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‘Tall oaks from little acorns grow’ is an adage that is appropriate for the Children’s Tumor Foundation Drug Discovery Initiative. This program offers modest grants to investigators to test candidate NF drug treatments. To date the program has funded over 30 projects and the first 20 – a cost to CTF of $500,000 – have already garnered $3.5 million in follow-on funds from NIH, DOD and other sources, as well as establishing multiple relationships with the biotech and pharma sector and publishing results of the research.

One such project published this month* describes the development and testing of Schweinfurthin A, a drug originally purified from a natural plant-derived product, as a treatment for NF1-related malignancies glioblastoma and astrocytoma.  CTF has partially funded this research through two DDI Awards to Dr. David Wiemer (University of Iowa) to optimize Schweinfurthin’s chemical function, and the drug was subsequently tested on human NF1 tumor-derived cells models in the laboratory of Dr. Karlyne Reilly at the National Cancer Institute.  The drug halts the growth of human tumor cells but not healthy cells derived from mice. The drug appears to act via blocking signaling target Rho. These findings suggest Schweinfurthin could have a tumor-specific mode of action- an exciting possibility for future development of drugs effective against NF1 malignancies.  

* Turbyville et al. (2010. Schweinfurthin A Selectively Inhibits Proliferation and Rho Signaling in Glioma and Neurofibromatosis Type 1 Tumor Cells in a NF1-GRD–Dependent Manner.  Mol Cancer Ther; 9(5); 1234–43.

After two very exciting but very long days of 'NF2: State of the Art', CTF kept about 20 scientists and clinicans on for a small workshop: 'NF2: State of the Trial'. The background to this  is that in 2007, CTF convened an expert NF2 group to figure out how we could accelerate NF2 clinical trials (at that time, not much was going on, certainly less than today). The outcome recommendations from this meeting - detailing how NF2 trials could be effectively done - were published in 2009 but were acted on much sooner by the docs, with the inception of clinical trials of bevacizumab (Avastin) Phase II, PTC 299 Phase II, and lapatinib Phase Zero as well as significant advancements in preclinical drug testing. Therefore we felt it to be time to reconvene the experts to ask are we doing as much as we can? What recommendations if any need to be updated? And, what resources are needed from CTF and other agencies (DOD, NIH) to support this? 
The outcome recommendations from the workshop are still to be distilled but in brief the group, under the auspices of CTF, is going to be publishing an UPDATE to the clinical trial recommendations just published last year - such has been the pace of progress! Looking ahead CTF will also be driving much more communication and collaboration between the 'mouse guys' and the 'clinical guys' - cross talk that will be essential to keep drilling and find the next promising drugs. Meningioma trials were discussed as a future focus in addition to further vestibular schwannoma focused trials. The NF2 clinicians are commited to commencing all-important discussions with the FDA, important to help this agency be familiar with NF2 in asvance of submitting drug applications. And importantly the group assembled has pledged to meet again one year from now and annually thereafter.
It has been a terrific few days of NF2 meetings and everyone left today feeling truly inspired about the future of NF2 trials. Look for a full report on the meeting soon at www.ctf.org!     

 Note:  apologies for not posting these Day 2 blogs earlier. Meetings were back to back today! An indicator of the huge amount of information exchange.

This afternoon focused on ‘Future Frontiers of NF2 Management’. The first three presentations focused on an NF2 and schwannomatosis genetics update (Ludwine Messiaen), an overview of England’s new NF2 national clinical management system (Sue Huson) and utility of three-dimensional imaging in NF2 management (Gordon Harris). Moving on to candidate therapeutics,  I gave a presentation on behalf of CTF offering some thoughts on issues the NF2 community should now be focused on as trials advance, including engaging industry, working with the FDA, and building links between preclinical researchers and clinical trialists. Marco Giovannini then provided a summary of his ongoing NF2 preclinical drug screening in the NF Preclinical Consortium and drug targets of interest including erbB, PI3 kinase and Akt.

Harry Miao of PTC Therapeutics provided an overview of the ongoing Phase II clinical trial of PTC-299 in vestibular schwannoma.  This trial is underway and has some positive but very preliminary indications of tumor shrinkage (notably vascular shrinkage). Scott Plotkin reviewed the status of the bevacizumab (Avastin) trial. This has doubled from the original 10 patients published last summer, and results continue to look promising with tumor shrinkage and some regained hearing, though responding tumors do re-grow when drug is stopped. In an exciting development, looking ahead, later in 2010 a second trial is set to commence in to give bevacizumab to children with NF2 who are 12 years and older.  

'NF2: State of the Art' closed with a terrific sense of promise and a commitment from the organizers to convene again in 2011. This evening we convened a smaller group for 'NF2: State of the Trial' to continue through tomorrow. This expert group will provide recommendations for programs to further accelerate NF2 trials. Higlights from this meeting will follow in a blog in a few days!  

