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As the 2011 Neurofibromatosis Conference disappears in the rear view mirror, its worth taking a look back to how this event has evolved in the past 5 years and how far we've come.

My first NF Conference was in 2005, Aspen, CO. I attended that conference as a guest of the Foundation, before taking on the role of Chief Scientific Officer at CTF that fall.  120 people were there. The agenda was almost entirely basic research and it was clear this was a committed and collaborative group of researchers. But the path to treatments was still a bit fuzzy. Over subsequent years our NF community has established NF activities including preclinical drug testing, local and national clinical trials, and a national clinic network. CTF has been a driving force in all of these areas. As the clinicians became more engaged, as we attracted researchers from other fields and even industry representatives to attend, the NF Conference grew to the current size of well over 300 attendees this year.

As the NF Conference has evolved and grown it has been interesting to see the evolution of collaborations especially between the clinicians and the preclinical and basic researchers. CTF has spent the past few years helping to cultivate these relationships, but as the saying goes (appropriate for the mountain setting of this year's conference) 'you can lead a horse to water but you can't make it drink'. In other words, collaborations can be aided but not forced. It is therefore truly exciting to report that from this year's NF Conference there is clear and overwhelming enthusiasm from both the scientists and the clinicians that collaboration is vital and from the Conference presentations, evidence that these partnerships, as well as partnerships with biotech and pharma partners, are underway.   

For those living with NF, I hope it is heartening to know that we are living in the most exciting time of NF research progress on all fronts, NF1, NF2 and schwannomatosis. With your support, we look forward to continuing support of this progress and keeping you informed as it unfolds.

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.

My name is Miranda. I am 7. I have NF1. Having NF1 makes me feel unique. It makes me feel unique because not that many people have NF. I don’t know anyone else with NF. I like to twist on the monkey bars. I like to play goalie, defense and offense in soccer.  I am good at school. My favorite thing in school is math. I want to be a veterinarian when I grow up. I like to draw animals like hawks, peacocks, cats and horses. I have scoliosis that makes my back sore sometimes. I have lots of café au lait marks. We call them beauty marks. I have to get a needle poked through my arm for my MRI’s. I see lots of doctors so they can check my NF. People don’t know lots about NF. Other kids think they can catch it from me but they can’t. If I met another kid with NF, I would tell them that it gets better in life and you get used to having NF.

The above was written by my beautiful, compassionate and intelligent daughter. It is the first time she has expressed her feelings about her NF – in her own words. I asked questions and she answered them. She was diagnosed with a missense spontaneous mutation of NF1 when she was almost 5. We were stunned, confused and worried when the diagnosis came to us and had no idea what to expect. We firmly believe that knowledge is power. Thanks to CTF.org and Miranda’s battalion of doctors, we know that it is as much a part of the wonderful person who wrote the paragraph above as any other genetically determined trait. We know how lucky we are that her manifestations have been mild. We know that if we make it something to stress out about, she will stress out about it. If we treat it as a normal part of her life, she will to.

- Miranda's mom, Jessica

Coming off the heels of the NF Conference, I have been reflecting upon the experience of witnessing firsthand the passion of the world's leading NF clinicians and researchers. It was amazing to see the true commitment they all share and the overwhelming spirit of collaboration. Somehow it was evident that their individual institutions took a backseat to learning and teaching each other their latest findings in NF research. The spotlight never  really focused on one person - but on a team of experts working together to find treatments.  

I found myself many times wishing that all NF families and all of our supporters could see for themselves the focus and drive these individuals have. Yet, I understood how imperative it is for these people to live, eat and socialize amongst themselves in a secluded place for just these few days figuring out how they can work together and deciding the next steps towards treatments and a cure.

I thought it even more appropriate that as everyone returned to their homes and labs, the Children's Tumor Foundaition staff went right back to work the very next day trying their best to support the research and tell the NF story to the world. The passion of the researchers is matched everyday by so many individuals who either live with NF or work on behalf of those who do. It is also seen in the commitment of four men and their crew as they journey across this nation -at this very moment - raising awareness and funds to support the crucial work that is being done. This Race Across America (RAAM) team embodies the same spirit of those researchers and clinicians that recently returned from Jackson Hole, WY. Like them, they know that they cannot accomplish this feat alone. They need each other.  For encouragement, support and inspiration. 

