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                As neurofibromatosis clinical trials increase in number, the clinicians leading them are keen to design the trials to be as effective and meaningful as possible. A key part of this effort is developing the right trial endpoints - measures and metrics that can be used to determine if a drug or intervention is effective or not.  To tackle this area, a team of neurofibromatosis clinicians and researchers has formed  a working group called Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS). Spearheaded by Dr. Scott Plotkin (MGH) and Dr. Brigitte Widemann (NCI) and first convened in June at the Children’s Tumor Foundation 2011 NF Conference, around 30 leading NF clinicans and researchers participating in the REiNS met in Boston to continue their planning and discussions.

                Past endpoints for neurofibromatosis clinical trials have included changes in maximum tumor dimension on MRI scans or changes in cognitive function on neuropsychological assessment (for learning disabilities).  Looking ahead, more advanced endpoints under discussion (and already being piloted in some cases) include volumetric tumor analysis and whole body MRIs; and the use of biomarkers – biological indicators in the blood or other body fluids to determine if a drug is working. REiNS members have organized into groups to focus on different measures and plan to meet every few months to continue advancing this project.

                The Children’s Tumor Foundation is delighted to be investing in endpoint development through our Clinical Research Awards program.  Currently our funded projects include developing a computerized test for more accurate assessment of learning disabilities trials; identifying a blood biomarker of NF1 status; and developing measures of response for optic pathway glioma trials. We will be announcing more funded awards in early 2012. 

                Clinicians or researchers interested in participating in REiNS can contact Vanessa Merker at MGH: vmerker@partners.org. 

Today we feature a Guest Blog featuring a report from the 2011 NF Conference from Dr. Fawn Leigh, a pediatric neurologist at the Massachusetts General and Harvard Medical School. Dr. Leigh presented the following project at the Conference, and is looking for further research collaborators, as well as any persons with NF1 who would be willing to participate and donate tissue, whether or not they are currently under care of an NF clinic.

At the 2011 NF Conference in Jackson Hole I gave a talk highlighting my findings from a pilot study to identify modifier genes that may inform the identification of potential drug targets and treatments in NF1. The study focused on a search for modifier genes of cutaneous (dermal) neurofibroma tumor burden in NF1. This was done through a genome-wide association study (GWAS).  300 NF1 subjects identified as having either the largest or least 15% of cutaneous tumor burden were genotyped using the Affymetrix GeneChip 6.0 platform. This provided 909, 622 single nucleotide polymorphism (SNP) markers and >946,000 probes for copy number variants (CNV).  The analysis revealed potential hits (P values of 10-4 to 10-7) with multiple SNPs at each of several regions of the genome. Each of these segments constitutes a candidate region that merits genotyping in an additional cohort of extreme subjects to either confirm or refute its modifier status, which is ongoing.  The CNV analysis is in progress. The current GWAS study is a collaboration of six centers across the world.  Five new centers recently joined this project. 

For researcher or patients seeking additional information about participating in this study, please contact:  Stephen Ranney (Clinical Research Coordinator)

Email: administrator@cnfad.org               Office: 617-724-2365

We still have much to understand and address about the challenges faced by individuals with NF1 as they age. These span from the practical challenges of transitioning from pediatric to adult clinical care in young adulthood; to the clinical challenges of understanding how the clinical manifestations NF1 itself might progress as a person ages. This is an area of NF1 that has not been heavily studied and it is therefore good news that Dr. John Mulvihill is hosting a Workshop on Aging in NF1, September 9-10, 2011 at the University of Oklahoma Health Sciences Center in Oklahoma City, OK. This is the first announcement of this meeting, which is intended for clinicans and scientists with a research interest in this area. Those interested in participating should contact Dr. Mulvihill at John-Mulvihill@ouhsc.edu or Shona Whitehead at Shona-Whitehead@ouhsc.edu. This meeting is funded in part by a United States Department of Defense contract #W81XWH-06-1-0465.

The 2011 NF Conference concluded today with a packed agenda of exciting talks, kicking off with some clinical trial updates. Kent Robertson (Indiana University) reported on a trial of Gleevec (Imatinib) in NF1 patients with clinically significant plexiform neurofibromas, age 3-65.  Individuals received drug for 6 months, and if they received benefit they were given the opportunity to stay on the drug.  60% of patients showed a response in one or more of their plexiforms, and 40% of those patients showed an improvement in ther symptoms such as issues with bladder control and airway function.  Dr. Dusica Babovic-Vuskanovic (Mayo Clinic) reported on the concluding Phase II trial assessing the response of NF1 plexiform neurofibromas to Cediranib (AZD2171), a VEGF-targeted agent. 26 patients, 18 years and older participated in the trial and received drug for periods of 18-41 months. 4 patients showed continuous and sustained tumor shrinkage. In addition the trial assessed changes in pain via a quality of life survey, and found that pain levels decreased over the period of drug treatment.  Kimberly Jett (University of Alberta) reported on her study showing that NF1 patients can have reduced levels of Vitamin D in the serum, and that treatment with Vitamin D can increase bone mineral density in these individuals, potentially helping to allay future bone problems.