The majority of this morning’s presentations focused on auditory rehabilitation using devices including the auditory brainstem implant (ABI), the more recently developed penetrating ABI, and the cochlear implant. The ABI was pioneered at the House Ear Institute, and Dr. William Hitselberger from that institution was honored with a Lifetime Achievement Award Monday evening to recognize a career that included his pioneering role in ABI development.   Use of ABI has now expanded around the world; overall, ABI implantation is deemed a safe procedure, though interestingly different clinics report not only different approaches to implantation but also different success rates in restoration of hearing function. Particular success in hearing restoration in adults has been accomplished by Dr. Vittorio Colletti in Europe, while Dr. Liliana Colletti reported successful implantation of ABIs into young children in Italy.  Dr. Pamela Roehm from NYU Langone reviewed data from the literature and from her own center regards experience with cochlear implants in NF2 patients. Observations included: implantation of cochlear implant at time of tumor removal appears to be a successful approach, though implanting a cochlear implant when hearing is still functional in contralateral ear may not yield the best long term results.  Group discussions raised the possible value of developing a combined cochlear implant – auditory brainstem implant device. 

The morning was rounded out by a controversial topic, use of radiosurgery for the treatment of schwannoma. Dr. John Adler (Stanford University) reported from the perspective that radiosurgery can be useful in treatment of NF2 schwannomas though not always with results as successful as sporadic schwannomas. He proposed that what is needed is an NF2 database to include outcomes of borth microsurgery and radiotherapy to provide a fair comparison.  Simon Lloyd, a late addition to the agenda, shared analysis of a small database of this nature from Manchester, which in a preliminary analysis suggested radiosurgery is overall less effective in controlling tumor growth and does carry risks including potential increased hearing loss and tumor regrowth.  

After a packed morning and a very late lunch, this afternoon began with one of the most fascinating sessions of the conference, a presentation of individual challenging NF2 cases, and an expert panel discussion on how those patients should be managed. Debate developed around meningioma management, whether to intervene by removing a spinal tumor not currently presenting problems but with the potential to do so, and other topics. Interestingly with the emergence of bevacizumab as the first potentially promising drug therapy for NF2 (more on this tomorrow), discussions for the neurosurgeons are expanding beyond, ‘should we operate or watch and wait?’ to include ‘ would this patient be appropriate for the drug bevacizumab?’ It is exciting to hear surgeons thinking in this way, and as more candidate NF2 drugs come on line, potential alternatives to surgery will continue to expand. 

The afternoon closed out with a presentation from Rachael Hornigold describing a new NF2 Severity Score being developed in the United Kingdom. The Score takes into consideration both clinician and patient measures; currently 31 questions, the Score aims to get down to just 10 questions making it easy to use by any clinic. Interestingly when interviewed, NF2 patients said the two factors impacting most on their lives were facial paralysis and balance, features they felt set them apart from other people.   

 More to follow! Follow us on Twitter for 'live' meeting updates!

‘NF2: State of the Art’ got off to an exciting start this morning. Gareth Evans opened the day with a talk on NF2 genetics, and speculated that though the generation of merlin protein from the NF2 gene is truncated when there is a nonsense mutation, nevertheless some protein must be made that is able to bind to ‘healthy’ NF2 protein, resulting in tumor growth.  A trio of talks from Andi McClatchey, Helen Morrison and Filippo Giancotti focused on the cellular and molecular basis of NF2. These reviewed mechanisms of cell growth regulation by different functional domains and forms of merlin protein at the cell membrane and also in the nucleus, opening up a diverse array of candidate drug targets for NF2 drug therapies.   In an intriguing presentation, Anat Stemmer-Rachamimov reported data from an examination of tumorlets taken from NF2 patients. Tumorlets are tiny tumors embedded in the nerve and often identified only at time of autopsy, but are believed to be the predecessor from which full blown NF2 vestibular schwannomas develop.  A comparison of tumorlets and vestibular schwannomas from NF2 patients and seen quite a difference in genes expressed between the two tumor types. This may help unravel and separate out the signals that trigger the initiation, and then the advancement of growth, of NF2 tumors.

Switching late morning to NF2 tumor management presentations, Bill Slattery and Michel Kalamarides presented natural history studies from the United States and France, respectively. Natural history studies provide an opportunity to follow the natural progression of NF2 tumor growth etc. so that appropriate clinical management strategies can be developed.  There were a number of common features, notably the left and right vestibular schwannoma in a person will usually have independent growth rates. There was discussion about spinal tumors and whether these are likely to grow and require treatment. A percentage of patients will have spinal tumors requiring surgery often because of cord compression. Certain spinal tumors such as ependymomas may be largely inactive but potentially could be a concern in older adults.  Dr. Karajannis and John Golfinos focused on meningiomas in NF2 patients. These are likely to be more problematic than sporadic meningiomas, should be very closely monitored, and when operated on the whole brain picture needs to be understood to consider which meningioma areas are likely to require surgery next.

