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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. 

Clinical trials are showing that drugs don’t always work on every person with a specific medical condition. This is most likely due to genetic differences that make some patients less responsive to specific drugs. Understanding an individual’s genetics is likely to be a key driver in future decision making on drug selection for individual patients. However, pharmaceutical companies have not yet fully embraced the practice of integrating genetic information into clinical trials, perhaps due to increased cost or the risk of introducing yet another variable into a trial. So if the pharma companies are not advancing this research, who will do this?

The answer may well rest with medical foundations like ours. Last week, the Multiple Myeloma Research Foundation (MMRF) launched a “Personalized Medicine Initiative” – a 1,000-patient study that will track patients from multiple myeloma diagnosis through treatment, over a minimum of five years. Sequential tissue sampling will identify how a person’s molecular profile may affect his or her clinical progression and response to treatment. This is a major undertaking for a foundation, but MMRF is addressing this need as no one else is doing this type of study.  Read more in this article.

Per our 2011 NF Strategic Plan, the Children’s Tumor Foundation will launch major new neurofibromatosis initiatives in genetics/genomics in 2012 to better understand how NF can be targeted by drug therapies. The Foundation has also recently began to fund research to identify biomarkers (e.g. blood components) that can serve as a surrogate measure and early predictor of whether or not a drug is being effective in treating NF in any one person. We will be expanding our biomarkers research in 2012.

The Children's Tumor Foundation is delighted to announce that a Foundation-spearheaded paper outlining progress in NF2 clinical trials and strategies for further accelerating these trials has been accepted for publication in the American Journal of Medical Genetics.  This paper, "Consensus Recommendations for Current Treatments and Accelerating Clinical Trials for Patients with Neurofibromatosis Type 2" was authored by 17 international NF2 clinical and research experts as an outcome of a Children's Tumor Foundation-convened Workshop to accelerate NF2 clinical trials hosted in Las Vegas, NV last year.  Lead authors of the report are Dr. Jaishri Blakeley (Johns Hopkins University), Dr. D. Gareth Evans (University of Manchester) and Dr. Marco Giovannini (House Ear Institute). This is the second NF2 clinical trials consensus paper published under the auspices of the Children's Tumor Foundation. The first paper, published in Clinical Cancer Research and the result of a 2007 Foundation NF2 Workshop, helped initiate collaborations for the pioneering of NF2 clinical trials in the past few years. 

The new AJMG publication should appear in the near future.       
  

Dr. Chris Moertel, Director of the Children's Tumor Foundation Neurofibromatosis Clinic Network Affiliate Clinic at the University of Minnesota, is making progress in what has largely been an elusive area for clinical researchers - the development of vaccines to treat brain tumors. Dr. Moertel pioneered these studies by successfully halting brain tumor growth in a dog which had been injected with cell matter harvested from its own tumor.  He has since advanced the trials into seven patients with malignant glioma who have been treated with vaccine made from their own tumor matter. It is very early days but these studies look promising and will continue.  Vaccines have been challenging to develop but if successful would reduce the need for using chemotherapy drugs.  The target is currently malignant cancer but looking ahead there may be potential to apply a similar approach to neurofibromatosis tumors.  View a short TV interview with Dr. Moertel talking about the work here.

Announcing a terrific funding opportunity from the National Institutes of Health - the NIH Director’s Transformative Research Awards: 

• Exceptionally innovative, high risk, original and/or unconventional research
• Clinical, basic, and/or behavioral/social science research projects
• Up to $25 million total costs per year for a single project
• One-third of total funding budget geared to projects with more than $1 Million in direct costs. 

 The deadline for submitting Transformative Research Project applications is January 12, 2012 with Letters of Intent due by December 12, 2011.  See the instructions in the RFA-RM-11-006.  Additional information, including Frequently Asked Questions about the Transformative Research Projects Program is available at: http://commonfund.nih.gov/TRA. Send questions to Transformative_Awards@mail.nih.gov.

 The NIH Common Fund (formerly the NIH Roadmap) encourages collaboration and supports a series of exceptionally high impact, trans-NIH programs. These programs are supported by the Common Fund, and managed by the NIH Office of the Director in partnership with the various NIH Institutes, Centers and Offices. Additional information about the NIH Common Fund can be found at http://commonfund.nih.gov. 

