Abstract 2862: Therapeutic intervention of preclinical symptoms in a NF1 mouse model

We previously generated a mouse model by using Schwann cell lineage-specific ablation of Nf1, which recapitulates human plexiform neurofibroma with high penetrance throughout the peripheral nerves including the sciatic nerves. Although it takes more than 12 months for these mutant mice to develop frank neurofibromas, we have identified pre-neoplastic phenotypes in mutant sciatic nerves at as early as 3 months of age. In sciatic nerves of mutant mice at post natal day 90 (P90), we identified a subset of non-myelinating Schwann cells (nmSCs) as early stage neurofibroma cells, which exhibit a spectrum of abnormalities. These abnormal nmSCs are either dissociated or dissociating from axons, often accompanied by axonal degeneration and mast cell infiltration. Proliferation of these abnormal nmSCs leads to significantly increased cellularity in mutant nerves. Altered mTOR (mammalian target of rapamycin) activity was also observed at this stage. Based upon these observations, we propose that deregulated mTOR activity may be underlying molecular mechanism of neurofibroma initiation. To test this hypothesis, we are using rapamycin, a mTOR inhibitor, to treat mice starting from P30 until P90, at which time point they are analyzed. The extent of pre-neoplastic phenotypes at P90 can serve as assays for the efficacy of this treatment. Our preliminary data show that rapamycin treatment may have effect in alleviating pre-neoplastic phenotypes in some mutant mice, evidenced by the absence of dissociated SCs and unassociated SCs, as well as decreased cellularity in the sciatic nerves of those mice. However, further experiments need to be done to confirm these results. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2862.