For me, there can be no better understanding of what we do at the Foundation then the events of this past week. It just shows us all one more time that we can accomplish great things. But perhaps the greatest lesson is this: we cannot do it alone - and we need each other.

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”.

Today at the NF Conference a number of presentations focused on how we can harness the biology of NF1 tumors to select and test candidate drug treatments.  A key focus was on the extent to which we can draw information from mouse models and apply it to the human situation to make rational decisions about which drugs emerging from mouse studies should be advanced to clinical trials.

This year’s NF Conference co-chair Dr. Nancy Ratner (University of Cincinnati) a member of the CTF NF Preclinical Consortium has developed a unique and valuable mouse model that develops NF1 plexiform tumors over many months, thereby reflecting the slow growth of these tumors seen in the human. This makes the mouse a good model for testing candidate drug therapies that may eventually advance to humans. Dr. Ratner showed promising though very preliminary findings from testing of a MEK targeted drug in these mice once tumor has established, and found the drug slowed further tumor growth in a proportion of the mice.   Dr. Kevin Shannon (UCSF), also a member of the CTF NFPC, described his work on mice that develop NF1-related leukemias.  Dr. Shannon has also had preliminary success with MEK inhibitors; in the case of the mouse leukemias the drug helps to restore normal blood cell proliferation and circumvents leukemia progression.  Dr. Wade Clapp (Indiana University) described his work focused on understanding the biology and role of mast cells in plexiform tumors, as mast cells are inflammatory cells thought to play a key role in promoting tumor growth. (Gleevec/Imatinib, currently in clinical trials for NF1 plexiform neurofibromas , targets mast cell signaling).

Dr. Brigitte Widemann (NCI) described two new clinical trials for NF1 tumors. The MEK inhibitor AZD6244 will be assessed as a treatment for plexiform neurofibromas, and a combination of mTOR inhibitor RAD001 + VEGF inhibitor bevacizumab (Avastin) will be assessed as a treatment for MPNSTs. Dr. Widemann emphasized the importance of  preclinical researchers collaborating closely with clinical trialists to ensure the most promising drugs advance to the clinic.  Dr. Scott Plotkin (Harvard/MGH) gave thought-provoking presentations offering some cautionary notes on the extent to which we can draw information from mice and apply it to humans, emphasizing the importance of well validated models that truly represent the human condition. 

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.   

The 2011 Neurofibromatosis Conference doesn't officially start til Saturday, but the action kicked off early Wednesday & Thursday with a specially convened workshop of 20 of the world's experts in the arena of NF1 learning disabilities. Two thirds of kids with NF1 are affected by some type of learning disability, and the Children's Tumor Foundation has helped spearhead significant progress in this area the past few years which has included the first clinical trials testing the drug Lovastatin.  CTF has played a key role in driving discussions and collaborations since 2006 through the group LeaDNet the Learning Disabilities Network).  This week's LeaDNet workshop headed by Dr. Maria Acosta (Children's National Medical Center) and Dr. Alcino Silva (UCLA) considered the state of the learning disabilities field today and began to define a strategic plan to accelerate clinical progress in the next few years. Many topics were discussed in the packed day-and-a-half LeaDNet agenda. Firstly, there is a clear need for better diagnosis of the variety of learning disabilities seen in NF1, and to address this, clinicians will now to share more data and figure out standardized ways to classify patients, including firming up potential links with autism and ADHD. This is to be accomplished in part by increasing the use of neuroimaging.

In the arena of mice, there are now a large number of genetically engineered mouse models of NF1 learning disabilities. Researchers agreed it is important to pool this information and figure out which mouse models are most useful, and what aspects of clinical NF1 learning disabilities they represent.  At the bench, researchers now think about NF1 learning disabilities as having potentially multiple genetic and molecular causes, which opens up the opportunity to explore new drug targets.  Perhaps the most exciting discussions centered around how to diagnose NF1 learning disabilities in young infants. This will be particularly useful once drug or even gene-based therapies are available, and there is the possibility to 'reverse' the learning disabilities early in life.

The next steps for LeaDNet will be to expand the recommendations from the meeting and develop next steps including a workplan; and to develop a white paper of consensus recommendations from this week's meeting. To maintain momentum, the LeaDNet group plans to meet again in early 2012. Look for more updates later this year!

