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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.   

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.

An article in this week's Time magazine 'Check your Charity' highlights parameters you should look for if considering supporting a medical research charity or foundation. Issues highlighted include - what percentage of the funds raised actually go to medical research programs?  Is the charity or foundation monitoring outcome metrics to demonstrate progress and success? Children's Tumor Foundation has already demonstrated fiscal success through our maintained 4 Star Charity Navigator rating and we received a mention in the New York Times last December in reference to wise charitable investments.  Now further recognition has come from our metrics of success. In December 2010 the Children's Tumor Foundation was invited by to join Mr. Mike Milken's  FasterCures group TRAIN (The Research Acceleration and Innovation Network). The FasterCures initiative is focused on bringing business acumen to medical foundations, having them set and live up to metrics, and to place foundations as the central pivot of research progress in the foundation/government/industry triangle.  The FasterCures TRAIN is a select group of foundations such as the Multiple Myeloma Research Foundation and Michael J Fox Foundation that have demonstrated innovative approaches to advancing research progress as well as developing successful approaches to monitoring the efficacy of our research programs.  This week's Time article highlights the value of TRAIN, in the words of FasterCures Executive Director Margaret Anderson, "those that are willing to change want to learn from other groups ... and believe in 'Let's make it as efficient as possible.'"
The Children's Tumor Foundation is delighted to be among the select foundations in TRAIN and will continue to strive to make our neurofibromatosis research programs as effective and accountable as possible.

The Children’s Tumor Foundation (CTF) is delighted to announce the funding of five new Drug Discovery Initiative (DDI) Awards totaling $125,000, from applications received for our spring 2011 deadline.   DDI Awards fund studies to test candidate neurofibromatosis (NF) drugs for NF1, NF2 or schwannomatosis, offering $15,000 for in vitro cell-based screens, up to $30,000 for in vivo animal model screens and up to $50,000 to continue outstanding in vivo research projects.  Launched in 2006, it is one of CTF’s most successful programs.

The Spring 2001 DDI Awards are as follows:

Cristina Fernadez-Valle, Ph.D., University of Central Florida - $15,000
In vitro DDI Award to screen a small molecule drug library on NF2 Schwannoma Cells 

Jan Friedman, MD, Ph.D., University of British Columbia - $15,000
In vitro DDI Award to test cytokine inhibitors for the treatment of NF1 Vasculopathy

Xu Wu, Ph.D., Harvard Medical School/ Massachusetts General Hospital - $15,000
In Vitro DDI Award to Test Small Molecule Library of Inhibitors of YAP Nuclear Localization in NF2 Schwannoma, Astrocytoma, Meningioma Cells

David Largaesapada, Ph.D., University of Minnesota - $30,000*
In vivo DDI Award to test of drug combinations for NF1 Plexiform Neurofibroma and MPNST (builds on previous DDI Award of $15,000)

David Wiemer, Ph.D., University of Iowa - $50,000
Advanced DDI Award to optimize Schweinfurthins for NF1 Astrocytoma (builds on previous DDI Award of $30,000)

*Dr. Largaespada’s Award is funded by the Texas Neurofibromatosis Foundation through CTF.

Since its launch in 2006 DDI has funded 44 projects – around 10 per year – of up to $50,000 per Award, totaling a CTF research investment of just over $1 million. DDI studies up to 1 year to complete.  To date, 27 concluded DDI studies have shown promising results and have been successful in securing $4.7M in follow-on funding (to continue building on the CTF-funded research) including government, industry, state and institutional grants. 19 scientific publications have emerged from DDI research, and 19 projects have included collaborations with biotechnology or pharmaceutical companies.  And all of these numbers continue to grow.

DDI forms the backbone of the Children’s Tumor Foundation-funded NF candidate drug pipeline. Through DDI, the NF Preclinical Consortium, and the Clinical Trials Award program the Foundation is currently supporting drug testing bench-to-bedside from cell-based assays in vitro to pilot clinical trials.

The next deadline for DDI Award apps is August 31st and info can be found here.

