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Ed. note: The below was written by Dr. Kim Hunter-Schaedle.

This year has seen some amazing progress in neurofibromatosis research. The path to finding treatments for NF1, NF2 and schwannomatosis is challenging, but researchers continue to unravel the biology and apply this information to identifying candidate drug interventions. Here are five areas worth highlighting from the year. We blogged on most of these and you can find more information by searching our archive. 

1. Neurofibromatosis Clinical Trials Pipeline Grows. July saw the reporting of a small but groundbreaking NF2 clinical trial of bevacizumab (Avastin) at Massachusetts General Hospital yielding preliminary evidence that the drug could shrink vestibular tumors and lead to some regained hearing. This study published in top-notch New England Journal of Medicine and made the national media. The Foundation funded our first clinical trials, Phase 0/lapatinib in NF2 and Phase I/Sorafenib in NF1 plexiform tumors and published consensus recommendations for conducting NF2 clinical trials. Other neurofibromatosis trials commencing this year included Phase II/PTC299 in NF2; and light-based therapy for NF1 plexiform tumors.
2. Basic Science Knowledge in Neurofibromatosis Advances. New research on cancer signaling this year, including several projects funded by the Children’s Tumor Foundation, opened up understanding of what makes benign cells become malignant, why and how cells metastasize, and how molecular targets ‘communicate’. We have the first mouse models of schwannomatosis and NF1 dermal neurofibromas, while other NF mouse models are now improved to better replicate the human condition as closely as possible.  This information and these tools are vital resources for developing targeted drug treatments for neurofibromatosis.
   
3. Getting the Right Diagnosis. Legius Syndrome (NF1 like, but caused by SPRED1 mutations and with milder clinical impact) moved from lab to clinic as a bona fide condition that can be diagnosed. Explorations into the genetic cause of schwannomatosis evolved and we now know this definitely goes beyond the first candidate gene identified, INI1/SMARCB1; this area will benefit from the information collected from patients in the US and Europe through the Foundation’s new Schwannomatosis Database project. Also this year the Foundation published consensus recommendations for management of NF1-related bone dysplasia. As the clinical spectrum of neurofibromatosis and our body of information grows the Foundation shares this broadly across our NF Clinic Network, now 40+ clinics strong. 
4. Fuelling the Neurofibromatosis Drug Pipeline. The Foundation’s Drug Discovery Initiative funded nine DDI Awards in 2009 including our first schwannomatosis award - to screen pain drugs. DDI projects span NF1 and NF2 tumors, learning disabilities and bone dysplasia. Drugs tested range from commercially available drugs, to industry pipeline drugs, to new chemical entities. Perhaps most unique in 2009 we funded induced pluripotent stem cell (iPS) as a therapeutic approach to treating NF1 plexiform tumors.  To date we have invested $735,000 in 31 Awards - and already, prior awardees have collectively secured $3.7M in follow on funding and spearheaded 14 industry collaborations!  The Foundation’s NF Preclinical Consortium also expanded its industry collaborations to include Novartis, Genentech and Avila Therapeutics. 
5. Our World Evolves. We are in this together like never before.  Biotech and pharma are merging, streamlining and even collaborating on clinical trials that combine their drugs.  Operations at the Food and Drug Administration are being closely examined.  Even the inner workings of the NIH, awarded an extra $10B in stimulus funding this year, are under the microscope, and have an enthusiastic new director at the helm in NF1 gene pioneer Dr. Francis Collins. Foundations like ours are gaining a bigger voice by working together such as at the ‘Partnering for Cures’ meeting in December. And don’t forget the changing healthcare system. We hope this time of change will lead to easier access drugs and accelerated clinical trials that benefit those living with neurofibromatosis and many other conditions.

The Children's Tumor Foundation Drug Discovery Initiative (DDI) Award program provides seed grants for pilot preclinical screening of candidate neurofibromatosis drug therapies.   To date the Foundation has funded over 30 DDI Awards including FIVE recently selected to be announced in the next few weeks.  

The DDI Awards program has primed a pipeline of candidate NF drug therapies; helped investigators generate the results needed to secure larger government grants; and importantly, stimulated collaboration between NF researchers and a number of biotech and pharmaceutical companies.

The DDI Award application is brief  just 3 pages - and the Foundation endeavors to have fast turnaround, and fund awards within 8 weeks of the deadline. For 2010, DDI Awards are available as follows: $15,000 for an in vitro (cell-based) study; $30,000 for an in vivo (animal-based) study. In addition $50,000 DDI Awards are available for continued bridge support of particularly outstanding in vivo Awards.  There are two application deadlines in 2010: February 26 and August 31.