The 2011 Neurofibromatosis Conference doesn't officially start til Saturday, but the action kicked off early Wednesday & Thursday with a specially convened workshop of 20 of the world's experts in the arena of NF1 learning disabilities. Two thirds of kids with NF1 are affected by some type of learning disability, and the Children's Tumor Foundation has helped spearhead significant progress in this area the past few years which has included the first clinical trials testing the drug Lovastatin.  CTF has played a key role in driving discussions and collaborations since 2006 through the group LeaDNet the Learning Disabilities Network).  This week's LeaDNet workshop headed by Dr. Maria Acosta (Children's National Medical Center) and Dr. Alcino Silva (UCLA) considered the state of the learning disabilities field today and began to define a strategic plan to accelerate clinical progress in the next few years. Many topics were discussed in the packed day-and-a-half LeaDNet agenda. Firstly, there is a clear need for better diagnosis of the variety of learning disabilities seen in NF1, and to address this, clinicians will now to share more data and figure out standardized ways to classify patients, including firming up potential links with autism and ADHD. This is to be accomplished in part by increasing the use of neuroimaging.

In the arena of mice, there are now a large number of genetically engineered mouse models of NF1 learning disabilities. Researchers agreed it is important to pool this information and figure out which mouse models are most useful, and what aspects of clinical NF1 learning disabilities they represent.  At the bench, researchers now think about NF1 learning disabilities as having potentially multiple genetic and molecular causes, which opens up the opportunity to explore new drug targets.  Perhaps the most exciting discussions centered around how to diagnose NF1 learning disabilities in young infants. This will be particularly useful once drug or even gene-based therapies are available, and there is the possibility to 'reverse' the learning disabilities early in life.

The next steps for LeaDNet will be to expand the recommendations from the meeting and develop next steps including a workplan; and to develop a white paper of consensus recommendations from this week's meeting. To maintain momentum, the LeaDNet group plans to meet again in early 2012. Look for more updates later this year!

Ed Note: The following is a preview of the 2011 NF Conference written by CTF Cheif Scientific Officer Kim Hunter-Schaedle.  The Conference is limited to the scientific and clinical community but the Foundation will be providing interactive updates for the lay community throughout the week.  If you have questions about NF (NF1, NF2, or schwannomatosis), management, clinical trials, or any of the manifestations email them to ggleeson@ctf.org and we'll interview the experts and present the answers via video throughout the week. 

In just over a week, the Children’s Tumor Foundation will convene around 350 neurofibromatosis researchers and clinicians for the 2011 Neurofibromatosis Conference. Organized by CTF for over 20 years, the NF Conference is the world’s premier gathering for sharing scientific and clinical updates on NF1, NF2 and schwannomatosis. The Conference has grown significantly in recent years – almost tripling in size since 2005 – an indication of the significant progress that has been made in NF research over that timeframe. In particular we have seen a significantly increased number of clinicians attending in the past few years, as basic research shows promise and drug discoveries transition into clinical trials.  

The 2011 NF Conference will be held in Jackson Hole, Wyoming June 11^th – 14^th. This location marks a return to a mountain setting. Until 2006 the Conference was held annually in Aspen, CO; since then we have hosted it in a range of venues from Portland, OR, and Baltimore, MD.

The 2011 NF Conference is chaired by two leaders of the NF community: Nancy Ratner (Cincinnati Children’s Hospital Medical Center) and Dr. Michel Kalamarides (Universite Paris 7). The agenda features a balanced mix of basic science, clinical care and clinical trials, with good representation from NF1, NF2 and schwannomatosis.  Here are some of the highlights we look forward to.

NF1

New understanding of early development will lead the way to treatments: NF1 sessions at the 2011 NF Conference run the gamut from studying the earliest developmental events in tumors, to clinical trials.  Updates on NF1 clinical trials and management will be shared in a session co-chaired by Ludwine Messiaen (University of Alabama) and Dusica Babovic-Vuksanovic (Mayo Clinic) which will include updates on the Imatinib (Gleevec) plexiform neurofibroma trial at University of Indiana (Kent Robertson) and the use of vitamin D3 for treatment of NF1 bone density (Kimberly Jett, University of Alberta).

