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The final morning of the 2010 NF Conference included some great gems. Two parallel abstract sessions opened the day.  One session focused on NF1 basic science abstracts; presentations included a significant focus on tumor initiation and malignancy and featured STAT3 as a candidate target for MPNST formation (Jianquiang Wu, Cincinnati), and two talks on the sources of cells that initiate tumor foramtion in NF and cause advancement to MPNST (Johanna Buchstaller, Michigan and Faris Farasatti, Kansas).  The other session covered basic and translational NF2 research, notably including well-attended presentations of the Phase II bevacizumab (Avastin) clinical trials from Massachusetts General Hospital (Scott Plotkin) and Phase 0 and Phase II lapatinib clinical trials ongoing at Johns Hopkins University and NYU Langone Medical Center (Matthias Karajannis).  As we reported from Las Vegas, these trials are moving forward and expanding; for Avastin there will be 2 US trials centered at MGH and Johns Hopkins respectively with different entry criteria.  Additional NF2 talks in this sesion included Janet Oblinger (Ohio State University) with an update on NF2 preclinical drug screening studies using OSU-03012 which has shown some promise in animal models (these studies were originally funded by a CTF DDI Award).  
A high-quality session closed out the day with the theme 'across the Ras-MAPK pathway' and touched on some aspects of neurofibromatosis  not already covered in the  Conference. Dr. Jonathan Epstein (U. Pennsylvania) reviewed progress in his research to understand cardiovascular manifestations in NF1, using zebrafish genetic models.  Cardiovascular complications of NF1 are understudied but can be a significant concern; and they have come to the fore in recent years due to our increased understanding of the role of the inflammatory system in NF1. Zebrafish are transparent and allow Dr. Epstein to image vascular flow in living animals.  The fish can also be bred easily with different genetic mutations making them a very useful model to unravel vascular complications. Having generated some fish with significant vascular provblems, Dr. Epstein can use these to test drugs that might correct the vasculature and could be NF1 clinical therapies.  Dr. Dave Stevenson (Utah) gave a fascinating overview of the many bony abnormalities that affect an estimated 38% persons with NF1 and which are also seen in other 'Ras-MAPK' conditions such as Noonan syndrome. Dr. Stevenson is working with a colalborative group planning the first Phase II biologic therapy intervention for NF1 long bone dysplasia to commence later this year.  This is exciting as today, children with long bone dysplasia often face amputation as the best available outcome.  Dr. Eric Legius (Leuven) provided an update on Legius Syndrome. Dr. Legius actually saw the first Legius Syndrome patient in 1980; but it was many years later, in 2001, when the SPRED-1 gene was identified through studies in flies, that he defined the condition at the molecular and genetic level.  Legius Syndrome has the appearance of 'mild' NF1 (cafe-au-lait spots; cognitive issues; mild bony malformations; but nerve tumors and vascular malformations seen only in very rare cases) and is due to mutation of the SPRED-1 gene on Chromosome 15.   142 patients with Legius Syndrome have now been identified worldwide.  This is a very rare condition and includes only around 1-4% of individuals who have had a clinical diagnosis of NF1. As a next step, Dr. Legius proposed the organization of an international clinical an molecular database of Legius Syndrome patients so the conditio can be better understood. 
The 2010 NF Conference ended with its traditional rousing cheer and lots of hope and promise. For me this ws the best NF Conference I have seen to date in terms of the quality of research ongoing and the advances made. Thanks to the 2010 NF Conference Chairs Sue Huson (Manchester) and Filippo Giancotti (Sloan Kettering) for putting on such a great event! Next: we hope for a professional publication of the 2010 NF Conference proceedings  as we did in 2009.   

