Phase II study of mTORC1 inhibition by everolimus in neurofibromatosis type 2 patients with growing vestibular schwannomas

Neurofibromatosis type 2 (NF2) is a genetic disorder with bilateral vestibular schwannomas (VS) as the most frequent manifestation. Merlin, the NF2 tumor suppressor, was identified as a negative regulator of mammalian target of rapamycin complex 1. Pre-clinical data in mice showed that mTORC1 inhibition delayed growth of NF2-schwannomas. We conducted a prospective single-institution open-label phase II study to evaluate the effects of everolimus in ten NF2 patients with progressive VS. Drug activity was monitored every 3 months. Everolimus was administered orally for 12 months and, if the decrease in tumor volume was >20 % from baseline, treatment was continued for 12 additional months. Other patients stopped when completed 12 months of everolimus but were allowed to resume treatment when VS volume was >20 % during 1 year follow-up. Nine patients were evaluable. Safety was evaluated using CTCAE 3.0 criteria. After 12 months of everolimus, no reduction in volume ≥20 % was observed. Four patients had progressive disease, and five patients had stable disease with a median annual growth rate decreasing from 67 %/year before treatment to 0.5 %/year during treatment. In these patients, tumor growth resumed within 3-6 months after treatment discontinuation. Everolimus was then reintroduced and VS decreased by a median 6.8 % at 24 months. Time to tumor progression increased threefold from 4.2 months before treatment to > 12 months. Hearing was stable under treatment. The safety of everolimus was manageable. Although the primary endpoint was not reached, further studies are required to confirm the potential for stabilization of everolimus

Effects of essential amino acid supplementation to promote honey bee gland and muscle development in cages and colonies.

There is growing concern about the impact of poor nutrition on honey bee health. With caged bee experiments and whole-colony field experiments, we examined the effects of supplementing bees with essential amino acids (EAA), or a control treatment of nonessential amino acids (NAA). Caged bees fed EAA developed significantly greater head weights than controls, weights that were similar to nurse bees. Caged bees fed EAA developed significantly greater thorax weights than controls, weights that were similar to foragers. Higher head and thorax weights may respectively reflect increased glandular development in nurse bees and higher flight muscle mass in forager bees. In our field study, 29% of the pollen collected by our honey bee colonies came from eucalyptus trees. Amino acid analyses revealed no EAA deficiencies for the bee-collected polyfloral pollen or for monofloral eucalyptus pollen. Colonies fed 29 g EAA supplement may have slightly increased individual bee growth and brood rearing, but this effect was not significant. A clear colony result was a correlation between nurse bee physiology and brood development: 17% increase in nurse bee weight corresponded to 100% more capped brood cells (R2 = 0.38). We suggest that colony supplementation should target nurse bee nutrition. Nurse bees eventually become forager bees. Hence, increased glandular development may support colony brood development and greater flight muscle mass may assist colony foraging

MS-29 * SORAFENIB AND REGORAFENIB INHIBIT GROWTH AND MIGRATION OF MENINGIOMA CELLS

Sorafenib and Regorafenib (Fluoro-Sorafenib) are closely related multikinase inhibitors, which possess activity in the treatment of some human cancers. The potential role of both drugs in meningiomas have not been elucidated so far. Therefore, we have studied their anti-tumor activity in various in vitro meningioma models. A moderate antiproliferative activity of both drugs applied for 48 h (p < 0.001) to malignant IOMM-Lee meningioma cells was found in microtiter-tetrazolium (MTT) assays with an IC50 of 15 µM for Regorafenib and an IC50 between 7.5 and 15 µM for Sorafenib. MTT assays just reflect the number of viable cells and may thus indicate solely an inhibition of proliferation of the rapidly growing IOMM-Lee cells. However, some degree of cell death induction must have been occured, because a strong induction of nucleosome liberation (p < 0.05) was observed for both drugs by ELISA. Both drugs consistently had lower effects (MTT assay) in two syngenous derivatives of the benign SF4068 meningioma line exhibiting a massive NF2 loss (shRNA mediated) as compared to two syngenous SF4068 derivatives with NF2 wildtype. This suggests a modifying role of the NF2 status on the effects of Regorafenib and Sorafenib. Moreover, both drugs (15 µM) dramatically inhibited cell migration (gap assay, p < 0.05) and invasion (matrigel transwell assay, p < 0.01). Therefore, Sorafenib and Regorafenib seem to target preferentially meningioma cell motility and brain invasion