DEPARTMENT OF DEFENSE - CONGRESSIONALLY DIRECTED MEDICAL RESEARCH PROGRAMS




Congressionally Directed Medical Research Program (CDMRP)-Funded Research Presented at the 2009 Neurofibromatosis (NF) Conference
Posted December 21, 2009

For more than 25 years, the Children's Tumor Foundation (CTF) has been dedicated to ending neurofibromatosis (NF) through research. To that end, CTF has funded NF research, provided resources for NF patients and their families, and endeavors to increase public awareness of NF. The Foundation also hosts the NF Conference, the premier annual event in the neurofibromatosis research and clinical calendar. The 2009 conference was held June 13-16 in Portland, Oregon, and brought together over 200 clinicians and researchers from around the world to present the latest developments in NF research and clinical care. Since 1996, the CDMRP's Neurofibromatosis Research Program (NFRP) has committed over $200 million to NF research. Some of the research funded by the NFRP was presented at the 2009 NF Conference and appears in the list below. Abstracts for these presentations can be found at http://www.ctf.org/images/stories/2009_conference_agenda.pdf.

Oral Presentations:

"Cells of Origin and Molecular Mechanisms of Tumor Initiation in a Mouse Model of Malignant Astrocytoma"
Sheila Llaguno Alcantara, University of Texas Southwestern Medical Center (PI: Luis Parada)

"The Multiple Faces of RAS: Oncogene, Tumor Suppressor, and Tumor Susceptibility Gene"
Allan Balmain, University of California, San Francisco

"Schwannomatosis Natural History Study Update"
Allan Belzberg, Johns Hopkins University

"Velopharyngeal Insufficiency in NF1 - A Clinical Sign of Underestimated Clinical Significance?"
Yemima Berman, Children's Hospital at Westmead, Australia

"Genetic Modification of NF1 Phenotypes"
Andre Bernards, Harvard Medical School/Massachusetts General Hospital

"Novel Murine Models of Malignant Peripheral Nerve Sheath Tumors"
Lou Chang, University of Michigan (PI: Yuan Zhu)

"Development of a Non-surgical Treatment for Dermal Neurofibromas in NF1"
Ruihong Chen, NexGenix Pharmaceuticals and NYU Medical Center

"Analysis of p21-activated Kinase Function in NF2 Signaling in Vivo"
Betty Chow, Fox Chase Cancer Center (PI: Jonathan Chernoff)

"NF2 Anti-Angiogenic Trial"
Emmanuelle di Tomaso, Harvard Medical School/Massachusetts General Hospital (PI: Scott Plotkin)

"Preliminary Success with Anti-Angiogenic Therapy of NF2-Related Tumors: One Year Later"
Emmanuelle di Tomaso, Harvard Medical School/Massachusetts General Hospital (PI: Scott Plotkin)

"NF1 Focal Bone Defects-Identification of the Cellular Culprits by Conditional Mouse Models"
Florent Elefteriou, Vanderbilt University

"Overactivation of Ral in MPNST: Cell Signaling and Therapeutic Ramifications"
Faris Farassati, University of Kansas

"Photodynamic Therapy in Children with NF1 and Plexiform Neurofibromas"
Michael Fisher, Children's Hospital of Philadelphia

"erbB Receptor Signaling in Vestibular Schwannomas"
Marlan Hansen, University of Iowa

"Nerve Gene Expression Patterning in NF1 Mouse Models"
Walter J. Jessen, Cincinnati Children's Medical Center (PI: Nancy Ratner)

"Defining the NF1 Phenotype"
Bruce Korf, University of Alabama at Birmingham

"Loss of NF2 Function in Schwann Cells Induces Dedifferentiation and Activation of Nerve Repair Mechanisms by Mimicking Impaired Axon-Schwann Cell Interaction"
Jan Manent, Inserm U674, France (PI: Nancy Ratner)

"Molecular Aspects of NF1-related Bone Abnormalities"
Kevin McHugh, Harvard Medical School

"Phase 2 Study of PTC299 in NF2"
Harry Miao, PTC Therapeutics (PI: Langdon Miller)

"NF1 in Old Age: International Interdisciplinary Analysis of the Issues"
John Mulvihill, University of Oklahoma

"Overview and Issues to Consider in Developing Effective Therapies for NF1 Learning Disabilities"
Kathryn North, Children's Hospital at Westmead, Australia

"NF1 Clinical Trials of CDMRP NFRP Clinical Trials Consortium"
Roger Packer, Children's National Medical Center

"A Decade of Modeling NF1 in the Mouse"
Luis Parada, University of Texas Southwestern Medical Center