Yesterday evening’s clinical satellite aboard the ‘Black Eyed Susan’ was a terrific success with the clinicians sharing opinions on difficult clinical cases. Thank you to our host Mr. Leonard Schleider owner of the vessel.  Today’s agenda was packed with an exciting roster of presentations. Today was a long and exciting day! The morning began with a focus on molecular mechanisms of NF1 tumor progression with talks from a series of leading experts. Yuan Zhu (Michigan) Nancy Ratner (Cincinnati) and Wade Clapp (Indiana) all offered their individual perspectives on the molecular progression of plexiform neurofibromas with a focus on the role of the environment, notably the mast cell, and on the cell interactions that drive initiation and growth of these tumors. This is well established as an important trigger of NF1 tumor growth and indeed intervention of c-kit signaling via mast cells is a key target of drug imatinib (Gleevec) currently in Phase II trials for plexiform neurofibromas.   Looking at the overarching message of the talks and following on from yesterday’s NF1 presentations, it is emerging that there are stages in the development of plexiform neurofibromas; some stages may be more critical than others, and may help us understand at what time points in the development of a plexiform tumor, drug intervention may actually be successful. Dr. Clapp described his preclinical drug screening approach, a rapid-fire process testing drugs already known to be safe in humans and already used in other condition. The approach requires a significant response of tumor to drug and has already identified multikinase inhibitors as promising drug candidates. In summing up this session co-chair Luis Parada (Texas) cautioned that there is still more that we don’t know, than that we do know, and that there is much still to be unraveled.

Following a keynote on the mTOR drug target by David Sabatini (MIT), was a session on NF2 mouse and fly models. Marco Giovannini (House Ear Institute) shared updates on mouse NF2 tumor model development and drug screening studies through the CTF NF Preclinical Consortium. Novartis drug BEZ-235, a PI3K/mTOR inhibitor, yielded some modest tumor shrinkage data in NF2 tumor xenograft models. Diving deeper into NF2 signaling, Helen McNeill (Toronto) and Duojia Pan (John Hopkins) reviewed recent developments in understanding regulation of the Hippo kinase pathway (the merlin signaling pathway in flies). Dr. McNeill discussed Fat cadherins, a newly identified signal that contributes to the Hippo pathway, can directly regulate Hippo pathway downstream element Yorkie and may also have a role in human merlin signaling. Dr. Pan, who actually first identified Hippo in flies, reviewed function of Kibra, a new element of the Hippo signaling pathway, and which has a human equivalent. He reviewed potential redundancy/duplication of function among elements of the Hippo signaling pathway. This is important information to understand normal cell signaling and points at which this goes awry as it does in tumor growth. 

The NF2 theme continued in the afternoon with an abstract session on NF2 basic science (the parallel session was focused on NF1 clinical abstracts but I can only be in one place at a time!). CTF funded research was well represented in the NF2 session where speakers included CTF Young Investigator Awardees Wei Li (Memorial Sloan Kettering Cancer Center) who showed his groups data that merlin acts via the nucleus, and Timmy Mani (Cincinnati) focused on the FERM domain of merlin protein and the protein’s membrane function. Together these two talks provoked a lot of discussion and debate; the question of exactly how merlin protein functions – perhaps via multiple mechanisms at membrane and in nucleus? -  will no doubt continue to be explored. Recent CTF Drug Discovery Initiative Award recipient Marianne James (Harvard Medical School) examining modulation of the TORC1 and TORC2 signals in NF2 schwannoma and meningioma   cells.  Fabrice Chareyre (House Ear Institute) reviewed CTF Drug Discovery Initiative Award funded research testing pan-erbB inhibitor Avila Therapeutics’ CNX-222 which looks highly promising in inhibiting schwannoma cell growth and has been taken forward by the CTF NF Preclinical Consortium.

Jeremy Vitte (House Ear Institute) described CTF-Schwannomatosis Award-supported generation of a mouse knockout of Snf5/INI1/SmarcB1 (candidate schwannomatosis gene) in nerve ensheathing cells (those expressing P0 protein). These mice develop a variety of cranial and optic nerve tumors of rhabdoid appearance; some of these tumors appear malignant but the mechanism of this is not yet clear. 

The day closed out with a timely panel discussion on an emerging topic of significant interest – modifier genes - chaired by Meena Upadhyaya (Cardiff) and Andre Bernards (Harvard Medical School). To paraphrase panelist Karlyne Reilly, ‘it is exciting to see this session in place as we are finally making progress in this area’. Dr. Reilly herself presented some new data from genetic mouse models in which the resulting predominant tumor type – MPNST or astrocytoma – is determined by whether a mouse inherits NF1 from its father or mother, respectively; this appears to be due to differential action of a modifier gene. As yet there is not sufficient data to know if this is paralleled in humans but studies are underway.

Bruce Korf (Alabama) put forward the case for ‘quantitative phenotyping’ that actually sets up a measurement scale for various NF1 clinical measures – from something as simple as counting café-au-lait spots to tumor volumetrics. Betty Schorry (Cincinnati) reviewed a number of cases of monozygotic twins (deriving from the same fertilized egg therefore in theory having the same DNA) but who have very different NF1 manifestations. Genetic analyses of some of these pairs of twins are underway to look for genetic modifications associated with the NF1 that might be dictating the manifestations that develop.