More to follow – please follow us on Twitter for ‘real time’ updates from the meeting!

Las Vegas is a beacon of hopes and dreams in the middle of a desert - perhaps an analogy for the enduring work of the NF2 scientific and clinical communities in seeking treatments and better management strategies for a confounding condition. The good news is, the bets that are being placed on candidate approaches for NF2 treatment are becoming progresively more focussed and more informed as we understand more about the molecular biology and natural history of NF2. Yesterday evening as meeting delegates filtered in to register, I heard a few snapshots about clinical trial updates and new information on implantable devices that confirmed this should make this an exciting and broad reaching meeting. Ironically Bally's, the NF2 meeting location, is right next door to the Paris casino, and it was in Paris, France that the NF2 community met for this same meeting series in 2006.  And just as that Paris meeting spurred a variety of NF2 collaborations and advancements, we hope that the adage 'what happens in Vegas stays in Vegas' will not apply to the new ideas and concepts that are bound emerge over the next few days.
Stay tuned!   

Next week Foundation staff will be at the House Ear Institute-convened meeting 'NF2: State of the Art' in Las Vegas. Top NF2 clinicans and researchers from around the world will be in attendance and we will bringing you updates daily on presentations and breaking news. The agenda topics will range from NF2 clinical management to use of auditory rehabilitation devices to NF2 drugs in preclinical testing development and of course the ongoing NF2 clinical trials. Immediately following (and partly overlapping with) 'NF2:State of the Art' the Foundation is hosting a smaller meeting 'NF2: State of the Trial'. This is a follow up to our landmark 2007 meeting that helped establish community-wide parameters forNF2 trials, charged up the field of NF2 clinical trials and led to the foundation  funding of the ongoing Johns Hopkins-led Phase Zero trial of Lapatinib. A couple of years on, 'NF2: State of the Trial' will ask what has been accomplished and what more the Foundation and other agencies can do now to further advance NF2 clinical trials. Be sure to sign up for what we hope will be an informative blog series, and leave a comment here if you have any feedback or questions! 

Survival rates following childhood cancer are now over 80%, but closer analysis shows the majority of success in the past 10 years has been in improved treatment of blood disorders such as leukemias. In contrast, solid tumors have remained the most challenging, and survival rates have not changed in the past 10-20 years. Though only a small proportion of NF-related tumors will be cancer (malignancy), it is important for us to see what we can learn from this finding, to ensure we advance as fast as possible with treatments for the benign tumors that can affect kids with NF1. 

So what is the reason? Thursday’s Wall Street Journal Health Blog discussed this with Eugenie Kleinerman, professor and head of pediatrics at M.D. Anderson Cancer Center. The reasons are those that we face with trying to find treatments for NF tumors: need to understand biology and test the right drug candidates; the small numbers of patients for each type of tumor makes it hard to do a proper study coordination with other centers is key; and the difficulties that can be faced in trying to bring an adult-approved drug to children (bevacizumab/Avastin for example was controversial for kids in case it stunted growth, leading to a 10-year delay in this drug being used in children). 

So what is most needed? Not surprisingly Dr. Kleinerman highlights the need for funding into childhood cancer studies and trials. He cites an example that from an NCI annual budget of $4.8 billion, only $173 million went to pediatric cancer. Hopefully this will change as the biology is unraveled, drugs are selected, and more pediatrics studies are designed and submitted to NIH for funding.

Since its introduction, the use of the auditory brainstem implant (ABI) for hearing restoration in NF2 has grown in popularity.  Over the last 10 years, ABI use has also been extended to adults and children without tumor conditions but with those with cochlear or cochlear nerve malfunctions but did not benefit from a cochlear implant. However currently, ABI transplants can only be done by a very limited number of medical centers, which restrict access to ABIs for many individuals who could benefit, including those with NF2.   ABIs have been shown to be effective in individual cases, but can their use be expanded to more medical centers to benefit more patients? A new report* does a retrospective analysis of 114 individual ABI surgeries (83 adults and 31 children) performed between 1997 and 2008. 36 cases were persons with NF2, and 78 persons had non-tumor related cochlear and cochlear nerve disorders.

Overall ABI surgery has had a very low rate of major complications, particularly in non-NF2 patients. Minor complications were easily controlled and resolved in all cases.  The complication rates in the non-tumor cases were comparable to those of cochlear implant surgery in both adults and children. Overall this analysis is favorable of ABI use, a safe procedure when performed by an experienced surgical and rehabilitation team. Looking ahead it is hoped the benefits of the ABI can be extended to a larger population of hearing-impaired patients.