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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. 

 Learning disabilities, ranging from mild to severe, may affect as many as two-thirds of those with NF1.  These learning disabilities were poorly understood for a long time, until around six years ago when groundbreaking research from the lab of Dr. Alcino Silva (UCLA) showed that the drug Lovastatin, traditionally prescribed for cholesterol lowering, appeared to correct NF1-related learning disabilities in mice genetically engineered to have these deficits. 

Over the past few years, Dr. Maria Acosta (Children's National Medical Center) and her colleagues have taken on the daunting task of translating this 'mouse result' to humans, by bringing Lovastatin to clinical trials to treat NF1-related learning disabilities. Dr. Acosta has now published the outcome of this trial in the journal Pediatric Neurology. This was a Phase I study (Phase I studies are designed to assess the safety of the drug). 24 children received Lovastatin over a three-month period,  and no safety issues were seen. Furthermore, and although this study was not designed to fully evaluate the effect of the drug,  the children on the study showed overall improvements in verbal and non-verbal memory functions. These exciting findings will pave the way to the Phase II trial in which the potential efficacy of Lovastatin will be thoroughly evaluated in a larger population. 

Looking ahead, researchers will  wish to identify additional approaches for the treatment of NF1 learning disabilities, and this will require identification of further drug targets. Current Children's Tumor Foundation Young Investigator Award recipient Dr. Jean Gouzi has done just this.  Dr. Gouzi is studying a molecular signaling element termed Anaplastic Lymphoma Kinase (Alk) - a molecule that is dysregulated in and associated with a number of cancers. Dr. Gouzi (jointly of Harvard Medical School/MGH and the Biomedical Sciences Research Center Alexander Fleming, Vari, Greece) is using genetically engineered Drosophila (fruit flies) as a study model. Genetically increasing the activity of Drosophila Alk (dAlk)  in the fly reduced learning ability; and reducing the level of dAlk improved learning behavior. This suggests that dAlk in its normal active state is an inhibitor of learning.  Dr. Gouzi went on to show that dAlk interacts functionally with Drosophila NF1 (dNf1) and the two molecules dAlk and dNf1 colocalize in the fly. Furthermore, in flies genetically engineered  to have overactive Nf1,  learning is inhibited; however, blocking function of dAlk in these dNf1 mutant flies can compensate for this and normalize learning capabilities.  This experiment suggests that dAlk is a key regulator of dNf1 function and that targeting and inhibiting dAlk function could be a rational approach for the treatment of NF1-related learning disabilities.  Dr. Gouzi's work is published in the September issue of the online journal PLOS Genetics and will shortly be available free at  http://www.plos.org/

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 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!