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The Drug Discovery Initiative Awards program is focused on seed funding preclinical drug testing studies on neurofibromatosis in cell or animal models, and is one of the most successful Children’s Tumor Foundation programs to date. Since this program began in 2006, we have funded over 45 DDI Awards focused on preclinical testing of drug therapies for all aspects of NF1, NF2 and schwannomatosis, from learning disabilities to tumor growth to pain. This has been an investment for the Foundation of $1 million, but we have seen our investment leveraged, as awardees have gone on to secure over $5 million in follow-on funding from federal and other sources.

We are delighted to announce the recipients of the Drug Discovery Initiative Awards from our fall 2011 round. Dr. Toshifumi Tomoda of the Beckman Research Institute receives a $15,000 in vitro Award to study autophagy-inducing compounds as candidate therapeutics for NF2. Dr. David Little of the University of Sydney receives a $30,000 in vivo Award to study MEK inhibition as a therapeutic approach in mouse models of NF1 related tibial pseudarthrosis.

We are also pleased to announce that for 2012 we are significantly increasing DDI Award levels! We now offer $25,000 for in vitro DDI Awards, $50,000 for in vivo DDI Awards, and $75,000 for Advanced DDI Awards. There are two DDI Award deadlines in 2012: February 28th and August 31st. No preliminary data is required for DDI Award applications, and cutting-edge ideas are encouraged. If you have any questions about the DDI program, please contact Min Wong at mwong@ctf.org.

The neurofibromatosis clinical team at the Cincinnati Children's Hospital Medical Center is conducting a research survey to find out if people with neurofibromatosis type 1 (NF1) break their bones more often and have different types of broken bones (fractures) than those who do not have NF1. Adults 40-70 years old with NF1 and their spouses and/or siblings who do not have NF1 may be eligible to participate. The information learned from this research study may indirectly benefit other patients with NF1 in the future by providing a better understanding of NF1-associated bone disease.  

This study consists of completing a survey that is estimated to take a total of 20 minutes and contains questions about participants’ fracture history, physical activity, and diet.

For more information on the study, click here.  

                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/

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.