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The NY Times published a three part series titled "Target Cancer" last week that is very informative.  While the focus is on melanoma, many of the issues the patients, researchers and clinicians faced during the trial are universal and have specific relevance to NF research.  

Story link:   http://nyti.ms/aV4iov

 

An intriguing article earlier this week in the New York Times* described a novel use of the drug bevacizumab (Avastin) for treatment of glioblastoma, one of the most deadly brain tumors. (Bevacizumab, as reported earlier this year, has shown promise in early stage trials to target NF2 vestibular schwannomas).  The New York Times reports that Dr. Howard Riina and Dr. John Boockvar at New York Presbyterian/Weill Cornell have ‘sprayed’ bevacizumab directly into the brain through a microcatheter in order to directly target the tumor site. The patient reported in the news article was the second person to undergo this procedure. The study is still in Phase I (safety). Five patients had been treated as of mid-November.

The study addresses an age old question – if you give a patient a pill or injection, how do you know the drug is reaching its target - - especially if the drug dose has to be limited to prevent potentially toxic side effects?  Brain tumors are especially challenging as drugs must cross the challenging blood brain barrier.  In Dr. Rina’s study, bevacizumab is delivered in conjunction with the drug mannitol which acts to temporarily ‘open up’ the blood brain barrier and facilitate the influx of drug to the tumor region. The microcatheters employed are fine, highly flexible tubes; these were originally developed to deliver clot-dissolving drugs to the brain to treat strokes.

While this study is assessing application of this technique to glioblastoma, the technique might also be useful for other tumors or neurological disorders like multiple sclerosis or Parkinson’s disease.

 

* Breaching a Barrier to Fight Brain Cancer. New York Times, November 17. 

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

This week an article was published on consensus recommendations on planning and conducting NF2 clinical trials; the result of a Children’s Tumor Foundation-driven initiative to accelerate progress in the identification of effective drug therapies for NF2. The genesis of this paper was a lunchtime brainstorming session at the 2007 NF Conference followed by a Foundation-convened two-day landmark NF2 Workshop held in New York in October 2007. The paper was published in the August 15th issue of Clinical Cancer Research (http://bit.ly/Cwox9) and is authored by an array of leading international NF2 experts headed by Dr. Marco Giovannini (House Ear Institute) and Dr. Gareth Evans (University of Manchester).

Some remarkable progress has already resulted from this initiative with three of the candidate NF2 drugs prioritized in the paper now in clinical testing. Bevacizumab NF2 Phase II pilot trial results were reported by Scott Plotkin et al (MGH) in the New England Journal of Medicine this summer.  Lapatinib is being tested in a Children’s Tumor Foundation-funded Phase Zero clinical trial (headed by Jaishri Blakeley (Johns Hopkins) and Matthias Karajannis (NYU)). Finally Phase II NF2 trials are now underway, also under direction of Dr. Plotkin at MGH, to test the PTC Therapeutics drug PTC299.

A post-doctoral position is available at the University of Central Florida in Orlando to study mechanisms of NF2 tumorigenesis. Studies will employ immunological techniques and basic cell biology approaches including live imaging of normal and tumor cells stimulated with growth factors. Can start early Fall 2009, multiple years of funding available; highly competitive salary commensurate with experience. Candidates should have received a PhD in cellular or molecular biology or neuroscience. Send resume, contact information for references and a letter describing background and career goals to: Dr. Cristina Fernandez-Valle at cfernand@mail.ucf.edu.

NF2 is prominently in the news this week. Another July publication** tackles the controversial topic of whether or not stereotactic radiotherapy (SRT) can be safely used for the treatment of vestibular schwannomas or other tumors seen in NF2. The potential benefit of SRT is that it is non-invasive and can be used to treat multiple tumors in a single session. The potential concern of SRT is that it might trigger otherwise largely benign NF2 tumors into malignant cancer. This issue is hotly debated by clinicians on either side of the argument, and reports from case studies and individual clinics have supported both perspectives. Some clarity on this matter may now be shed by this paper which suggests risk of SRT-induced malignancy in NF2 might predominantly be in those individuals with a germline NF2 gene mutation (NF2 mutation can be detected in the blood as well as tumors), rather than those persons with a sporadic NF2 gene mutation (mutation can be detected in tumor but not in blood). Though early days, hopefully this finding could help unravel previous mixed findings and pave the way to a true clinical community consensus on using SRT in NF2. ** Carlson, Babovic-Vuskanovic, Messiaen, Scheithauer, Neff and Link (2009) Radiation induced rhabdomysosarcoma of the brainstem in patient with neurofibromatosis Type 2. Journal of Neurosurgery July 3.

Today sees the landmark report that blocking blood vessels in NF2 vestibular schwannomas with the drug bevacizumab (Avastin) reduced tumor growth, and in some patients even improved hearing. The paper from Dr. Scott Plotkin and colleagues at Massachusetts General Hospital is truly groundbreaking in reporting evidence of the first potentially effective drug therapy for the treatment of NF2 tumors.

The Children’s Tumor Foundation helped support this research, and Dr. Scott Plotkin and collaborator Dr. Emmanuelle Di Tomaso, reported early findings in these studies at the Children’s Tumor Foundation’s 2008 NF Conference. The full study is published in the July 23 issue of the NEJM. The story has been covered by multiple news outlets.

The National Institute on Deafness and Other Communication Disorders (NIDCD) of the National Institutes of Health (NIH) has announced a new research funding opportunity to use proteomics to study inner ear development and diseases. This approach will develop a catalog of protein content in the inner ear and essentially offer researchers another window into understanding both normal tissue development as well as what happens in disorders like NF2. The ultimate goal of course is to use this information to understand how disorders like NF2 that affect the inner ear can be treated. More information:  http://grants.nih.gov/grants/guide/pa-files/PA-09-228.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.