Neurofibromatosis Clinical Trials Consortium

Neurofibromatosis type 1 is an autosomal dominant condition often diagnosed in childhood that causes tumors to grow on nerve tissue, producing skin and bone abnormalities. As the tumors grow, they can press on vital areas of the body, causing problems including seizures, high blood pressure, scoliosis, speech impairment, optic nerve tumors, early or delayed puberty, and, rarely, can become cancerous. With funding from the U.S. Department of Defense, a consortium of thirteen academic institutions (Boston Children’s Hospital (partners with Dana-Farber Cancer Institute and Massachusetts General Hospital), University of Alabama at Birmingham, Children's Hospital of Los Angeles (with House Research Institute/UCLA), Children's National Medical Center (with Johns Hopkins Hospital), University of Pennsylvania, Cincinnati Children's Hospital (with Ohio State University Hospital), National Cancer Institute, New York University Medical Center, University of Chicago (with Lurie Children’s Hospital), University of Indiana, University of Utah, Washington University St Louis, and Children's Hospital at Westmead, Sydney, Australia) has been established to seek new therapies for this rare genetic disease. Bruce Korf, M.D., Ph.D., chair of the UAB Department of Genetics, chairs activities at the lead site. The combined expertise of the participating sites and the size of their combined patient populations positioned the consortium to launch four clinical trials in its first five years. The gene responsible for NF1 also encodes a protein that regulates another protein, RAS, which is known to drive abnormal growth in common cancers. The first trial involved the use of Rapamycin — also called sirolimus – which shuts down a protein called mTOR that is used by RAS to pass on growth signals to cells. Three of the first four consortium-funded clinical trials tested rapamycin or its derivative, everolimus, to see if it can reverse or slow various aspects of NF. A fourth trial examined the use of the anti-cholesterol drug lovastatin in the treatment of learning problems in children with NF1. The hypothesis is that lovastatin may be able to block the binding of RAS to the membrane and reduce excessive RAS signaling. An ancillary study by Dr. Ullrich is evaluating an innovative computerized measure to assess spatial learning functions in children with NF1 before and after treatment with lovastatin. The new grant cycle was funded in 2012 which will fund four additional clinical trials. The first new trial is an open-label phase 2 study of bevacizumab in children and young adults with neurofibromatosis 2 and progressive vestibular schwannomas that are poor candidates for standard treatment with surgery or radiation. The second trial is to apply bone-morphogenic protein during fixation for NF-associated tibial dysplasia. The third trial will evaluate a novel MEK inhibitor for NF and non-NF associated low grade glioma.  Lastly, a new trial is planned to investigate a combined pharmacologic and cognitive remediation program to improve cognitive functioning in NF1.