In the arena of clinical care, Anat Stemmer-Rachamimov (Harvard/MGH) will moderate a panel discussion focused on gliomas in NF1, covering optic pathway gliomas and other brain tumors which are rare but potentially very dangerous manifestations of NF1 particularly seen in children. Vijaya Ramesh (Harvard/MGH) will chair a session on NF1 peripheral nerve neurogenesis which looks at the emerging area of understanding how very early events in embryonic development might predict future sites of tumor growth in NF1. 

Peggy Wallace (University of Florida) and Meena Upadhyaya (University of Cardiff, United Kingdom) will co-chair a session on emerging targets in NF1 which will look at some of the up-and-coming drug targeting approaches that may soon find their way to the clinic.  An area of emerging interest in NF1 is the study of vasculopathy, as evidence accumulates that those with NF1 may be at greater risk of cardiac events than the general population.  David Ingram (Indiana University) has been one of the pioneers in this area and will provide an update of his findings from both mice and humans.

Immediately prior to the 2011 NF Conference CTF is hosting a Learning Disabilities Workshop co-chaired by Dr. Maria Acosta (Children’s National Medical Center) and Dr. Alcino Silva (UCLA). The understanding and treatment of NF1 learning disabilities has made significant progress in the last few years with Lovastatin now in Phase II trials. However much remains unknown.  This workshop will bring together thinking from those who study NF1 learning disabilities as well as from other areas such as autism and fragile X. The goal of the workshop is both to provide updates on the status of understanding and treating NF1 learning disabilities, and to see how cross-pollination of knowledge and collaboration across different conditions might drive progress.

NF2

As clinical trials and clinical care advance, the search for new drug targets continues: It is only a few years since NF2 clinical trials commenced, and the NF Conference includes updates from a few of these, including bevacizumab (Avastin) for the treatment of meningiomas (Fabio Nunes, Harvard/MGH) and Lapatinib for treatment of vestibular schwannomas (a Children’s Tumor Foundation-funded study by Dr. Jaishri Blakeley, Johns Hopkins). A panel discussion moderated by Michel Kalamarides will focus on best options for hearing preservation in NF2, a key issue given the different opinions on radiation therapy and the emergence of candidate drug therapies.   One session of the NF Conference, chaired by Filippo Giancotti (Memorial Sloan-Kettering Cancer Center) and Helen Morrison, PhD (Leibniz Institute for Age Research, Germany) will examine the development and use of genetically-engineered mouse models to understand and test drug therapies for NF2.  Meanwhile, the search for new NF2 drug targets continues. In 2010, one of the most heavily discussed issues of the NF Conference was new evidence that the NF2 gene protein merlin could act both outside and inside the cell nucleus. This has opened up new thinking and discussion on how drugs should target NF2 tumors, and a session of the 2011 Conference chaired by DJ Pan (Johns Hopkins University) will examine this.

Schwannomatosis

An International Database and a forthcoming Workshop: In 2009 CTF funded the development of an International Schwannomatosis Database. Given the very modest number of persons with schwannomatosis seen at any one clinic, the Database is intended to provide a means for any clinic worldwide to enter information on their schwannomatosis patients.  This will become a valuable resource for future clinical research and clinical trials. Spearheaded and managed by Allan Belzberg at Johns Hopkins University, the Database is now ‘live’ at www.schwannomatosis.com. Amanda Bergner (Johns Hopkins University) will provide an update on the project.  Additional schwannomatosis presentations will focus on the impact of tumor burden on quality of life (Vanessa Merker, Harvard/MGH), emotional distress in adults with schwannomatosis (Daphne Wang, Harvard/MGH), and whether pain in NF1 has parallels with pain in schwannomatosis (Maria Acosta).  CTF is hosting a Schwannomatosis Workshop in Los Angeles at the end of June, and we look forward to reporting further updates in the field from that meeting.

Lay Presentations
A Heartfelt Inspiration: A regular feature of the NF Conference for the past five years has been the presentations made by three lay individuals whose lives are affected by NF1, NF2 or schwannomatosis. This year we are delighted to have Sheila Heal, President of AdvoCure NF2, speaking about her family’s experience with NF2; Jill Beck, CTF staff member speaking about her family’s experience with schwannomatosis; and Jackson Hole local Benjamin Ellis, talking about his family’s experience with NF1. These presentations are so very inspiring especially for the scientist attending, who do not interface with patients and families day to day.  We are ever grateful to the families that give their time and honesty to this treasured part of the NF Conference.