Understanding Brain Tumors in NF1

NF1-associated brain tumors

While children with NF1 are at risk for developing a low-grade brain tumor involving the optic nerve called an optic pathway glioma (OPG), it is not known how best to predict which child will develop an OPG or who will require treatment. Moreover, it is not clear whether some groups of children with NF1-associated optic gliomas are at higher risk for vision loss or treatment failure.

Optic pathway glioma (OPG

As part of an international consortium, NF Center director, David H. Gutmann, MD, PhD, and his colleagues are studying the impact of chemotherapy on vision in children with NF1. These investigations are aimed at identifying risk factors for vision loss in children with OPGs. In addition, Dr. Gutmann and his colleagues have spearheaded a multi-investigator study to define the genetic and genomic alterations in pediatric NF1 low-grade brain tumors (gliomas) relevant to improved patient management. Finally, Washington University NF Center investigators have developed uniform criteria for classifying brain tumors in children with NF1. These studies have led to a greater appreciation of the spectrum of brain tumors in NF1 important for optimizing the care of affected individuals.

Identification and preclinical evaluation of new brain tumor therapies in Nf1 genetically-engineered mice

After the identification of the Nf1 gene and its protein (neurofibromin), it became possible to envision a time when new drug therapies for NF1-associated tumors might replace the missing function of neurofibromin. Over the past decade, several promising candidate compounds have been identified, are currently being evaluated in model organisms prior to the application to children and adults with NF1.

To this end, Dr. Gutmann and his colleagues at the Washington University NF Center have an active research program to evaluate new drugs for the treatment of optic glioma using Nf1 genetically-engineered mice. These studies are designed to rapidly test the most promising candidate drugs prior to their evaluation in children and adults with NF1. Drugs like mTOR (Sirolimus) and MEK inhibitors are now in clinical trials for children with NF1-associated glioma. Additional compounds are also currently being evaluated in several Nf1 genetically-engineered mice with optic glioma to restore or prevent vision loss.

Understanding the role of the tumor microenvironment in brain tumor formation and growth

Brain tumors are composed of both cancerous and non-cancerous cells. Studies in Dr. Gutmann’s laboratory have revealed that the non-cancerous cells may play a critical role in the development and growth of optic gliomas in Nf1 genetically-engineered mice.

To further define the contribution of these non-cancerous cells to glioma growth, investigators at the Washington University NF Center are working together to combine their individual expertise. Dr. Gutmann and his colleagues showed that immune system-like cells, called microglia and T cells, are found in both human and mouse optic gliomas and that these cells are critical for optic glioma growth in Nf1 genetically-engineered mice. These exciting findings suggest that new targets for therapeutic drug design might result from the identification of the factors made by glioma-associated microglia.

Understanding the cellular origins of brain tumors

Research over the past decade has shown that brain tumors can arise from a number of different types of cells in the brain. Determining where these come from in children with NF1 may yield new insights into how best to prevent their formation.

To understand the origins of optic pathway gliomas in NF1, Dr. Gutmann and his colleagues are using novel strains of genetically-engineered mice and human induced pluripotent stem cell models. These studies are focused on finding which cells in the developing brain give rise to optic pathway gliomas in children. In addition, similar studies are underway to identify the cells in the developing brain responsible for childhood brain tumors in people without NF1.