"NF1 Dermal Neurofibromas - Ongoing Trials"
Scott Plotkin, Harvard Medical School/Massachusetts General Hospital

"Whole Body MRI Evaluation in NF1, NF2, and Schwannomatosis"
Scott Plotkin, Harvard Medical School/Massachusetts General Hospital

"Using Gene Expression Analysis to Identify NF1 Clinical Targets"
Nancy Ratner, Cincinnati Children's Hospital

"Natural Product Schweinfurthin Inhibits NF1 Tumor Growth Through a NF1-dependent Pathway Affecting Rho Signaling and Cytoskeletal Alteration"
Karlyne Reilly, National Institutes of Health, National Cancer Institute at Frederick

"Mechanisms of Learning Disabilities Associated with Disruptions of Ras/MAPK Signaling: From Lab to Clinic"
Alcino Silva, University of California, Los Angeles

"Molecular Pathology of Schwannomas and Neurofibromas"
Anat Stemmer-Rachamimov, Massachusetts General Hospital/Harvard Medical School (PIs: Scott Plotkin and David Gutmann)

"Pathology of Neurofibromas and Schwannomas"
Anat Stemmer-Rachamimov, Massachusetts General Hospital/Harvard Medical School

"NF1 Optic Pathway Glioma Trials"
Nicole Ulrich, Children's Hospital Boston

"Spine Abnormalities in Asymptomatic Children with NF1"
David Viskochil, University of Utah

"Drosophila as a Model to Study the Role of SMARCB1 in Schwannomatosis"
James A. Walker, Harvard Medical School/Massachusetts General Hospital (PI: Andre Bernards)

"Trials for NF1 Plexiform Neurofibromas and MPNSTs"
Brigitte Widemann, National Institutes of Health, National Cancer Institute

"Merlin Modulates Rac-Pak, Downstream MAPK Signaling through Tight Junction-Associated Proteins"
Chunling Yi, The Wistar Institute (PI: Joseph Kissil)

"NF1 Heterozygous Environment in Initiation and Progress of Plexiform Neurofibromas"
Yuan Zhu, University of Michigan

"Role of the Nf1 Heterozygous Microenvironment in the Development of Benign and Malignant Peripheral Nerve Sheath Tumor"
Yuan Zhu, University of Michigan

Poster Presentations:

"Timing of NF2 Inactivation Differentiates between Merlin's Role in Neural Tube Development and Tumorigenesis"
Elena M. Akhmametyeva, Nationwide Children's Hospital and Ohio State University (PI: Long-Sheng Chang)

"Leucine-ric Pentatricopeptide Repeat Cassette (LRPPRC): A Novel Interacting Protein of the Tubulin Binding Domain (TBD) of Neurofibromin"
Vedant Arun, University of Toronto, Canada (PI: Abhijit Guha)

"Preclinical Evaluation of HDAC Inhibitors and an EGFR Inhibitor on Human Vestibular Schwannoma and Meningioma"
Matthew Bush, The Ohio State University (PI: Long-Sheng Chang)

"Novel Murine Models of Malignant Peripheral Nerve Sheath Tumors"
Lou Chang, University of Michigan Medical School (PI: Yuan Zhu)

"Working Memory Contributions to Academic Achievement in NF1"
Peter J. Duquette, Children's National Medical Center CDMRP NFRP (PI: Kathryn North)

"Ras Signaling Enhances Permissiveness of Malignant Peripheral Nerve Sheath Tumor Cells to Oncolytic Herpes"
Faris Farassati, University of Kansas Medical School

"Retrospective Analysis of NF1-Associated Optic Glioma Visual Outcomes"
Michael J. Fisher, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine

"The Types Distribution, and Evolution of Hyperintensities in Children with Neurofibromatosis Type 1 (NF1)"
Robert S. Greenwood, University of North Carolina, School of Medicine

"Xenografting Plexiform Neurofibromas in Nude Mice and Testing Efficacy of Glivec"
Lan Kluwe, University Hospital Eppendorf, Germany (PIs: Victor Mautner and Samuel Rabkin)

"Vascular Inflammation Contributes to Neointima Formation in Nf1 +/- Mice"
Elisabeth A. Lasater, Indiana University School of Medicine (PI: David Ingram)

"Immortalization of NF1 Neurofibroma-Derived Schwann Cells"
Hua Li, University of Florida (PI: Margaret Wallace)

"Augmented Sodium Currents Contribute to the Enhanced Excitability of Sensory Neurons in Nf1+/- Mice"
Grant D. Nicol, Indiana University School of Medicine (PI: Cynthia Hingtgen)

