CONFERENCE REPORT What’s New in Neurofibromatosis? Proceedings From the 2009 NF Conference: New Frontiers Joseph L. Kissil,1 Jaishri O. Blakeley,2 Rosalie E. Ferner,3 Susan M. Huson,4 Michel Kalamarides,5 Victor-Felix Mautner,6 Frank McCormick,7 Helen Morrison,8 Roger Packer,9 Vijaya Ramesh,10 Nancy Ratner,11 Katherine A. Rauen,7 David A. Stevenson,12 Kim Hunter-Schaedle,13* and Kathryn North14 1The Wistar Institute, Philadelphia, Pennsylvania 2Johns Hopkins University, Baltimore, Maryland 3Guy’s and St Thomas’!NHS Trust, London, United Kingdom 4St. Mary’s Hospital, University of Manchester, Manchester, United Kingdom 5Hopital Beaujon, APHP, Clichy, France and Inserm U674 6University Eppendorf, Hamburg, Germany 7University of California, San Francisco, California 8Leibniz Institute for Age Research, Jena, Germany 9Children’s National Medical Center, Washington, District of Columbia 10Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 11Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio 12University of Utah, Salt Lake City, Utah 13Children’s Tumor Foundation, New York, New York 14University of Sydney and The Children’s Hospital at Westmead, Sydney, Australia Received 30 September 2009; Accepted 17 October 2009 The NF Conference is the largest annual gathering of researchers and clinicians focused on neurofibromatosis and has been con- How to Cite this Article: vened by the Children’s Tumor Foundation for over 20 years. The Kissil JL, Blakeley JO, Ferner RE, Huson SM, 2009 NF Conference was held in Portland, Oregon from June 13 to Kalamarides M, Mautner V-F, McCormick F, June 16, 2009 andco-chaired by Kathryn North from the University Morrison H, Packer R, Ramesh V, Ratner N, of Sydney and The Children’s Hospital at Westmead, Sydney, Rauen KA, Stevenson DA, Hunter-Schaedle Australia; and Joseph Kissil from the Wistar Institute, Philadel- K, North K. 2010. What’s new in phia. The Conference included 80 platform presentations in 9 neurofibromatosis? Proceedings from the sessions over 4 days; over 100 abstracts presented as posters; and 2009 NF conference: New Frontiers. three Keynote presentations. To date, there have been tremendous advances in basic research in the pathogenesis of neurofibromato- Am J Med Genet Part A 152A:269–283. sis, and more recently in progress toward identifying effective drug therapies and the commencement of neurofibromatosis clinical trials. The NF Conference attendees have significantly increased (doubling from 140 in 2005 to 280 attending in 2009) with a significant increase in attendance of physicians and clinical re- searchers. Correspondingly the NF Conferencescope hasexpanded Grant sponsor: National Institutes of Health; Grant number: to include translational research, clinical trials and clinical man- 1R13NS066550-01. agement issues while retaining a core of basic research. These The conference abstract book may be downloaded at www.ctf.org. themes are reflected in the highlights from the 2009 NF Conference *Correspondence to: presented here. Ó 2010 Wiley-Liss, Inc. Dr. Kim Hunter-Schaedle, Children’s Tumor Foundation, 95 Pine St, 16th Floor, New York, NY 10005. E-mail: [email protected] Key words: neurofibromatosis type 1; neurofibromatosis type 2; Published online 15 January 2010 in Wiley InterScience NF1; NF2; schwannomatosis; tumor suppressor; Ras/MAPK; learn- (www.interscience.wiley.com) ing disabilities; bone dysplasia DOI 10.1002/ajmg.a.33189 Ó 2010 Wiley-Liss, Inc. 269 270 AMERICAN JOURNAL OF MEDICAL GENETICS PART A INTRODUCTION program and he provided an update of progress. The Phase II NF Clinical Trials Consortium includes nine core sites in the United Neurofibromatosis affects 1:3,000 individuals, and characteristi- States. Additional sites, including international collaborators, may cally causes largely benign but often debilitating tumors to grow in be included for selected studies. The Phase II NF Clinical Trials the nervous system. There are three main forms of NF: NF1, NF2 Consortium is focused on designing and implementing trials for and schwannomatosis. NF1 and NF2 are autosomal dominant NF1 manifestations; these include benign plexiform neurofibroma, disorders caused by mutations in tumor-suppressor protein encod- optic pathway glioma or dermal neurofibroma tumors; malignant ing genes. NF1 is typically diagnosed in childhood by appearance of peripheral nerve sheath tumors; bone abnormalities such as tibial dermal cafe au lait spots. Its course is unpredictable: it can cause a dysplasia; or learning disabilities. variety of benign nerve tumors including plexiform, dermal and The first trial of the Phase II NF Clinical Trials Consortium is optic glioma tumors; in some cases malignant peripheral nerve evaluating the mTOR inhibitor Rapamycin in NF1 patients