This morning began bright and early with a committee meeting of the Children’s Foundation Clinical Care Advisory Board which, amongst other activities, oversees our NF Clinic Network and is this summer charged to take forward our patient Registry and BioBank for an anticipated launch in late 2010.   At the Conference itself, Jeffrey Settleman (Harvard Medical School) gave a keynote talk on tumor resistance mechanisms, and proposed his model that tumors can evolve and a sub population of cancer cells may become resistant to drug therapy and represent those cells that will drive future tumor recurrence.  Following this was an exciting session focused on understanding and targeting NF1 signaling.  Karen Cichowski (Harvard Medical School) is testing candidate drugs for malignant peripheral nerve sheath tumor (MPNSTs) in genetic mouse models that develop this tumor.  She presented some exciting data illustrating that a combination drug therapy of Rapamycin plus agents that cause endoplasmic reticulum stress will in combination induce tumor cells to undergo autophagy (‘self –eating’). As both drugs have already been used in (non-NF) patients, they may be worth pursuing as MPNST therapies in humans.  Kevin Shannon (UCSF) reviewed his recent studies using leukemia ‘factory mouse’ models for rapid screening of drugs and drug combinations.  Dr. Shannon is using this model to test drugs through the CTF NF Preclinical Consortium including inhibitors of PI3K, mTOR and MEK.  Luis Parada rounded out this session with a presentation of his hypothesis from genetic mouse models that plexiform neurofibromas become ‘defined’ early in life during a particular period of development, while Schwann cells are precursors or immature.  This intriguing but very preliminary and early stage theory points toward the suggestion that in an individual with NF1, future plexiform neurofibromas become pre-determined at the cellular level early in life. 

Today’s agenda began and ended with a focus on NF2 molecular signaling and the challenges that lie ahead to fully understand it. The morning opened with presentations from Andi McClatchey (Harvard Medical School), Helen Morrison (Institute for Aging) and Filippo Giancotti on the signaling mechanisms of merlin in the cell cytoplasm and nucleus (an important topic that was covered by the same individuals at the Las Vegas meeting last month). However the NF2 highlight of the day was a late-afternoon panel discussion ‘New Frontiers in NF2 Research’ chaired by Dr. Jon Chernoff (Fox Chase Cancer Center) and featuring Dr. McClatchey, Giovanni and Giancotti as well as Dr. Gareth Evans (Manchester), Dr. Vijaya Ramesh (Harvard) and Dr. Oliver Hanemann (Plymouth). Panel members each presented a slide on something they felt was important for the NF2 community at large to pay attention to in order to advance our understanding of NF2 biology and ultimately find effective drug therapies. These included the need to better understand merlin protein biochemistry and its full variety of binding interactions whether these are in the nucleus or in the cytoplasm; a call to spend more time testing drugs on human tumor cells; the need to fully evaluate all of the mutations in the NF2 gene and their consequences.

This evening we are headed out for a harbor cruise on the paddlewheel boat ‘Black Eyed Susan’ for an evening of ‘diagnostic dilemmas’ where clinicians will share with each other difficult cases for discussion and brainstorming. A report to follow tomorrow! 