The report from the 2010 NF Conference was published earlier this year in the American Journal of Medical Genetics and  is now available for FREE download.
The NF Conference is the worlds premier annual gathering of researchers and clinicians focused on neurofibromatosis now attended by over 300 professionals.

The 2011 NF Conference will be held in Jackson Hole, Wyoming June 11-14. For more information on this meeting and how to register click here.  The NF Conference is not generally open to lay persons, but in 2011 we will be taking a multimedia approach to keep everyone abreast of the meeting highlights, including blogging, tweeting and presenting short researcher interviews on the CTF website.

The Collaborative Science Center of Excellence (CSCoE) at Bristol-Myers Squibb is offering Investigator Sponsored Research (ISR) funding.  There are opportunities to fund clinical research/clinical trials, non-interventional research, non-clinical research, a co-operative groups and networks portal, and an immunoscience, virology and oncology MD fellows research program. BMS will be accepting research proposals/applications beginning April 15, 2011 through midnight June 30, 2011. It is imperative that your application is received on or before June 30, 2011, to ensure that it is considered during the established review cycle. An internal Scientific Research committee will be assessing all submitted applications with the intent of conveying the committee's decision by August 15, 2011.
More information: click here

The Neurofibromatosis Research Program (NFRP) has announced the funding mechanisms for the FY11 appropriation of $16M. For full info visit: http://cdmrp.army.mil/funding/nfrp.shtml

Clinical Consortium Award - Maximum funding $9M for direct costs

Clinical Trial Award - Maximum funding $900K for direct costs

Exploration-Hypothesis Development Award - Maximum funding $100K for direct costs

Investigator-Initiated Research Award - Maximum funding $525K or $675K for Optional Qualified Collaborator for direct costs

Investigator-Initiated Focused Research Award - Maximum funding $525K or $675K for Optional Qualified Collaborator for direct costs

New Investigator Award - Maximum funding $400K in direct costs

Postdoctoral Traineeship Award - Maximum funding $100K in direct costs

The April 12 issue of the journal Cancer Cell reports the exciting findings uncovering how the NF2 protein Merlin functions, and suggesting Merlin could be involved in many other types of cancer. This research was funded in part by the Children's Tumor Foundation to Dr. Chunling Yi in the research group. Senior author Dr. Joe Kissil is a past recipient of the CTF Drug Discovery Initiative Award; and preliminary findings of this work were presented at the CTF 2010 NF Conference.

The researchers describe, for the first time, that Merlin, the protein encoded within the NF2 gene interacts with a protein called angiomotin which has a key role in cell movement in the formation of new blood vessels. This connection between Merlin and angiomotin also brings together two important information networks in cells, both of which have been implicated in numerous forms of cancer.

Dr, Kissil says,"The discovery opens up a potential new method to treat NF2 by attacking the tumor cells directly and by starvation, a strategy already employed in certain cancer therapies." This is different than drugs like Avastin, which shrinks blood vessels; angiomotin is used by both blood vessels and the growing tumor cells, so targeting this with drugs could be a 'double whammy'.

The Kissil laboratory plans to continue their exploration of angiomotin as a potential therapeutic target for treating NF2, as well as look into the role of angiomotin in other cancers known to be affected by NF2 mutations.

I am pleased to announce that Congress has appropriated $16 million for NF research for fiscal year 2011.  This research, conducted through the Department of Defense, is critical both to those living with the challenges of NF and the brave men and women serving our country. 

As many of you know, research into treatments and cures for NF and its various manifestations has implications for those beyond the NF community.  Advancing our understanding of mast cells to stop tumor growth helps us understand how we may also speed wound healing for our war fighters.  Understanding the mechanisms of pain in NF can allow us to understand the signaling pathways that can block the pain our soldiers may face.  Imaging technologies advanced to understand NF tumor growth are proving essential in MRI volumetric imaging to the broader community, particularly our armed forces. 

We are grateful that those serving in Congress recognize the importance of NF research for those serving our country, and those living with NF.  We know that the importance of NF research validates that recognition.