Characterizing the role of specific Ras proteins in neurofibroma and MPNST format

Cincinnati Childrens Hosp Med Ctr, Cincinnati OH

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Abstract

DESCRIPTION (provided by applicant): Mutations in the NF1 gene cause Neurofibromatosis type 1 (NF1), a disease characterized by the formation of benign and malignant tumors of the peripheral nervous system. Neurofibromin, the protein encoded by the NF1 gene, functions as a tumor suppressor, largely by inhibiting multiple small G-proteins from the classic Ras (H-Ras, N-Ras and K-Ras) and R-Ras (R-Ras, TC21 and M-Ras) subfamilies. While Ras activation has been implicated in the pathogenesis of NF1 associated tumors, the relative contributions of specific classic Ras family proteins to tumorigenesis remain poorly understood. Increasing evidence supports the notion that Ras hyperactivation and NF1 loss induces the secretion of various cytokines, which in turn promote tumor growth. Specifically, Nf1-/- Schwann cells secrete Kit Ligand, which stimulates mast cell migration and thus contributes to neurofibroma pathogenesis. Since the role of tumor microenvironment in NF1 tumorigenesis is becoming increasingly apparent, it is important to understand the mechanisms that alter tumor stroma to facilitate malignant transformation and progression. In order to characterize the role of H-Ras, N-Ras and K-Ras proteins in neurofibroma and MPNST development, we hypothesize that specific Ras proteins play distinct roles in neurofibroma and MPNST formation. Two specific aims are proposed to test this hypothesis: 1) Assess the role of H, N and K-Ras proteins in mediating survival, proliferation and inflammatory cell infiltration in Nf1 deficient neurofibromas and MPNSTs. 2) Identify novel compounds that inhibit Ras signaling and prevent survival of NF1 deficient neurofibroma and MPNST cells.The overall goal of this research is to delineate the functions of Ras proteins in NF1 pathogenesis and to identify novel therapeutic strategies based on inhibition of specific Ras proteins.