"OSU-03012 and HDAC-42: Novel Small Molecule Inhibitors of the AKT Pathway for the Treatment of Vestibular Schwannoma and Malignant Schwannoma"
Janet L. Oblinger, The Ohio State University and Nationwide Children's Hospital (PI: Long-Sheng Chang)

"Whole-body Tumor Burden in Patients with Familial and Sporadic Schwannomatosis"
Miriam Smith, Harvard Medical School, Massachusetts General Hospital (PI: Scott Plotkin)

"Phase II Trial of Pirfenidone in Children and Young Adults with Neurofibromatosis Type 1 (NF1) and Progressive Plexiform Neurofibromas (PN)"
Brigitte Widemann, National Cancer Institute

"Phase II Randomized, Flexible Cross-Over, Double-Blinded, Placebo-Controlled Trial of the Farnesyltransferase Inhibitor (FTI) Tipifarnib (R115777) in Pediatric Patients with Neurofibromatosis Type 1 (NF1) and Progressive Plexiform Neurofibromas (PN)"
Brigitte Widemann, National Cancer Institute

"Examination of Key Signaling Pathways in Clinically Aggressive Vestibular Schwannomas"
Charles W. Yates, The Ohio State University (PI: Long-Sheng Chang)

"Therapeutic Intervention of Preclinical Symptoms in a NF1 Mouse Model"
Huarui Zheng, University of Michigan Medical School (PI: Yuan Zhu)

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Hu is Making the Decisions?
Posted November 25, 2009
Hua Lou, Ph.D., Case Western Reserve University, Cleveland, Ohio

Neurofibromatosis type 1 (NF1) is one of the most common heritable dominant disorders, yet while mutations on the NF1 gene are responsible for the disease, they cannot explain the high degree of phenotypic variation. Other modifier genes must be involved in the disease development. With funding from a Fiscal Year 2006 Neurofibromatosis Research Program New Investigator Award, Dr. Hua Lou began investigating the process by which multiple protein products of the NF1 gene are produced by alternative splicing of the NF1 pre-mRNA. One alternative splicing event of interest occurs around exon 23a. Neurofibromin proteins that contain the product from this exon are much weaker tumor suppressors than those that do not. The splicing factors that regulate splicing of the NF1 transcript, and the role they play in NF1 disease, are still relatively unknown. Dr. Lou examined the requirements for inclusion of the exon, specifically splicing factors, and found that the Hu proteins are at least partially responsible for blocking inclusion in the nervous system. Thus, Hu proteins may be considered modifier proteins of NF1 gene function. The researcher is currently investigating the biological consequences that result from the two neurofibromin products. Dr. Lou will generate genetically engineered mouse embryonic stem cells in which only one type of neurofibromin is produced and will then compare growth and neural differentiation potential between normal mouse embryonic stem cells and the engineered embryonic stem cells to define the biological functions of the two different neurofibromin protein isoforms. This research could offer insight into the diverse clinical manifestations of the NF1 disease and provide a new basis for disease therapy.

Publications:

Zhu H, Hinman MN, Hasman RA, Mehta P, and Lou H 2008. Regulation of neuron-specific alternative splicing of neurofibromatosis type 1 pre-mRNA. Molecular and Cellular Biology 28:1240.

Hinman MN and Lou H. 2008. Diverse molecular functions of Hu proteins. Cellular and Molecular Life Sciences 65(20):3168-3181.

Links:

Public and Technical Abstracts: Role of Neuron-Specific Splicing Regulators as Modifiers of Neurofibromatosis Type I

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Mouse Model Replicates Skeletal Abnormalities of Neurofibromatosis Type I
Posted May 12, 2009
Feng-Chun Yang, M.D., Ph.D., Indiana University School of Medicine, Indianapolis, Indiana

Approximately 50% of neurofibromatosis type I (NF1) patients have one or more skeletal abnormalities. Individuals with NF1 have a high incidence of generalized and focal skeletal manifestations that include: (1) Short stature, (2) kyphoscoliosis (an abnormal curvature of the spine, which affects roughly 35% of those with NF1, is painful, and can require multiple surgeries), (3) pseudoarthrosis (a spontaneous fracture, particularly of the tibia, that can require amputation), and (4) osteoporosis. Research focused on understanding the molecular mechanisms underlying the pathogenesis of the skeletal manifestations of all NF1 patients has been limited. Dr. Feng-Chun Yang of Indiana University School of Medicine, recipient of a Department of Defense Fiscal Year 2007 New Investigator Award, has developed a mouse model that has many of the skeletal manifestations of NF1 patients. Yang crossed an Nf1 conditional mouse model system that carried a PeriostinCre transgene with Nf1+/- mice to generate a mouse colony (Nf1 flox/-, peri-Cre +) in which osteoblasts are Nf1-/- and osteoclasts are Nf1+/-. Dr. Yang characterized the model and found that osteoclast resorptive activity was significantly higher than osteoblast activity. This imbalance between bone resorption and bone formation results in decreased bone mass. Dr. Yang also found that this novel mouse model recapitulates the human NF1 skeletal manifestations that include short stature, osteoporosis, scoliosis, and kyphosis. Biomechanical and detailed molecular studies can be conducted in this model that, ethically, could not be conducted in human patients, allowing for a greater understanding of the basic mechanisms underlying the skeletal disorders associated with NF1.