 For more information about NIH and its programs, visit http://www.nih.gov.

 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/

Malignant peripheral nerve sheath tumors (MPNSTs) are among the tumors that can occur in NF1, but these malignancies are particularly challenging to treat and control. One reason for this is that MPNST cells appear to undergo changes that make them reistant to traditional treatments such as chemotherapy. Cuurent Children’s Tumor Foundation Young Investigator Awardee Dr. Thomas de Raedt, a postdoctoral fellow in  the laboratory of Dr. Karen Cichowski at Harvard Medical School, has published a paper this week in leading journal ‘Cancer Cell’ describing his work in mice, showing a new and seemingly highly effective way to treat MPNSTs via a ‘double-hit’ - using two drugs in combination.  Dr. de Raedt and his colleagues combined the drug rapamycin, which targets the cell signaling element mTOR, with the drug IPI-504, which targets another cell signalling element called HSP90.  In the face of this treatment, the mouse MPNSTs underwent dramatic shrinkage. The tumors also underwent what is termed autophagy, where the cells die and collapse under stress so rapidly that they create spaces where the tumors were.  The success of this approach comes from the fact that combining rapamycin and IPI-504 leads to a collapse of cell structures called the endoplasmic reticulum (ER) and mitochondria which together, constitute the energy source or ‘engine’ of the cell.  By shutting down the ER and mitochondria, the cell dies.  We look forward to seeing the next steps of this exciting finding.

Dr. Cichowski and Dr. de Raedt are also members of the Children’s Tumor Foundation Neurofibromatosis Preclinical Consortium.

Dr. Chris Moertel, Director of the Children's Tumor Foundation Neurofibromatosis Clinic Network Affiliate Clinic at the University of Minnesota, is making progress in what has largely been an elusive area for clinical researchers - the development of vaccines to treat brain tumors. Dr. Moertel pioneered these studies by successfully halting brain tumor growth in a dog which had been injected with cell matter harvested from its own tumor.  He has since advanced the trials into seven patients with malignant glioma who have been treated with vaccine made from their own tumor matter. It is very early days but these studies look promising and will continue.  Vaccines have been challenging to develop but if successful would reduce the need for using chemotherapy drugs.  The target is currently malignant cancer but looking ahead there may be potential to apply a similar approach to neurofibromatosis tumors.  View a short TV interview with Dr. Moertel talking about the work here.

NIH invites proposals for 2012 NIH Director's Pioneer Awards and New Innovator Awards for innovative approaches to major challenges in biomedical or behavioral research. 

• Pioneer Awards:  
  • Up to $2.5 million in direct costs over 5 years
  • Open to scientists at any career stage. 
•  New Innovator Awards: 
  • Up to $1.5 million in direct costs over 5 years
  • For early career stage investigators (ESI), defined as those who have not received an NIH R01 or similar grant and are within 10 years of completing their terminal research degree or medical residency.   

NIH expects to make at least 7 Pioneer Awards and at least 33 New Innovator Awards in summer 2012.  The deadline for submitting Pioneer Award applications is October 7, 2011. See the instructions in the Funding Opportunity Announcement RFA-RM-11-004.  
The deadline for submitting New Innovator Award applications is October 14, 2011. See the instructions in the Funding Opportunity Announcement RFA-RM-11-005.  

The National Institutes of Health (NIH) has a program called the Common Fund that supports exceptionally innovative and potentially high impact programs that are inherently high-risk but have the potential for high-payoff by catalyzing research across all of NIH and in the biomedical research community. These programs are managed by the NIH Office of the Director in partnership with the various NIH Institutes, Centers and Offices. Additional information about the NIH Common Fund can be found at http://commonfund.nih.gov.
New ideas for Common Fund programs are identified annually, and public comment is encouraged. NIH is now asking for YOUR input for 2013 programs.  Which ideas you think have the potential to fundamentally change how we think about, support, or do research in a specific field, or to create a new field all together?
Provide your input today:  http://commonfund.nih.gov/strategicplanning
The feedback period is open until Wednesday, September 14, 2011.