NF2, a genetic disorder caused by a mutation on the NF2 gene, leads to CNS tumor growth including bilateral vestibular schwannomas and meningiomas. Current treatments, including conventional chemotherapy and surgery, are unable to eliminate tumor reappearance, thus medical-research aims to find new non-invasive drug therapies.

Based on previous studies, NF2 loss upregulates mTOR pathways leading to enhanced cell growth. Thus downstream effectors of this pathway could be targeted to inhibit tumor growth. In this study, 2D and 3D NF2 models were generated for evaluating different mTORC inhibitors, RMC-6272 and INK128, as well as Brigatinib, which inhibits multiple tyrosine kinases and is in phase 2 clinical trials for NF2. To test for the retention time of mTORC inhibitors, meningioma cell-monolayers were exposed to the drugs for 24 hours, then replaced with fresh media. Lysates were collected after 0, 3, 8, and 24 hours and used for immunoblotting. RMC-6272 showed longer mTORC inhibition than INK128, thus it was carried forward to be used in 3D spheroid testing, a model that better mimics the tumor microenvironment than 2D cell-monolayers.  Spheroids were generated from both meningioma and schwannoma cells, and were treated every third day for two weeks. RMC-6272 led to the most significant decrease in spheroid size when applied to schwannoma spheroids. While Brigatinib appeared to be less effective than RMC in the schwannoma model, it caused more shrinkage in schwannoma spheroids than in meningioma spheroids. The novel 3D spheroid model development from NF2-null cells allows future evaluation of additional therapeutic agents for NF2.

For more information: lkosa@eckerd.edu

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