “If we are effective at treating the mouse tumors, we have every reason to believe this may be equally effective for treating patients with brain tumors associated with neurofibromatosis 1.”

Gutmann notes that the identification of mTOR pathway and the discovery of the effect of rapamycin on Nf1-deficient astrocyte growth highlight the impact of the newly established Washington University Neurofibromatosis Center. The center facilitates synergistic multidisciplinary neurofibromatosis research and is dedicated to developing better treatments to improve the lives of patients affected with neurofibromatosis

Dasgupta B, Yi Y, Chen DY, Weber JD, Gutmann DH. Proteomic analysis reveals hyperactivation of the mTOR pathway in NF1-associated human and mouse brain tumors. Cancer Research, April 1, 2005.

Funding from the Department of Defense supported this research.

Washington University School of Medicine’s full-time 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 second 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.