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.
