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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 following was written by CTF Chief Scientific Officer Dr. Kim Hunter-Schaedle:

Earlier this week the Children’s Tumor Foundation hosted a workshop/think tank convening 25 international researchers and clinicians to review recent progress in schwannomatosis research and clinical management, and set priorities to advance future progress. The meeting was planned and chaired by Dr. Scott Plotkin (Harvard/MGH), Dr. Marco Giovannini (House Research Institute) and Dr. Gareth Evans (University of Manchester) and included updates on genetics, cell biology, surgical intervention and the potential of advancing to clinical drug therapies for schwannomatosis, the rarest form of neurofibromatosis affecting an estimated 1:40,000 persons.

In part through CTF funded projects, significant progress has been made since the gene SMARCB1 (also known as INI-1) was in 2007 identified as a causal factor in inherited schwannomatosis.  Researchers have further unraveled the genetics of schwannomatosis, and learned that while SMARCB1 is important in inherited cases of schwannomatosis, this disease onset also involves the NF2 gene; and that in spontaneous (non-inherited) cases, SMARCB1 is not necessarily involved but that there are as yet unidentified genes involved.   The first mouse models of schwannomatosis tumors and pain are now developed and being used to study tumor and pain biology and test drug therapies.  And an international schwannomatosis database is established to collect information on schwannomatosis patients worldwide and facilitate future research projects and clinical trials.

At the workshop a series of priorities for the future was identified. There is a need to identify the additional genes and genetic modifiers that may be involved in interacting with the SMARCB1 or NF2 genes to lead to schwannomatosis. There is a need to develop more refined mouse models that represent schwannomatosis seen in humans as closely as possible, so that these can be used to study biology and tumor growth/pain and to test candidate drug treatments.  The biology and mechanisms of pain - which is such a central and poorly understood element of schwannomatosis - need to be unraveled and understood.  In terms of candidate drug therapies, it is rational to look at those drugs that are showing promise in mouse models of NF2 tumors, and see if they have impact on the tumors in mouse models of schwannomatosis.

Very importantly, now that we have a patient database, there is a need to plan clinical research studies to better understand schwannomatosis, such as understanding how individual patients condition has progressed following surgery, especially multiple surgeries; identifying whether there are blood-based or other biomarkers of schwannomatosis; and developing a pain survey for patients to better define the type and range of pain seen in schwannomatosis.; and looking ahead, prospective studies monitoring patients from time of diagnosis ongoing such as by whole body MRI. It is considered to be premature to consider clinical trials for schwannomatosis as we don’t have sufficient knowledge to do this; but that for patients in states of extreme crisis, there is the potential to begin testing drugs such as bevacizumab (Avastin) that have shown promise in NF2 patients.

Finally the clinical diagnostic guidelines for schwannomatosis were published in 2005 and the group reviewed these and made some recommendations to update these based on new genetics and clinical knowledge.

As a follow up to this workshop CTF will be spearheading the publication of a meeting report summarizing the latest update and recommendations for schwannomatosis. Also – in the next month – CTF will be releasing a Request for Applications to fund further schwannomatosis research.  After this great meeting we look forward to seeing further research progress.

On June 27th-28th the Children's Tumor Foundation is convening a Schwannomatosis Workshop (think tank) in Los Angeles. International expert researchers and clinicians will review the most recent findings in schwannomatosis research and clinical care, share progress and chart the future path to improving care and finding effective treatments for schwannomatosis.  I look forward to reporting the outcome of  the next 2 days of meetings. Below is a preview to set the stage.

I'll be staying in LA for the remainder of the week to attend the Acoustic Neuroma 2011 Meeting which includes a lot of NF2-relevant presentations, and will be reporting on that later in the week too. 
Schwannomatosis is the most rare form of neurofibromatosis affecting an estimated 1:40,000 persons. It causes the growth of multiple peripheral nerve tunors called schwannomas, and in addition it causes chronic, severe and unmanageable pain. There are no treatments for this. For a long time schwannomatosis was not well understood and in fact the first guidelines for its clinical diagnosis were not published until 2005.  A breakthrough came in 2007 with the publication of the first candidate schwannomatosis gene, INI-1/SmarcB1/Snf5. This gene has emerged to be a key player in schwannomatosis but interestingly there may also be involvement of the NF2 gene in the onset and progression of schwannomatosis. Schwannomatosis research faces added challenges as there are so few patients, so to accelerate progress CTF has brought this community of researchers and clinicians together since 2007 for a series of think tanks and they have shared and collaborated extensively with each other. CTF has been a major force in advancing schwannomatosis research in the past 4 years since the candidate gene was identified. In addition to hosting the think tanks, CTF has invested more than $700,000 in schwannomatosis research in this period. Projects we have funded include the creation of a schwannomatosis patient database now up and running;  the creation of the first 2 mouse models of schwannomatosis, both of which are now  being utilized for preclinical drug testing to reduce tumor growth and pain; and further genetics studies. Look for updates from the schwannomatosis think tank in the next day or so!

Today we feature a Guest Blog featuring a report from the 2011 NF Conference from Dr. Fawn Leigh, a pediatric neurologist at the Massachusetts General and Harvard Medical School. Dr. Leigh presented the following project at the Conference, and is looking for further research collaborators, as well as any persons with NF1 who would be willing to participate and donate tissue, whether or not they are currently under care of an NF clinic.

At the 2011 NF Conference in Jackson Hole I gave a talk highlighting my findings from a pilot study to identify modifier genes that may inform the identification of potential drug targets and treatments in NF1. The study focused on a search for modifier genes of cutaneous (dermal) neurofibroma tumor burden in NF1. This was done through a genome-wide association study (GWAS).  300 NF1 subjects identified as having either the largest or least 15% of cutaneous tumor burden were genotyped using the Affymetrix GeneChip 6.0 platform. This provided 909, 622 single nucleotide polymorphism (SNP) markers and >946,000 probes for copy number variants (CNV).  The analysis revealed potential hits (P values of 10-4 to 10-7) with multiple SNPs at each of several regions of the genome. Each of these segments constitutes a candidate region that merits genotyping in an additional cohort of extreme subjects to either confirm or refute its modifier status, which is ongoing.  The CNV analysis is in progress. The current GWAS study is a collaboration of six centers across the world.  Five new centers recently joined this project. 

For researcher or patients seeking additional information about participating in this study, please contact:  Stephen Ranney (Clinical Research Coordinator)

Email: administrator@cnfad.org               Office: 617-724-2365

Interesting stories this week on  full genome sequencing done on two individuals.   In Japan, a team from the RIKEN center used massively parallel sequencing technology to  analyze the complete genome of a Japanese individual, the first time this has ever been done.  While the work will be published in Nature Genetics, early story found at FierceBiotech.