Publication:

Li H, Liu Y, Zhang Q, Jing Y, Chen S, Song Z, Yan J, Li Y, Wu X, Zhang X, Zhang Y, Case J, Yu M, Ingram DA, Yang FC. 2009. Ras dependent paracrine secretion of osteopontin by Nf1+/- osteoblasts promoteosteoclast activation in a neurofibromatosis type I murine model. Pediatr Res. [Epub ahead of print]

Yan J, Chen S, Zhang Y, Li X, Li Y, Wu X, Yuan J, Robling AG, Kapur R, Chan RJ, Yang FC. 2008. Rac1 mediates the osteoclast gains-in-function induced by haploinsufficiency of Nf1. Hum Mol Genet.

Links:

Public and Technical Abstracts: Identification of the Cellular and Molecular Mechanisms Underlying the Osseous Manifestations of NF1 in Murine and Human Systems

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Finding the Positive in Negative Feedback
Posted February 9, 2009
Michael Stern, Ph.D., Rice University, Houston, Texas

Serendipity has long been a part of scientific discovery. And, so it was for Eric Howlett, a Ph.D. student working in the lab of Department of Defense Neurofibromatosis Research Program-funded researcher Dr. Michael Stern. While engaged in neurofibromatosis research to study the control of growth within Drosophila peripheral nerves by Ras and Protein Kinase A, Howlett and colleagues identified a novel mechanism for negative feedback control of excitability in the Drosophila larval motor neuron. Negative feedback processes can maintain neuronal homeostasis and are widely observed in neuronal systems. Disruption of this homeostasis can lead to neurological disorders, such as epilepsy, neurofibromatosis, autism, and schizophrenia.

The mechanism identified by the researchers involved phosphatidylinositol 3-kinase (PI3K) and the Drosophila metabotropic glutamate receptor (DmGluRA) located at motor nerve terminals. Several labs have demonstrated a significant role for the PI3K pathway in mediating the effects of Nf1 on growth in neurons, glia, and other cells. Metabotropic glutamate receptors (mGluRs) are a family of G protein-coupled receptors for which the excitatory amino acid glutamate (a major neurotransmitter in both the mammalian central nervous system and glia, as well as at the Drosophila neuromuscular junction) acts as ligand. Howlett found that PI3K regulates motor axon diameter in the larval peripheral nerve. When activated, the PI3K pathway increased axon diameter while suppression of the pathway had the opposite effect. The researchers also found that the effects of PI3K on neuronal activity seemed to be mediated by the transcription factor FOXO, which negatively regulates PI3K-induced transcription and is inhibited by Akt-dependent phosphorylation. In addition, they observed that alterations in the DmGluRA affect both neuronal excitability and synaptogenesis similar to what they observed with PI3K. In this mechanism, activation of mGluRs by glutamate decreases excitability by activating PI3K, which in turn causes the phosphorylation and inhibition of Foxo. Foxo inhibition consequently decreases neuronal excitability.

The team's findings have broader implications, in that altered PI3K activity and group II mGluRs are associated with a number of neurological disorders, such as autism, neurofibromatosis, epilepsy, anxiety disorders, and schizophrenia. Their results provide a previously uncharacterized role for PI3K in regulating the relative excitability of neurons in vivo and suggest that some of the deficits in the aforementioned neurological disorders might result from disruption of glutamate-mediated homeostasis. Finally, the results suggest that the PI3K pathway may be a vital mediator of signaling by these mGluRs and that a similar negative feedback process functioning in the mammalian CNS may be implicated in neuronal disorders involving the group II mGluRs or PI3K.

Publication:

Howlett E, Lin CC-J, Lavery W, et al. 2008. A PI3-kinase-mediated negative feedback regulates neuronal excitability. PLoS Genetics 4(11):e1000277 [Epub 2008 Nov 28].

Links:

Public and Technical Abstracts: Control of Growth Within Drosophila Peripheral Nerves by Ras and Protein Kinase A

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