- Dissecting the Molecular and Genetic Mechanisms of Neurofibroma Formation in NF1
- Targeting Angiogenesis for the Treatment of NF1 Tumors
- Mitochondrial Aberrations in NF1 Tumors - A Potential Explanation for Disease Variability?
Dr. Karen Stephens, an investigator at the University of Washington in Seattle, has received four awards from the Neurofibromatosis Research Program since 1996 to conduct research into the molecular genetics of neurofibromatosis type 1 (NF1). Her latest work, supported by a FY02 Investigator-Initiated Research Award, focuses on the genetic and molecular mechanisms underlying the formation of skin neurofibromas, the most common tumors in individuals with NF1. She is studying a group of NF1 patients who carry deletions of the NF1 gene and several adjacent genes of unknown function. Because these patients tend to develop large numbers of skin neurofibromas at an early age, she hypothesizes that deletion of one of the genes adjacent to NF1 favors the development of skin neurofibromas and possibly other tumors. Dr. Stephens will evaluate tumor characteristics and other clinical features in patients with NF1 deletions. She also will look for specific genetic changes in skin neurofibromas in patients with NF1 deletions to provide insight into how the tumors develop. She has already determined how the large NF1 gene deletions occur on the chromosome. Dr. Stephens' research has the potential to improve our understanding of neurofibroma formation, which may aid in the development of new therapies to slow or halt the growth of potentially devastating tumors.
Neurofibromatosis type 1 (NF1) is a common genetic disorder that affects about 1 in 4,000 people worldwide. NF1 is characterized by developmental abnormalities in the nervous system, skin, bones, and other tissues. Many NF1 patients develop plexiform neurofibromas, nerve tumors that often grow very large and can be debilitating or fatal. A more complete understanding of what causes neurofibromas to grow is needed in order to develop better therapies to manage NF1 tumor growth. Dr. David Muir of the University of Florida, a recipient of an FY02 NFRP Investigator-Initiated Research Award, is using mice lacking the Nf1 gene (Nf1+/- mice) to investigate the mechanisms by which NF1 tumors induce angiogenesis, the formation of new blood vessels required for tumor growth. The ultimate goal of this research is to discover effective therapies for the treatment of plexiform neurofibromas by blocking angiogenesis. Dr. Muir found that angiogenesis in response to low oxygen levels is higher in the retinas of Nf1+/- mice than in normal control mice. Additionally, he showed that formation of new blood vessels in response to a protein called fibroblast growth factor 2 is enhanced in the corneas of Nf1+/- mice compared to control mice. Importantly, Dr. Muir also developed a new animal model of NF1 by implanting Schwann cells from human NF1 neurofibromas into the nerves of Nf1+/- mice. The effects of anti-angiogenic agents on tumor vascularity and growth will be assessed in living mice using noninvasive magnetic resonance imaging. These ongoing studies may lead to the development of improved treatments for plexiform neurofibromas in NF1 patients.
Neurofibromatosis type 1 is an inherited disorder affecting approximately 1 in 4,000 people. All individuals with mutations in the NF1 gene develop disease symptoms, but the severity of those symptoms varies greatly between patients and even between family members. Alterations in mitochondria, the energy-producing structures of the cell, cause several diseases that exhibit heterogeneous expression. Importantly, mitochondria interact with neurofibromin, the product of the NF1 gene. Dr. Andreas Kurtz and colleagues at Massachusetts General Hospital are examining mitochondrial DNA (mtDNA) mutations in NF1 tumors. Dr. Kurtz's team found that mtDNA mutations are present in normal tissues from NF1 patients and that those mutations accumulate in neurofibromas. These findings suggest that mitochondrial aberrations may contribute to neurofibroma development and growth. Studies are in progress to examine the correlation between mtDNA mutations and neurofibroma tumor burden. Elucidation of the role of mitochondria in NF1 tumor development may aid in the prediction of disease severity and eventually lead to new preventive treatments for high-risk patients.
Kurtz A, Lueth M, Kluwe L, Zhang T, Foster R, Mautner V-F, Hartmann M, Tan D-J, Martuza RL, Friedrich RE, Hernáiz Driever P, Wong LJ. 2004 Somatic mitochondrial DNA mutations in Neurofibromatosis type 1-associated tumors. Molecular Cancer Research. (In Press).