For more information:  http://ctf.org/For-Scientists/drug-discovery-initiative.html

We are delighted that the Children's Tumor Foundation's 2009 NF Conference Report: What's New in Neurofibromatosis? has been accepted for publication in the American Journal of Medical Genetics. The paper includes neurofibromatosis highlights presented at the Conference, spanning from basic research to clinical care and clinical trials, and should appear in AJMG in the next couple of months. This is the first time in a number of years that the NF Conference meeting report has been published in a professional journal. The paper is authored by the session chairs from the 2009 NF Conference,  spearheaded by 2009 NF Conference Chairs Dr. Kathryn North (Children's Hospital at Westmead, University of Sydney) and Dr. Joseph Kissil (The Wistar Institute). 

For over 20 years the Foundation has convened the premier annual conference for the professional neurofibromatosis community. The 2009 NF Conference was held in Portland, OR June 13-16 and attracted a record number of close to 300 attendees.  The 2010 NF Conference will be held in Baltimore, MD June 5-8. For more information: http://ctf.org/For-Scientists/nf-conference.html

Tuesday morning included a session on new NF mouse models. Michel Kalamarides reported his mouse model of NF2 meningioma, in which these tumors can only develop if the NF2 gene is inactivated at a certain point in embryonic development.

Larry Sherman described his newly developed mouse model in which the schwannoma-related Brg1 gene is mutated.  Schwann cells derived from this mouse are hyperproliferative (divide too much) and make abnormally high levels of a growth factor BDNF; he is investigating whether this could potentially contribute to pain and a schwannomatosis phenotype.

Yuan Zhu presented a new mouse model that develops NF1 related of plexiform neurofibromas, dermal tumors and MPNSTs that are progressive and somewhat mimic the human state.  

The final session of the conference included presentations on new NF drug targets. Ronen Marmorstein is using structural design to optimize novel PAK inhibitors; this is partly in conjunction with Joe Kissil through a recently funded Children's Tumor Foundation DDI Award which will test them in animals with NF2 tumors.

Best 2009 Posters were a coup for Finland: Minja Laulajainen, University of Helsinki won Basic Science category for a merlin-focused study, and Lotta Alivuotila, University of Turku won Clinical category for a cognitive-focused NF1 study.  The 2009 NF Conference closed with the announcement of the 2011 NF Conference Chairs, Nancy Ratner and Michel Kalamarides. Before then of course, the 2010 NF Conference (‘NF- Back to the Future') - will take place in Baltimore, MD June 5-8, 2010 and will be co-chaired by Sue Huson and Filippo Giancotti.    

Monday kicked off with a session focused on cognitive deficits of NF1 tackling topics such as the challenges of translating learning disabilities mouse research findings into human trials, as well as molecular drug target updates. This included results from testing drugs in learning disabilities fruit fly models (a well received presentation from Foundation-funded Young Investigator Linnea Vose). It is emerging that the clinical features of NF1 cognitive deficits are driven by many things in the brain, including potentially the way that some of the neurons (nerve cells) develop and ‘wire up' in the first place. Learning disabilities continues to be a really exciting and fast moving area of NF1 research.

Among today's NF2 presentations Vijaya Ramesh reported that cell signaling element mTORC, long recognized as an important candidate drug target for the treatment of NF1 tumors, may also be a key drug target in NF2 tumors meningioma and vestibular schwannoma. For example rapamycin which targets mTORC was able to shrink meningioma tumor cells - which are overly large -  back to a more normal size.   

 The theme of the 2009 NF Conference is ‘New Frontiers', a nod to the remarkable progress made in NF research and the tackling of new challenges, such as sorting through emerging clinical trial options. However, some truly brand new frontiers remain. Schwannomatosis, the rarest form of NF, causes peripheral nerve tumors and unmanageable pain. A candidate gene for schwannomatosis, called INI1, was identified just two year ago, but many mysteries remain. Are NF2 mutations also involved in schwannomatosis? What about other genes?   Some of these issues were addressed in a session Monday morning. A major challenge to answering these questions is lack of patients, since many clinics will at most see only a handful of schwannomatosis patients, and a lot of the patients are being seen elsewhere perhaps in pain or plastic surgery clinics. For this reason the Children's Tumor Foundation is supporting a special initiative to establish a collaborative schwannomatosis database that will collect patient data from as many clinics as possible. On Monday evening representatives from about ten clinics US and international met to hammer out the questions this database must ask - these need to be detailed enough to make the data collected ‘mineable' (searchable, meaningful) to identify patients for follow up studies. Also though, at the first cut, the amount of data to be entered can't be too onerous as to put clinics off taking the time to enter it. The Foundation is providing initial funding to get this database up and running, but perhaps our most important role in this will be to encourage and drive as many clinics as possible to participate. We are very fortunate that this effort is being driven the enthusiastic Allan Belzberg and Amanda Bergner at Johns Hopkins and excited to see it move forward.