Sarah Burns (Ohio State University) described research using the PI3K/AKT targeted drugs AR42 and AR12. These drugs are in development at Arno Therapeutics and in clinical trials for a number of cancers. Previous CTF-funded preclinical research by this group has shown that these drugs are candidate therapies for NF2 vestibular schwannomas.   This presentation reported potential efficacy of these drugs in halting or slowing the growth of benign meningiomas.  David Ingram (Indiana University) is focused on the area of vascular disease in NF1. Persons with NF1 are at increased risk of vascular disease. Dr. Ingram has developed mouse models that develop the features of vascular disease, such as infiltration of macrophages. These mice will be valuable study models for understanding the biology and testing drug interventions. Looking ahead, the goal is to be able to identify early subclinical vascular disease so it can be treated before it progresses.

112 posters were presented at this year’s NF Conference, and these were judged by small committees of researchers and clinicians to determine Best Poster in Basic Research and Clinical Research categories.  Consideration was given to merit, originality and depth of data. The winners were: Best Poster – Basic Research: Juliana Ferreira de Souza (Federal University of Mina Gerais, Brazil) – “Aerobic Capacity Is Reduced In Patients With NF1: A Preliminary Report”; and Best Poster-Clinical Research:  Melissa Hinman (Case Western Reserve University) - “The Biological Role of the Regulation of NF1 Exon 23a alternative splicing”.

The 2011 NF Conference kicked off this weekend with some interesting and exciting presentations.  On Saturday, Dr. Filippo Giancotti (MSKCC) provided an update on his novel research first reported in 2010 that described for the first time a role for NF2 merlin protein in the cell's nucleus. Dr. Giancotti has continued to unravel the signaling activities of merlin in the nucleus, and interestingly also showed that in sections of human meningioma tissue,  merlin protein is not present in the nucleus. This would provide support for Dr. Giancotti's unique idea that merlin controls normal cell division and that lack of its nuclear function might be a factor in promoting NF2 tumor growth.  

On Sunday, Dr. Alison Lloyd (University College London) chaired a session on the biology of peripheral nerve development and what we can learn from this and apply to understanding disease and specifically NF1. Dr. Lloyd herself presented some really interesting findings  in mice where Erk signaling was disrupted in peripheral nerves by genetic mutation. The result is that the nerves undergo an inflammatory response, the blood nerve barrier function is lost and in short the nerve looks to all intents and purposes like they have been physically injured. Because Erk signaling is also disrupted in NF1 neurofibromas, this research opens the door to comparing this model of nerve injury to disease progression in NF1 tumors to see what one can teach the other. In the same session Dr. Luis Parada (University of Texas Southwestern) described an ongoing study in which he is screening pairs of drugs from a large compound library on malignant peripheral nerve sheath tumor cells.  The study is beginning to identify potentially novel drug targets for the treatment of these NF1 tumors. Dr. David Largaespada (University of Minnesota) closed out the session with a report o his CTF-funded research focused on better understanding the exact nature of gene mutations that lead to neurofibromas, and how this can help us identify new drug targets. 

On Sunday evening, Dr. Jaishri Blakeley  (Johns Hopkins University) provided an update of her CTF-funded clinical trial of Lapatinib in vestibular schwannomas. This ‘Phase Zero’ trial is focused on giving patients drug prior to vestibular schwannoma surgery so that the excised tumor can be studied to see if the drug reached the target. This type of study provides a rapid preliminary evaluation to determine if a full scale Phase II trial is worthwhile. So far there is not compelling evidence that Lapatinib is effective but the trial is not yet complete so we look forward to seeing the final data.  Dr. Fabio Nunes (Harvard) did a retrospective review of NF2 patients treated with bevacizumab (Avastin) for their vestibular schwannomas, to see if there were also additional effects on meningiomas. While there were modest effects of the drug in some tumors within some patients, this was not strongly compelling suggesting bevacizumab is not likely to be a promising therapeutic for meningioma.  CTF Young Investigator Irma Rangel-Alarcon (UCSF) proposed a function for the protein encoded by the Spred-1 (Legius Syndrome) gene suggesting it has close interactions with the NF1 protein (neurofibromin) in the cell. This study could potentially help unravel why there is overlap in the clinical presentation of NF1 and Legius Syndrome.  

Closing out Sunday evening Amanda Bergner (Johns Hopkins) provided an update of the CTF-funded Schwannomatosis Database which now has 14 US and international sites participating, has enrolled 27 patients and aims to have 200 patients registered by the end of 2011.