with sheath tumors can develop from plexiforms. Around two-thirds of progressive plexiform neurofibromas. The trial utilizes three-di- individuals with NF1 develop learning disabilities, and around a mensional volumetric analysis imaging to monitor growth and quarter may develop bone abnormalities such as tibial dysplasia [for shrinkage in these tumors which are often diffuse and otherwise recent NF1 review, see Boyd et al., 2009; Williams et al., 2009]. difficult to measure. Prior natural history studies have shown that Recently, a milder NF1-like phenotype, termed Legius syndrome, the time to progression for plexiform neurofibromas is 10.6 months was characterized, and is associated with cafe-au-lait spots, learning on placebo, and these data will be used as the comparison arm for disabilities and minor bone abnormalities, but with absence of the Rapamycin Phase II clinical trials. This first trial of the Phase II neural tumors [Brems et al., 2007; Spurlock et al., 2009]. NF2 is NF Clinical Trials Consortium has completed accrual in patients usually diagnosed in young adults by tinnitus or imbalance, and is with symptomatic disease, and is near completion of initial accrual characterized by bilateral vestibular schwannomas growing on the goals for patients with radiographically progressive disease. The 8th cranial nerves. Those with NF2 will often lose their hearing due trial may be expanded to include patients with progressive lesions. to auditory nerve damage during necessary surgery to remove these The second trial of the Phase II NF Clinical Trials Consortium is tumors. NF2 can also cause spinal schwannomas and meningiomas evaluating Lovastatin for the treatment of cognitive deficits, par- [for recent NF2 review, see Evans, 2009]. Overall the underlying ticularly visuospatial learning and attention, in a prospective, genetics, biology and signaling pathways of NF1 and NF2 are fairly placebo-controlled randomized trial for children with NF1 between well understood and clinical trials are now underway. Schwanno- 10 and 17 years of age. This study opened in summer 2009. The matosis is the least understood form of neurofibromatosis. It is third trial of the Phase II NF Clinical Trials Consortium was largely diagnosed in adulthood and characterized by peripheral outlined by Nicole Ullrich (Children’s Hospital Boston) and will schwannomas and pain that is very difficult to manage [MacCollin assess a novel mTOR inhibitor RAD-001 in NF1 patients with et al., 2005]. A candidate gene for schwannomatosis was recently progressive low-grade gliomas. Finally, a proposal has recently been identified [Hulsebos et al., 2007], and though not yet fully under- submitted to the Phase II NF Clinical Trials Consortium to assess a stood, efforts are well underway to better understand the genetics new biologic agent in NF1 patients with recurrent malignant and clinical diagnosis of schwannomatosis as well to develop peripheral nerve sheath tumors (MPNSTs). This trial would be research tools such as mouse models for cellular and molecular conducted in conjunction with the national Sarcoma Clinical Trials studies. Consortium. All of these topics were addressed at the 2009 NF Conference: Ype Elgersma (Erasmus University, the Netherlands) described New Frontiers, and the highlights summarized here provide a the results of a randomized, double-blind, placebo-controlled trial snapshot of the current state of the neurofibromatosis research in 62 children evaluating whether the related statin drug simvastat- and clinical arena. in, might improve neuropsychological outcome in children with NF1. Though no clear-cut clinical improvement was seen with WHAT IS THE STATUS OF NF CLINICAL TRIALS? simvastatin treatment, there were a number of limitations in this study including marked practice effect in outcome measures in both Roger Packer (Children’s National Medical Center) and Jaishri controls and treated patients, inclusion of children with intellectual Blakeley (Johns Hopkins University) chaired the opening session of impairment, inclusion of patients on stimulant medication and the Conference, reviewing the status of therapeutic clinical trials for very short duration of treatment on full dosage. These limitations children and adults with NF1 and NF2, an area that has seen a have been taken into account in the design of the CDMRP dramatic increase in activity over the past few years. The earliest Consortium’s Lovastatin study described above; in addition only NF1 clinical trial efforts were funded by the Congressionally children with deficits in the primary outcome measures will be Directed Medical Research Program for Neurofibromatosis included in the current trial—since these demonstrated the greatest (CDMRP NFRP) and tested pirfenidone