The 2010 NF conference kicked off with a Keynote Presentation from Dr. Susan Lindquist on Heat Shock Factor proteins as candidate signaling targets for NF1 therapeutic intervention, then transitioned to an afternoon of updates on ongoing NF clinical trials chaired by Dr. Kathryn North (University of Sydney) and Dr. Roger Packer (Children’s National Medical Center). Keeping in the 2010 NF Conference theme of ‘Back to the Future’, Dr. Brigitte Widemann (National Cancer Institute) opened with a review of 'lessons learned' from NF1 clinical trials and the challenges ahead. Dr. Widemann is widely recognized as a world expert on NF1 tumor trials. Through planning and running a number of NF1 trials to date, she noted that NF1 clinicians now have a solid understanding of how to conduct Phase I (safety) trials and are advancing into therapeutic (Phase II) trials.  Front and center in plexiform neurofibroma trials is to monitor tumor volume and ‘burden’; however getting industry to understand this can be challenging, as testing drugs in these tumors will mean long-term trials, something industry may not be familiar with (being more used to short-term cancer trials). Three dimensional monitoring of NF tumors is critical to make trials as rapid and accurate as possible. Other issues addressed by Dr. Widemann included the importance of the clinical community to focus on how to make clinical trials sufficiently safe so as to include the very youngest patients, those under three years old who may benefit significantly from inclusion in trials. Specific ongoing NF1 trials presented included Dr. Dusica Babovic (Mayo Clinic)  - Phase II of cediranib;  Dr. Michael Fisher (Children’s Hospital of Philadelphia) - Phase II of sirolimus (through the CDMRP consortium);  and Dr. Aerang Kim (NCI) - pediatric Phase I of sorafenib – all trials in testing in NF1 plexiform neurofibromas. These are all ongoing with safety data and efficacy being assessed; though as yet no drug looks especially promising the investigators are learning how to do NF1 trials as safely and efficiently as possible. Dr. Maria Acosta (Children’s National Medical Center) presented a promising update on the Phase II trial of Lovastatin for NF1 learning disabilities, a drug that seems to be both safe and at least to some extent effective.   Dr. Jay Gibbs (AstraZeneca) reviewed some of the drug pathways that may be of interest in NF therapy including the JAK/STAT pathway which is of increasing interest, and also gave an overview of the drug pipeline and activities of the CTF NF Preclinical Consortium which include currently testing of drugs targeted at PI3K/mTOR, erbB receptors and additional targets in partnership with companies including Novartis, Genentech, Avila Therapeutics.  Dr. Scott Plotkin (Harvard Medical School) and Dr. Ambereen Kurwa (NCI) presented data on the use of imaging for three dimensional tumor volume assessment and whole body tumor burden assessment and in Dr. Kurwa’s study even how to use this imaging to sub-classify plexiform neurofibromas. As noted by Dr. Widemann earlier in the afternoon, these technologies are emerging as an invaluable part of NF clinical care and trials. The first patient representative to speak at the 2010 NF Conference, Tracy Galloway shared her family’s experience of her teenage daughter’s diagnosis with NF2, and how she has responded with such determination to accelerate research in any way she can. Communication and sharing between researchers, she noted, is absolutely critical. Dr. Brad Welling (Ohio State University) provided a terrific overview for the group of the recent NF2 meetings in Las Vegas (which we covered extensively in the May blogs). Further NF2 trial reports will come later in the NF Conference, so stay tuned!

This blog entry was written by Dr. Kim Hunter-Schaedle and posted by Garrett Gleeson.

The upcoming 2010 NF Conference features a packed program of scientific and clinical presentations, but perhaps the most anticipated will be the opening session, chaired by Dr. Roger Packer (Children’s National Medical Center) and Dr. Kathryn North (University of Sydney). The session will feature updates on a number of major ongoing neurofibromatosis clinical trials (though such is their number that updates on additional trials will be reported later in the Conference). The NF community now has a number of NF1 clinical trials underway including trials for plexiform neurofibromas learning disabilities and next, optic pathway glioma, and these continue to expand; Dr. Brigitte Widemann (National Cancer Institute) will review ‘lessons learned’ in these past few years of implementing NF1 trials. NF2 clinical trials have also commenced with an initial focus on the key tumor, vestibular schwannoma; these will be presented, and Dr. Bradley Welling (Ohio State University) will give a reprise of the Foundation’s recent Las Vegas ‘State of the Trial’ Workshop including plans to update the consensus guidelines for how NF2 trials should be conducted.    Dr. Jay Gibbs (AstraZeneca, and also Chair of the CTF NF Preclinical Consortium Oversight Committee) will offer a perspective on potential next-in-line drug candidates for NF trials.

Also well represented on the 2010 agenda are advances in the resources that clinicians need to give patients the best possible clinical care.  Prior to the NF Conference, CTF staff will host a networking forum for NF clinic coordinators – often the first and most prominent point of contacts for patients visiting and NF clinic. And three-dimensional imaging of tumors is gradually becoming integrated into clinical care as well as clinical trials; advances in this area will be presented at the NF Conference. And an entire evening of the Conference hosted by Dr. Ros Ferner (Guy’s and St. Thomas’ NHS Trust, London) and Dr. Bob Listernick (Northwestern University)  will be dedicated to a ‘clinical care satellite’ where physicians will share wisdom on clinical management approaches and on challenging cases of NF that they have managed.